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  • 1.
    Alsiö, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Gastambide, F.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Wang, R. A. H.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Dam, S. A.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Tricklebank, M.
    Eli Lilly & Co Ltd, Lilly Ctr Cognit Neurosci, Erl Wood Manor, Windlesham GU20 6PH, Surrey, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 4017-4031Article in journal (Refereed)
    Abstract [en]

    Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 mu g/side) on performance in this task. In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.

  • 2.
    Brooks, Samantha J.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. UCT Department of Psychiatry and Mental Health Groote Schuur Hospital Cape Town South Africa.
    Wiemerslage, L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Burch, K H
    Maiorana, S A
    Cocolas, E
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Kamaloodien, K
    Stein, D J
    The impact of cognitive training in substance use disorder: the effect of working memory training on impulse control in methamphetamine users2017In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, no 12, p. 1911-1921Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: Impulsivity is a vulnerability trait for poor self-regulation in substance use disorder (SUD). Working memory (WM) training improves impulsivity and self-regulation in psychiatric disorders. Here we test WM training in methamphetamine use disorder (MUD).

    METHODS: There are 15 MUD patients receiving inpatient treatment as usual (TAU) and 20 who additionally completed WM cognitive training (CT) and 25 healthy controls (HC). MANCOVA repeated measures analyses examined changes in impulsivity and self-regulation at baseline and after 4 weeks.

    RESULTS:  = 0.3523, p < 0.05). Compared to follow-up TAU, follow-up CT group had higher self-reported mood scores (t = 2.784, p = 0.01) and higher compared to CT baseline (t = 2.386, p = 0.036). Feelings of self-control were higher in CT than TAU at follow-up (t = 2.736, p = 0.012) and also compared to CT baseline (t = 3.390, p = 0.006), lack of planning significantly improved in CT between baseline and follow-up (t = 2.219, p = 0.048), as did total impulsivity scores (t = 2.085, p = 0.048). Measures of self-regulation were improved in the CT group compared to TAU at follow-up, in total score (t = 2.442, p = 0.038), receiving score (t = 2.314, p = 0.029) and searching score (t = 2.362, p = 0.027). Implementing self-regulation was higher in the CT group compared to TAU (t = 2.373, p = 0.026).

    CONCLUSIONS: WM training may improve control of impulsivity and self-regulation in people with MUD.

  • 3. De Luca, Maria Antonietta
    et al.
    Bimpisidis, Zisis
    Bassareo, Valentina
    Di Chiara, Gaetano
    Influence of morphine sensitization on the responsiveness of mesolimbic and mesocortical dopamine transmission to appetitive and aversive gustatory stimuli2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 216, p. 345-353Article in journal (Refereed)
  • 4. Frånberg, Olivia
    et al.
    Wiker, Charlotte
    Marcus, Monica M
    Konradsson, Asa
    Jardemark, Kent
    Schilström, Björn
    Shahid, Mohammed
    Wong, Erik H F
    Svensson, Torgny H
    Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia.2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 196, no 3Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.

    MATERIALS AND METHODS: The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed.

    RESULTS: Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC.

    CONCLUSIONS: These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.

  • 5.
    Ghersi, Marisa S
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gabach, L A
    Buteler, F
    Vilcaes, A A
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Perez, M F
    de Barioglio, S R
    Ghrelin increases memory consolidation through hippocampal mechanisms dependent on glutamate release and NR2B-subunits of the NMDA receptor2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 10, p. 1843-1857Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Ghrelin (Ghr) is a peptide that participates in the modulation of several biological processes. Ghr administration into the hippocampus improves learning and memory in different memory tests. However, the possible mechanisms underlying this effect on memory have not yet been clarified.

    OBJECTIVE: The purpose of the present work is to add new insights about the mechanisms by which Ghr modulates long-term memory consolidation in the hippocampus. We examined Ghr effects upon processes related to increased synaptic efficacy as presynaptic glutamate release and changes in the expression of the NR2B-subunits containing n-methyl-d-aspartate receptors (NMDAR), which are critical for LTP induction. We also attempted to determine the temporal window in which Ghr administration induces memory facilitation and if the described effects depend on GHS-R1a stimulation.

    RESULTS: The present research demonstrated that Ghr increased glutamate release from hippocampal synaptosomes; intra-hippocampal Ghr administration increased NR2B-subunits expression in CA1 and DG subareas and also reversed the deleterious effects of the NR2B-subunit-specific antagonist, Ro 25-6981, upon memory consolidation and LTP generation in the hippocampus. These effects are likely to be the consequence of GHS-R1a activation.

