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  • 1.
    Ahlenius, Sven
    et al.
    Göteborgs universitet.
    Heimann, Mikael
    Göteborgs universitet.
    Larsson, Knut
    Göteborgs universitet.
    Prolongation of the ejaculation latency in the male rat by thioridazine and chlorimipramine.1979In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 65, no 2, p. 137-140Article in journal (Refereed)
    Abstract [en]

    Thioridazine (3 mg/kg) and chlorimipramine (1.5–6.0 mg/kg) prolonged the ejaculation latency and increased the number of mounts but did not change the number of intromissions preceding ejaculation. Blockade of peripheral and central noradrenaline receptors by phentolamine and phenoxybenzamine respectively resulted in a suppression of all aspects of the sexual behavior with increasing doses. dl-5-HTP (25–100 mg/kg) in combination with an inhibitor of peripheral 5-HTP decarboxylase (benserazide, 25 mg/kg) produced, like chlorimipramine and thioridazine, a prolongation of ejaculation latency and an increase in the number of mounts preceding ejaculation. Selective inhibition of 5-HT reuptake however, by zimelidine (0–20 mg/kg) or alaproclate (0–20 mg/kg) did not affect the mating behavior. At higher doses of these drugs some animals failed to initiate sexual activities. There was an increase in the postejaculatory interval but no change in the ejaculatory latency.It is concluded that the prolonged ejaculation latencies observed following treatment with thioridazine or chlorimipramine is not due to a blockade of central or peripheral adrenergic -receptors.

  • 2. Apelqvist, G
    et al.
    Wikell, C.
    Hindfeldt, B
    Bergqvist, PBF
    Andersson, G.
    Bengtsson, Finn
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Psychiatry. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Altered open-field behavior in experimental chronic hepatic encephalopathy after single venlafaxine and citalopram challenges.1999In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 143, p. 408-416Article in journal (Refereed)
  • 3.
    Atkins, Alison Lynn
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Helms, M L
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    O'Toole, L A
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    Belknap, J K
    Department of Behavioral Neuroscience, Oregon Health & Sciences University, 3710 SW US Veterans Hospital Road, R & D5, Portland, OR 97201, USA.
    Stereotypic behaviors in mice selectively bred for high and low methamphetamine-induced stereotypic chewing.2001In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 157, no 1, p. 96-104Article in journal (Refereed)
    Abstract [en]

    RATIONALE: At high doses, methamphetamine produces repetitive stereotypic behaviors, and the degree to which this occurs is heritable.

    OBJECTIVES: Mice of a B6D2F2 genetic background were selectively bred for four generations for high (HMA) and low (LMA) numbers of stereotyped chewing episodes measured for 1 min at 33 min post-injection following 10 mg/kg methamphetamine (changed to 7 mg/kg for the high line and 15 mg/kg for the low line in the third selected generation to avoid ceiling and floor effects, respectively). We sought to determine whether stereotypic behaviors other than number of repetitive chewing episodes were altered by the selective breeding process.

    METHODS: HMA and LMA mice of the third and fourth selected generations were tested for chewing stereotypy, for a number of other stereotypic behaviors previously observed in rodents, and for several other non-stereotypic responses to methamphetamine. Testing in the third selected generation was conducted by observing behaviors on videotape following 7 mg/kg methamphetamine. In the fourth selected generation, mice were also tested in automated activity monitors following 10 mg/kg methamphetamine and in climbing chimneys following 16 mg/kg methamphetamine. Dose-response curves with doses of 1, 2, 3.5, 7, 10, and 15 mg/kg methamphetamine were constructed for the most commonly observed behaviors.

    RESULTS: LMA mice, which exhibited low stereotyped chewing, exhibited high stereotyped circling and climbing, and the reverse was true for these behaviors for HMA mice. For most of the other behaviors measured, there were drug effects but no differences between selected lines.

    CONCLUSIONS: These results suggest that these three stereotyped behaviors, chewing, circling, and climbing, at least partly share the same mechanisms, and therefore are influenced by at least some of the same genes, since animals selectively bred for low methamphetamine-induced stereotyped chewing exhibited high amounts of circling and climbing when given methamphetamine. This also suggests that the other stereotypic behaviors that we measured do not occur by the same genetically determined mechanisms as stereotypic chewing.

  • 4.
    Aziz, Abdul Maruf Asif
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brothers, Shaun
    University of Miami Health System, University of Miami, Miami, USA.
    Sartor, Gregory
    University of Miami Health System, University of Miami, Miami, USA.
    Holm, Lovisa
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Wahlestedt, Claes
    University of Miami Health System, University of Miami, Miami, USA.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 19-20, p. 3553-3563Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior.

    OBJECTIVES: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats.

    RESULTS: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination.

    CONCLUSION: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics.