    CONCLUSION: According to the results above mentioned and previous findings, we can hypothesize some of the mechanisms by which Ghr modulates memory consolidation. At presynaptic level, Ghr stimulates glutamate release, probably by enhancing [Ca(2+)]i. At postsynaptic level, the glutamate released activates NMDAR while Ghr also mediates effects directly activating its specific receptors and increases NR2B-subunit expression.

  • 6.
    Granholm, Linnea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Rowley, S.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Ellgren, M.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Segerström, Lova
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Impact of adolescent ethanol exposure and adult amphetamine self-administration on evoked striatal dopamine release in male rats2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 24, p. 4421-4431Article in journal (Refereed)
    Abstract [en]

    Adolescent binge drinking is common and associated with increased risk of substance use disorders. Transition from recreational to habitual ethanol consumption involves alterations in dorsal striatal function, but the long-term impact of adolescent ethanol exposure upon this region remains unclear. This study aimed to characterise and describe relationships between adolescent ethanol exposure, amphetamine self-administration and adult dopamine dynamics in dorsal striatum, including response to amphetamine challenge, in male Wistar rats. Ethanol (2 g/kg) or water was administered intragastrically in an episodic binge-like regimen (three continuous days/week) between 4 and 9 weeks of age (i.e. post-natal days 28-59). In adulthood, animals were divided into two groups. In the first, dorsal striatal potassium-evoked dopamine release was examined via chronoamperometry, in the basal state and after a single amphetamine challenge (2 mg/kg, i.v.). In the second, amphetamine self-administration behaviour was studied (i.e. fixed and progressive ratio) before chronoamperometric analysis was conducted as described above. Adolescent ethanol exposure suppressed locally evoked dopamine response after amphetamine challenge in adulthood, whereas in the basal state, no differences in dopamine dynamics were detected. Ethanol-exposed animals showed no differences in adult amphetamine self-administration behaviour but an abolished effect on dopamine removal in response to a single amphetamine challenge after self-administration. Amphetamine challenges in adult rats revealed differences in in vivo dopamine function after adolescent ethanol exposure. The attenuated drug response in ethanol-exposed animals may affect habit formation and contribute to increased risk for substance use disorders as a consequence of adolescent ethanol.

  • 7.
    Gunes, Arzu
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Scordo, Maria Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Jaanson, Peeter
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine-treated schizophrenic patients2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 190, no 4, p. 479-484Article in journal (Refereed)
    Abstract [en]

    Rationale: Perphenazine, a classical antipsychotic drug, has the potential to induce extrapyramidal side effects (EPS). Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug. Objectives: To evaluate the impact of polymorphisms in the dopamine D 2 and D3 and serotonin 2A and 2C receptor genes (DRD2, DRD3, HTR2A, and HTR2C) on short-term effects of perphenazine monotherapy in schizophrenic patients. Materials and methods: Forty-seven Estonian inpatients were evaluated before and after 4-6 weeks of treatment by Simpson-Angus rating scale, Barnes scale, and Positive and Negative Symptom Scale. Genotyping was performed for common DRD2, DRD3, HTR2A, and HTR2C gene polymorphisms, previously reported to influence receptor expression and/or function. Results: Most of the patients (n = 37) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response. The 102C allele of HTR2A and the -697C and 23Ser alleles of HTR2C were more frequent among patients with EPS (n = 25) compared to patients without EPS (n = 22) (p = 0.02, 0.01, and 0.02, respectively). The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age, gender, and duration of antipsychotic treatment as covariants. There was no significant association between EPS occurrence and polymorphisms in the DRD2 and DRD3 genes. Conclusions: An association was observed between polymorphisms in HTR2A and HTR2C genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy. Larger study populations are needed to confirm our findings.

  • 8.
    Hvoslef-Eide, M.
    et al.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Mar, A. C.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England.;NYU, Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA..
    Nilsson, S. R. O.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Alsioe, J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Heath, C. J.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Saksida, L. M.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Robbins, T. W.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    Bussey, T. J.
    Univ Cambridge, Dept Psychol, Cambridge CB2 3EB, England.;Univ Cambridge, MRC, Cambridge CB2 3EB, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge CB2 3EB, England..
    The NEWMEDS rodent touchscreen test battery for cognition relevant to schizophrenia2015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 21-22, p. 3853-3872Article, review/survey (Refereed)
    Abstract [en]

    The NEWMEDS initiative (Novel Methods leading to New Medications in Depression and Schizophrenia, http://www.newmeds-europe.com) is a large industrial-academic collaborative project aimed at developing new methods for drug discovery for schizophrenia. As part of this project, Work package 2 (WP02) has developed and validated a comprehensive battery of novel touchscreen tasks for rats and mice for assessing cognitive domains relevant to schizophrenia. This article provides a review of the touchscreen battery of tasks for rats and mice for assessing cognitive domains relevant to schizophrenia and highlights validation data presented in several primary articles in this issue and elsewhere. The battery consists of the five-choice serial reaction time task and a novel rodent continuous performance task for measuring attention, a three-stimulus visual reversal and the serial visual reversal task for measuring cognitive flexibility, novel non-matching to sample-based tasks for measuring spatial working memory and paired-associates learning for measuring long-term memory. The rodent (i.e. both rats and mice) touchscreen operant chamber and battery has high translational value across species due to its emphasis on construct as well as face validity. In addition, it offers cognitive profiling of models of diseases with cognitive symptoms (not limited to schizophrenia) through a battery approach, whereby multiple cognitive constructs can be measured using the same apparatus, enabling comparisons of performance across tasks. This battery of tests constitutes an extensive tool package for both model characterisation and pre-clinical drug discovery.

  • 9. Kadir, Ahmadul
    et al.
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    PET imaging of cortical 11C-nicotine binding correlates with the cognitive function of attention in Alzheimer's disease2006In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 188, no 4, p. 509-520Article in journal (Refereed)
    Abstract [en]

    RATIONALE:

    Patients suffering from Alzheimer's disease (AD) experience a marked reduction in cortical nicotinic acetylcholine receptors (nAChRs). In particular, selective loss of the alpha4beta2 nAChR subtype was observed in postmortem AD brain tissue. The alpha4 and alpha7 nAChR subunits were suggested to play an important role in cognitive function. Positron emission tomography (PET) has so far been used to visualize neuronal nAChRs in vivo by 11C-nicotine binding.

    OBJECTIVES:

    To investigate the relationship between measures of cognitive function and in vivo 11C-nicotine binding in mild AD brain as assessed by PET.

    MATERIALS AND METHODS:

    Twenty-seven patients with mild AD were recruited in this study. A dual tracer model with administration of 15O-water for regional cerebral blood flow and (S)(-)11C-nicotine was used to assess nicotine binding sites in the brain by PET. Cognitive function was assessed using neuropsychological tests of global cognition, episodic memory, attention, and visuospatial ability.

    RESULTS:

    Mean cortical 11C-nicotine binding significantly correlated with the results of attention tests [Digit Symbol test (r = -0.44 and p = 0.02) and Trail Making Test A (TMT-A) (r = 0.42 and p = 0.03)]. No significant correlation was observed between 11C-nicotine binding and the results of tests of episodic memory or visuospatial ability. Regional analysis showed that 11C-nicotine binding in the frontal and parietal cortex, which are the main areas for attention, correlated significantly with the Digit Symbol test and TMT-A results.

    CONCLUSION:

    Cortical nicotinic receptors in vivo in mild AD patients are robustly associated with the cognitive function of attention.

  • 10. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Wall, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Section of Nuclear Medicine and PET.
    Nordberg, Agneta
    Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale  

    Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer’s disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD.

    Objective  

    To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment.

    Materials and methods  

    Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of 15O–water and (S)(–)11C–nicotine was used to assess 11C–nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically.

    Results  

    The 11C–nicotine binding sites were significantly increased 12–19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical 11C–nicotine binding. The 11C–nicotine binding positively correlated with attentional task at the 12-month follow-up.

    Conclusion  

    Changes in the 11C–nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 11. Kadir, Ahmadul
    et al.
    Darreh-Shori, Taher
    Almkvist, Ove
    Wall, Anders
    Långström, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Nordberg, Agneta
    Changes in brain 11C-nicotine binding sites in patients with mild Alzheimer's disease following rivastigmine treatment as assessed by PET2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 191, no 4, p. 1005-1014Article in journal (Refereed)
    Abstract [en]