  • 5.
    Bjartmar, Lisa
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics.
    Johansson, Inga-Maj
    Department of Public Health and Clinical Medicine, Medicine, Umeå University Hospital, Umeå, Sweden.
    Marcusson, Jan
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Neuroscience and Locomotion, Geriatrics. Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Geriatric Medicine.
    Ross, S-B
    Astra Arcus AB, Södertälje, Sweden.
    Seckl, JR
    Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Edinburgh, UK.
    Olsson, T
    Department of Public Health and Clinical Medicine, Medicine, Umeå University Hospital, Umeå, Sweden.
    Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat2000In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 151, no 1, p. 7-12Article in journal (Refereed)
    Abstract [en]

    There is a latency period of several weeks before the onset of clinical effect of antidepressant drugs. The detailed mechanisms underlying drug-induced adaptive neuronal changes are not known. To elucidate the involvement of changes in gene expression of candidate transcription factors, we treated rats for 21 days with buspirone, fluoxetine, 8-OH-DPAT and moclobemide. In situ hybridization was used to study mRNAs encoding NGFI-A, NGFI-B and the glucocorticoid receptors, MR and GR. NGFI-A mRNA expression increased profoundly in the hippocampal formation and the cerebral cortex after all drug treatments, especially after moclobemide treatment (77-122% increase), with the exception of buspirone. MR mRNA expression was induced in hippocampal CA1/CA2 subregions (27-37%) by all antidepressants, while moclobemide and 8-OH-DPAT significantly increased GR gene expression mainly in the CA1 region (31-44%). NGFI-B mRNA was significantly decreased in the hippocampal CA3 subfield (23%) and restrosplenial granular cortex (38%) by moclobemide treatment. There are selective effects of antidepressant drugs on specific transcription factors. These may be important for adaptive neuronal and neuroendocrine changes after antidepressant treatment including HPA axis negative feedback regulation.

  • 6.
    Björk, Karl
    et al.
    Karolinska Institute, Stockholm, Sweden .
    Tronci, Valeria
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Tanda, Gianluigi
    Psychobiology Section, NIDA, National Institutes of Health, Baltimore, MD, USA .
    Hirth, Natalie
    University of Heidelberg, Mannheim, Germany .
    Heilig, Markus
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA .
    Hansson, Anita C.
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    Sommer, Wolfgang H
    Laboratory of Clinical and Translational Studies, NIAAA, National Institutes of Health, Bethesda, MD, USA.
    β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol2013In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 230, no 3, p. 439-449Article in journal (Refereed)
    Abstract [en]

    Rationale

    The rewarding effects of alcohol have been attributed to interactions between opioid and dopaminergic system within the mesolimbic reward pathway. We have previously shown that ablation of β-arrestin 2 (Arrb2), a crucial regulator of μ-opioid receptor function, attenuates alcohol-induced hyperlocomotion and c-fos activation in the nucleus accumbens.

    Objectives

    Here, we further investigated the role of Arrb2 in modulating alcohol-induced dopamine (DA) release and conditioned place preference (CPP). We also assessed the functional importance of Arrb2 for μ-opioid receptor surface expression and signaling following an acute alcohol challenge.

    Methods

    Alcohol-evoked (0.375, 0.75, and 1.5 g/kg intraperitoneally) DA release was measured by in vivo microdialysis in the shell of nucleus accumbens. Reward was assessed by the CPP paradigm. Receptor function was assessed by μ-receptor binding and [35S]GTP-γ-S autoradiography.

    Results

    In Arrb2 knockout mice accumbal DA levels reach maximum response at a lower dose compared to wild-type (wt) animals. In line with these results, Arrb2 knockout mice display increased CPP for alcohol as compared to wt mice. Finally, Arrb2 mutant mice display increased μ-opioid receptor signaling in the ventral and dorsal striatum and amygdala in response to a low dose of alcohol, indicating impaired desensitization mechanisms in these mice.

    Conclusions

    Our results show that Arrb2 modulates the response to low doses of alcohol on various levels including μ-opioid receptor signaling, DA release, and reward. They also reveal a clear dissociation between the effects of Arrb2 on psychomotor and reward behaviors.

  • 7.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Damadzic, Ruslan
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hansson, Anita C.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Sommer, Wolfgang H.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Eskay, Robert
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 208, no 3, p. 417-426Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Reinstatement of responding to a previously alcohol-associated lever following extinction is an established model of relapse-like behavior and can be triggered by stress exposure. Here, we examined whether neuropeptide Y (NPY), an endogenous anti-stress mediator, blocks reinstatement of alcohol-seeking induced by the pharmacological stressor yohimbine.