    Rationale  Marked reduction in the cortical nicotinic acetylcholine receptors is observed in the brain of patients suffering from Alzheimer’s disease (AD). Although cholinesterase inhibitors are used for symptomatic treatment of mild to moderate AD patients, numerous long-term treatment studies indicate that they might stabilize or halt the progression of the disease by restoring the central cholinergic neurotransmission. Thus, we used positron emission tomography (PET) technique as a sensitive approach to assess longitudinal changes in the nicotine binding sites in the brains of patients with AD. Objective  To evaluate changes in brain nicotinic binding sites in relation to inhibition level of cholinesterases in cerebrospinal fluid (CSF) and plasma and changes in cognitive performance of the patients in different neuropsychological tests after rivastigmine treatment. Materials and methods  Ten mild AD patients received rivastigmine for 12 months. A dual-tracer PET model with administration of 15O–water and (S)(–)11C–nicotine was used to assess 11C–nicotine binding sites in the brain at baseline and after 3 and 12 months of the treatment. Cholinesterase activities in CSF and plasma were assessed colorimetrically. Results  The 11C–nicotine binding sites were significantly increased 12–19% in several cortical brain regions after 3 months compared with baseline, while the increase was not significant after 12 months of the treatment. After 3 months treatment, low enzyme inhibition in CSF and plasma was correlated with higher cortical 11C–nicotine binding. The 11C–nicotine binding positively correlated with attentional task at the 12-month follow-up. Conclusion  Changes in the 11C–nicotine binding during rivastigmine treatment might represent remodeling of the cholinergic and related neuronal network.

  • 12.
    Kask, Kristiina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Bäckström, Torbjörn
    Department of Clinical Science, Obstetrics and Gynecology, Umeå University, Umeå, Sweden.
    Nilsson, Lars-Göran
    Department of Psychology, Stockholm University, Stockholm, Sweden.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Allopregnanolone impairs episodic memory in healthy women2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 199, no 2, p. 161-168Article in journal (Refereed)
    Abstract [en]

    Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the γ-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women.

    Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed.The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task.Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.

  • 13.
    Kuzmin, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Jerlhag, E
    Liljequist, S
    Engel, J
    Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, p. 99-108Article in journal (Refereed)
    Abstract [en]

    RATIONALE AND OBJECTIVES:

    The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, alpha-conotoxin MII (alphaCtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DHbetaE, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats.

    METHODS:

    The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. alphaCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHbetaE, and MLA were administered systemically.

    RESULTS:

    alphaCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHbetaE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation.

    CONCLUSIONS:

    Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.

  • 14.
    Kuzmin, Alexander
    et al.
    Department of Clinical Neuroscience, Division of Drug Dependence, Karolinska University Hospital, Stockholm, Sweden.
    Jerlhag, Elisabet
    Institute of Neuroscience and Physiology, Section of Pharmacology, Göteborg University, Göteborg, Sweden.
    Liljequist, Sture
    Department of Clinical Neuroscience, Division of Drug Dependence, Karolinska University Hospital, Stockholm, Sweden.
    Engel, Jörgen
    Institute of Neuroscience and Physiology, Section of Pharmacology, Göteborg University, Göteborg, Sweden.
    Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 203, no 1, p. 99-108Article in journal (Refereed)
    Abstract [en]

    RATIONALE AND OBJECTIVES: The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, alpha-conotoxin MII (alphaCtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DHbetaE, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats. METHODS: The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. alphaCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHbetaE, and MLA were administered systemically. RESULTS: alphaCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHbetaE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation. CONCLUSIONS: Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.

  • 15.
    Lindström, Leif H.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    Meyerson, Bengt J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine.
    The effect of pilocarpine, oxotremorine and arecoline in combination with methyl-atropine or atropine on hormone activated oestrous behaviour in ovariectomized rats1967In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 11, no 5, p. 405-405Article in journal (Refereed)
    Abstract [en]

    The effects of pilocarpine, oxotremorine and arecoline were studied on oestradiol/progesterone activated oestrous behaviour in ovariectomized rats. A heat-inhibitory effect was obtained, which could be more effectively counteracted by atrophie than methyl-atropine.No positive correlation was seen between the inhibitory effect on oestrous behaviour and the ability of the different cholinergic compounds to induce tremor or decrease the locomotor activity.The data indicate that in addition to earlier described monoaminergic pathways mediating inhibition of oestrous behaviour, cholinergic mechanisms are also involved.The results of this study were presented in part at the XII Scandinavian Congress of Physiology 1966 at Turku, Finland.

  • 16.
    Mar, Adam C.
    et al.
    NYU Med Ctr, Neurosci Inst, New York, NY 10016 USA.;NYU Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA.;Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Nilsson, Simon R. O.
    NYU Med Ctr, Neurosci Inst, New York, NY 10016 USA.;NYU Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA.;Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Gamallo-Lana, Begona
    NYU Med Ctr, Neurosci Inst, New York, NY 10016 USA.;NYU Med Ctr, Dept Neurosci & Physiol, New York, NY 10016 USA.;Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Lei, Ming
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England.;Beijing Int Studies Univ, Dept Hlth Ind Management, 1 Dingfuzhuang Nanli, Beijing, Peoples R China..
    Dourado, Theda
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    Saksida, Lisa M.
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England.;Western Univ, Robarts Res Inst, Mol Med Res Grp, London, ON, Canada.;Western Univ, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, Canada.;Western Univ, Brain & Mind Inst, London, ON, Canada..
    Bussey, Timothy J.
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England.;Western Univ, Robarts Res Inst, Mol Med Res Grp, London, ON, Canada.;Western Univ, Schulich Sch Med & Dent, Dept Physiol & Pharmacol, London, ON, Canada.;Western Univ, Brain & Mind Inst, London, ON, Canada..
    Robbins, Trevor W.
    Univ Cambridge, Dept Psychol, Cambridge, England.;Univ Cambridge, MRC, Cambridge, England.;Univ Cambridge, Wellcome Trust Behav & Clin Neurosci Inst, Cambridge, England..
    MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs2017In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, no 19, p. 2837-2857Article in journal (Refereed)
    Abstract [en]

    Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 mu g/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.

  • 17. Melkersson, Kristina
    et al.
    Dahl, Marja-Liisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hulting, Anna-Lena
    Guidelines for prevention and treatment of adverse effects of antipsychotic drugs on glucose-insulin homeostasis and lipid metabolism2004In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 175, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    RATIONALE: With the antipsychotic drugs available today, especially with some of the newer, atypical antipsychotics, metabolic side effects, such as weight gain, diabetes mellitus and lipid abnormalities, have become a complication to the drug therapy that have to be recognized and treated. OBJECTIVE: The aim of this article is to suggest guidelines for prevention and treatment of adverse effects of antipsychotics on glucose-insulin homeostasis and lipid metabolism, whereas strategies for management of antipsychotic-induced weight gain are summarized elsewhere. METHOD: The guidelines are based on results of experimental and clinical studies presented in the article, as well as on a recently published review of 180 articles in the field. RESULTS: Both conventional and atypical antipsychotics can indirectly, by causing obesity, promote development of insulin resistance and type-2 diabetes. In addition, some atypical agents probably directly induce hyperinsulinemia, followed by weight gain, insulin resistance and drug-induced, sometimes insulin-dependent, diabetes. CONCLUSION: In this article, guidelines for the management of adverse metabolic effects of antipsychotics are described.

  • 18. Merenäkk, Liis
    et al.
    Mäestu, Jarek
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Parik, Jüri
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Loit, Helle-Mai
    Harro, Jaanus
    Effects of the serotonin transporter (5-HTTLPR) and alpha(2A)-adrenoceptor (C-1291G) genotypes on substance use in children and adolescents: a longitudinal study2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 1, p. 13-22Article in journal (Refereed)
    Abstract [en]

    Twin studies suggest that substance use initiation in children and adolescents is determined primarily by environmental influences, whereas the establishment of use patterns is strongly controlled by genetic factors. The present study analysed the effects of the serotonin transporter promoter polymorphism [5-HT transporter gene-linked polymorphic region (5-HTTLPR)] and the alpha(2A)-adrenoceptor C-1291G genotype (ADRA2A C-1291G) as well as their interaction effects on alcohol, tobacco and drug use from preadolescence to the late adolescence. Initial sample of 9-year-old children of Estonian Children Personality Behaviour and Health Study (n = 583) was recalled at ages 15 and 18. Participants reported in all waves how frequently they smoked and used alcohol and illicit drugs. 5-HTTLPR had age-dependent effects on alcohol, tobacco and drug use: substance use did not differ by genotype at age 9, but at age 15, the participants with the short (s)/s genotype had higher tobacco use, and at age 18, they were more active alcohol, drug and tobacco users. Effects of ADRA2A C-1291G on drug use were dependent on gender, age and 5-HTTLPR. Males (age 18) with ADRA2A CG genotype, when compared to other participants, tended to have higher drug use especially when they had s/s genotype of 5-HTTLPR. Our results reveal that expression of genetic vulnerability for substance use in children and adolescents may depend on age, gender, interaction of genes, and type of substance.

  • 19.
    Nylander, Ingrid
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Roman, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Is the rodent maternal separation model a valid and effective model for studies on the early-life impact on ethanol consumption?2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 229, no 4, p. 555-569Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Early-life events can cause long-term neurobiological and behavioural changes with a resultant effect upon reward and addiction processes that enhance risk to develop alcohol use disorders. Maternal separation (MS) is used to study the mediating mechanisms of early-life influences in rodents. In MS studies, the pups are exposed to maternal absence during the first postnatal weeks. The outcome of MS experiments exhibits considerable variation and questions have been raised about the validity of MS models.

    OBJECTIVES: This short review aims to provide information about experimental conditions that are important to consider when assessing the impact of early-life environment on voluntary ethanol consumption.

    RESULTS: The results from currently used MS protocols are not uniform. However, studies consistently show that longer separations of intact litters predispose for higher ethanol consumption and/or preference in adult male rats as compared to shorter periods of MS. Studies using individual pup MS paradigms, other controls, low ethanol concentrations, adult females or examining adolescent consumption reported no differences or inconsistent results.

    CONCLUSIONS: There is no "a rodent MS model", there are several models and they generate different results. The compiled literature shows that MS is a model of choice for analysis of early-life effects on voluntary ethanol consumption but there are examples of MS paradigms that are not suitable. These studies emphasize the importance to carefully designed MS experiments to supply the optimal conditions to definitely test the research hypothesis and to be particulate in the interpretation of the outcome.

  • 20. Paaver, Marika
    et al.
    Nordquist, Niklas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Parik, Jüri
    Harro, Maarike
    Oreland, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Harro, Jaanus
    Platelet MAO activity and the 5-HTT gene promoter polymorphism are associated with impulsivity and cognitive style in visual information processing2007In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 194, no 4, p. 545-554Article in journal (Refereed)
    Abstract [en]

    Low capacity of the central serotonergic system has been associated with impulsive behaviour. Both low platelet monoamine oxidase (MAO) activity and the short (S) allele of the serotonin transporter gene promoter region polymorphism (5-HTTLPR) are proposed to be markers of less efficient serotonergic functioning.The effect of the two markers for serotonin system efficiency on performance in a visual comparison task (VCT) and self-reported impulsiveness (Barratt Impulsiveness Scale, BIS-11) were investigated in healthy adolescents participating in the Estonian Children Personality Behaviour and Health Study. Possible confounding effect of general cognitive abilities on the performance in VCT was controlled for.Low platelet MAO activity and carrying of the S allele of 5-HTTLPR were both associated with higher error-rate and more impulsive performance in VCT. Platelet MAO activity and 5-HTTLPR S allele had a significant interactive effect on self-reported impulsivity (BIS-11). The effect of platelet MAO activity on both self-reported and performance impulsivity was significant only in the S allele carriers. The effect of 5-HTTLPR S allele on impulsive performance remained significant after controlling for general cognitive abilities.The two markers of lower serotonergic capacity, 5-HTTLPR S allele and low platelet MAO activity, have a similar and partly synergistic influence on self-reported as well as performance measures of impulsivity.

  • 21.
    Pickering, Chris
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Hulting, Anna-Lena
    Department of Endocrinology, Metabolism and Diabetology, Karolinska Institutet, Stockholm.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Withdrawal from free-choice high-fat high-sugar diet induces craving only in obesity-prone animals2009In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 204, no 3, p. 431-443Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION:

    Vulnerability for weight gain is an individual trait. Obese people undertake dieting, but permanent weight loss is difficult to attain due to repeated phases of relapse to excess consumption.

    MATERIALS AND METHODS:

    In this study, male Wistar rats were trained to operantly self-administer pellets followed by free-choice access in the homecage to high-fat high-sugar (HFHS) diet consisting of 30% sucrose, lard, standard rodent chow and water. Animals were divided into obesity-prone (OP) and obesity-resistant (OR) groups based on relative weight gain compared to normally fed controls despite equal consumption of HFHS.

    RESULTS AND DISCUSSION:

    After 4 weeks of HFHS access, OP and OR animals did not differ in motivation for food pellets in terms of progressive ratio break point, lever pressing or response rate. However, upon discontinuation of the HFHS diet, differences between the OP and OR groups were noted. OP animals increased their motivation (i.e. craving) during the second withdrawal week and reduced time spent in the centre of an open field (increased anxiety) compared to the OR animals. Both OP and OR animals consumed less of the standard rodent chow during the first week of withdrawal when compared to normally fed controls. But, while the OR animals quickly returned to control levels of food consumption, OP animals continued to consume less standard rodent chow.

    CONCLUSION:

    The results show for the first time that withdrawal from free-choice HFHS induces craving that is specific to the OP animals and suggests that OP individuals may have withdrawal symptoms that are similar to those induced by addictive drugs.

  • 22.
    Poretti, María Belén
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Sawant, Rahul S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Rask-Andersen, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    de Cuneo, Marta Fiol
    Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Farmakologi 3.
    Perez, Mariela F
    Departamento de Farmacología, Instituto de Farmacología Experimental de Córdoba (IFEC-CONICET), Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina .
    Carlini, Valeria Paola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology. Instituto de Fisiología, Instituto de Investigaciones en Ciencias de la Salud (INICSA, UNC-CONICET), Facultad de Ciencias Médicas, CONICET and Universidad Nacional de Córdoba, Córdoba, Argentina .
    Reduced vasopressin receptors activation mediates the anti-depressant effects of fluoxetine and venlafaxine in bulbectomy model of depression2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 6, p. 1077-1086Article in journal (Refereed)
    Abstract [en]

    RATIONALE: In response to stress, corticotropin releasing hormone (CRH) and vasopressin (AVP) are released from the hypothalamus, activate their receptors (CRHR1, CRHR2 or AVPr1b), and synergistically act to induce adrenocorticotropic hormone (ACTH) release from the anterior pituitary. Overstimulation of this system has been frequently associated with major depression states.

    OBJECTIVE: The objective of the study is to assess the role of AVP and CRH receptors in fluoxetine and venlafaxine effects on the expression of depression-related behavior.

    METHODS: In an animal model of depression (olfactory bulbectomy in mice, OB), we evaluated the effects of fluoxetine or venlafaxine (both 10 mg/kg/day) chronic administration on depression-related behavior in the tail suspension test. Plasma levels of AVP, CRH, and ACTH were determined as well as participation of their receptors in the expression of depression related-behavior and gene expression of AVP and CRH receptors (AVPr1b, CRHR1, and CRHR2) in the pituitary gland.

    RESULTS: The expression of depressive-like behavior in OB animals was reversed by treatment with both antidepressants. Surprisingly, OB-saline mice exhibited increased AVP and ACTH plasma levels, with no alterations in CRH levels when compared to sham mice. Chronic fluoxetine or venlafaxine reversed these effects. In addition, a significant increase only in AVPr1b gene expression was found in OB-saline.

    CONCLUSION: The antidepressant therapy used seems to be more likely related to a reduced activation of AVP rather than CRH receptors, since a positive correlation between AVP levels and depressive-like behavior was observed in OB animals. Furthermore, a full restoration of depressive behavior was observed in OB-fluoxetine- or venlafaxine-treated mice only when AVP was centrally administered but not CRH.

  • 23. Rowland, N E
    et al.
    Marshall, Misty
    Roth, J D
    Comparison of either norepinephrine-uptake inhibitors or phentermine combined with serotonergic agents on food intake in rats2000In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 149, no 1Article in journal (Refereed)
    Abstract [en]

    RATIONALE: We have shown previously that the anorectic effects of the catecholamine-releasing agent phentermine (PHEN) and the serotonin (5-HT)-releasing agent dexfenfluramine (DFEN) are greater than additive in rats. In the present study, we examined whether the norepinephrine-uptake inhibitors desmethylimipramine (DMI) and thionisoxetine (TNIX) have additive effects with either DFEN or with the 5-HT-uptake inhibitor fluoxetine (FLX). We also examined whether PHEN interacts with a postsynaptically acting 5-HT agonist.

    METHODS: Undeprived rats were trained to eat a daily sweet-milk dessert and on test days were systemically administered single or combination drugs and the intakes recorded.

    RESULTS: Both DMI and TNIX produced dose-related suppressions of food intake. However, by isobolographic analysis, they did not enhance the anorectic actions of either DFEN or FLX. In contrast, confirming and extending our previous work, PHEN had a greater potentiating effect on the anorectic actions of DFEN and FLX than TNIX. Further, the anorectic action of the 5-HT2c receptor agonist TFMPP was enhanced by PHEN.

    CONCLUSIONS: These and other data are consistent with the idea that 5-HT agents may work "upstream" of critical catecholaminergic synapses in the production of anorexia, and explain the diminished efficacy of norepinephrine-uptake inhibitors relative to PHEN. The implications for clinically useful anorectic agents are discussed briefly.

  • 24.
    Wallin-Miller, Kathryn G.
    et al.
    Univ Southern Calif, Neurosci Grad Program, Los Angeles, CA 90033 USA.
    Kreutz, Frida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Li, Grace
    Univ Southern Calif, Keck Sch Med, Dept Integrated Anat Sci, 1333 San Pablo St,BMT 401, Los Angeles, CA 90033 USA.
    Wood, Ruth I.
    Univ Southern Calif, Keck Sch Med, Dept Integrated Anat Sci, 1333 San Pablo St,BMT 401, Los Angeles, CA 90033 USA.
    Anabolic-androgenic steroids (AAS) increase sensitivity to uncertainty by inhibition of dopamine D1 and D2 receptors2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 4, p. 959-969Article in journal (Refereed)
    Abstract [en]

    Anabolic-androgenic steroid abuse is implicated in maladaptive behaviors such as impaired cognition in humans. In a rat model, our lab has shown that testosterone decreases preference for a large/uncertain reward in probability discounting. Other studies have shown that androgens decrease dopamine D1 and D2 receptors in the nucleus accumbens shell, a region important for decision-making behavior in probability discounting. Thus, we attempted to restore selection of the large/uncertain reward in testosterone-treated rats by administering the D2 receptor agonist quinpirole or the D1 receptor agonist SKF81297 and testing probability discounting. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for probability discounting after injections of saline, 0.1 and 0.5 mg/kg of quinpirole or SKF81297. Rats chose between a small/certain reward (1 sugar pellet, 100% probability) and a large/uncertain reward (4 pellets, decreasing probability: 100, 75, 50, 25, 0%). Testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls after saline injection. However, acute injection with 0.1 mg/kg quinpirole increased large/uncertain reward preference in testosterone-treated rats only, indicated by a testosterone x quinpirole interaction. At 0.5 mg/kg, quinpirole increased large/uncertain reward preference in all rats. Acute injection with SKF81297 at 0.1 or 0.5 mg/kg rescued large/uncertain reward preference in testosterone-treated rats by eliminating the difference between groups. It appears that altered probability discounting behavior in testosterone-treated rats is due to both decreased D1 and D2 receptor function.

  • 25. Zheng, Ming
    et al.
    Appel, Lieuwe
    Luo, Feng
    Lane, Roger
    Risinger, Robert
    Antoni, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preclinical PET Platform.
    Cahir, Matthews
    Sanjay, Keswani
    Hayes, Wendy
    Burt, David
    Zubin, Bhagwaragar
    Safety, Pharmacokinetic, and Positron Emission Tomography Evaluation of Serotonin and Dopamine Transporter Occupancy Following Multiple-Dose Administration of the Triple Monoamine Reuptake Inhibitor BMS-8208362015In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 3, p. 529-540Article in journal (Refereed)
    Abstract [en]

    Rationale

    BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.

    Objective

    This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [11C]MADAM or [11C]PE2I, respectively.

    Methods

    Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1–4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4–8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.

    Results

    Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0–5.5 h post-dose; estimated elimination half-life was 44–74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.

    Conclusions

    Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

  • 26.
    Zhukovsky, Peter
    et al.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Alsiö, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Jupp, Bianca
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.;Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia..
    Xia, Jing
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Giuliano, Chiara
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Jenner, Lucy
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Griffiths, Jessica
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Riley, Errin
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Ali, Sajeed
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Roberts, Angela C.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.;Univ Cambridge, Dept Physiol Dev & Neurosci, Cambridge, England..
    Robbins, Trevor W.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England..
    Dalley, Jeffrey W.
    Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge, England.;Univ Cambridge, Dept Psychol, Downing St, Cambridge CB2 3EB, England.;Univ Cambridge, Dept Psychiat, Cambridge, England..
    Perseveration in a spatial-discrimination serial reversal learning task is differentially affected by MAO-A and MAO-B inhibition and associated with reduced anxiety and peripheral serotonin levels2017In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 234, no 9-10, p. 1557-1571Article in journal (Refereed)
    Abstract [en]

    Impairments in behavioral flexibility lie at the core of anxiety and obsessive-compulsive disorders. Few studies, however, have investigated the neural substrates of natural variation in behavioral flexibility and whether inflexible behavior is linked to anxiety and peripheral markers of stress and monoamine function. The objective of the study was to investigate peripheral and central markers associated with perseverative behavior on a spatial-discrimination serial reversal learning task. Rats were trained on a reversal learning task prior to blood sampling, anxiety assessment, and the behavioral evaluation of selective monoamine oxidase-A (MAO-A) and MAO-B inhibitors, which block the degradation of serotonin (5-HT), dopamine (DA), and noradrenaline (NA). Perseveration correlated positively with 5-HT levels in blood plasma and inversely with trait anxiety, as measured on the elevated plus maze. No significant relationships were found between perseveration and the stress hormone corticosterone or the 5-HT precursor tryptophan. Reversal learning was significantly improved by systemic administration of the MAO-A inhibitor moclobemide but not by the MAO-B inhibitor lazabemide. Moclobemide also increased latencies to initiate a new trial following an incorrect response suggesting a possible role in modulating behavioral inhibition to negative feedback. MAO-A but not MAO-B inhibition resulted in pronounced increases in 5-HT and NA content in the orbitofrontal cortex and dorsal raph, nuclei and increased 5-HT and DA content in the basolateral amygdala and dorsomedial striatum. These findings indicate that central and peripheral monoaminergic mechanisms underlie inter-individual variation in behavioral flexibility, which overlaps with trait anxiety and depends on functional MAO-A activity.

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