    MATERIALS AND METHODS: NPY [5.0 or 10.0 mug/rat, intracerebroventricularly (ICV)] dose-dependently blocked the reinstatement of alcohol seeking induced by yohimbine (1.25 mg/kg, i.p.) but failed to significantly suppress the maintenance of alcohol self-administration. We then used c-fos expression mapping to examine neuronal activation following treatment with yohimbine or NPY alone or yohimbine following NPY pre-treatment.

    RESULTS AND DISCUSSION: The analysis was focused on a network of structures previously implicated in yohimbine-induced reinstatement, comprised of central (CeA) and basolateral (BLA) amygdala and the shell of the nucleus accumbens (Nc AccS). Within this network, both yohimbine and NPY potently induced neuronal activation, and their effects were additive, presumably indicating activation of excitatory and inhibitory neuronal populations, respectively.

    CONCLUSION: These results suggest that NPY selectively suppresses relapse to alcohol seeking induced by stressful events and support the NPY system as an attractive target for the treatment of alcohol addiction.

  • 8.
    Cippitelli, Andrea
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Karlsson, Camilla
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Shaw, Janice L.
    Eli Lilly, Indianapolis, IN, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Gehlert, Donald R.
    Eli Lilly, Indianapolis, IN, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 211, no 4, p. 367-375Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Melanin-concentrating hormone (MCH) is involved in regulation of appetitive behaviors as well as emotional reactivity and reward, behavioral domains relevant to alcohol addiction.

    MATERIALS AND METHODS: We evaluated the effects of the non-peptide MCH1 receptor antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one; 3-30 mg/kg, i.p.] on alcohol-related behaviors in Wistar rats.

    RESULTS: Ex vivo binding experiments demonstrated that the GW803430 dose range used resulted in high central MCH1 receptor occupancy. Alcohol self-administration was dose-dependently and potently suppressed, by approximately 80% at the highest dose. Reinstatement of alcohol-seeking induced by alcohol-associated cues was essentially eliminated. In contrast, reinstatement induced by footshock stress was not significantly altered. Taste preference for a quinine/saccharin solution, locomotor activity, and alcohol elimination were unaffected.

    CONCLUSION: Together, these observations support a specific involvement of the MCH system in mediating alcohol reward and cue-induced relapse to alcohol seeking. MCH1-R antagonism may constitute an attractive treatment target for alcohol use disorders.

  • 9.
    Hjalmdahl, Magnus
    et al.
    Swedish Road and Transport Research Institute, Linköping.
    Vadeby, Anna
    Swedish Road and Transport Research Institute, Linköping.
    Forsman, Asa
    Swedish Road and Transport Research Institute, Linköping.
    Fors, Carina
    Swedish Road and Transport Research Institute, Linköping.
    Ceder, Gunnel
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Woxler, Per
    Östergötlands Läns Landsting, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Kronstrand, Robert
    Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Health Sciences. Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden.
    Effects of d-amphetamine on simulated driving performance before and after sleep deprivation2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 222, no 3, p. 401-411Article in journal (Refereed)
    Abstract [en]

    Stimulant drugs are commonly abused and also used to promote wakefulness, yet their effects on driving performance during sleep deprivation have not been thoroughly researched in experimental studies. The aims were to assess the effects on fundamental driving parameters during simulated driving of two doses of d-amphetamine and further to assess the interaction between d-amphetamine and sleep deprivation. A double-blind, placebo-controlled experiment including 18 healthy male volunteers was conducted. The participants felt more alert when taking a dose of d-amphetamine than when taking placebo, and the effect was stronger for the higher dose. However, the data did not show any evidence that taking d-amphetamine prevented the subjects from becoming successively sleepier during the night. A significant main effect of the dose was found for three out of the five primary indicators where the lower dose led to improved driving. These indicators were crossing-car reaction time, and coherence and delay from a car-following event. Regarding sleep deprivation, a main effect was found for four of the primary indicators and three of the secondary indicators. The results showed overall impaired driving with respect to standard deviation of lateral position and delay in reaction time when the sleep-deprived conditions were compared to the alert condition. We found no interactions between dose and sleep deprivation for any of the performance indicators. Our results suggest that administration of d-amphetamine does not compensate for impairment of driving due to fatigue. The positive effects of 10 mg were not further improved or even sustained when increasing the dose to 40 mg.

  • 10.
    Homman, Lina
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Department of Psychology, University of Sussex, Brighton, UK.
    Seglert, Jessica
    Department of Psychology, University of Sussex, Brighton, UK.
    Morgan, Michael J.
    Department of Psychology, University of Sussex, Brighton, UK; Norwegian Center for Addiction Research, University of Oslo, Oslo, Norway.
    An observational study on the sub-acute effects of mephedrone on mood, cognition, sleep and physical problems in regular mephedrone users2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 9, p. 2609-2618Article in journal (Refereed)
    Abstract [en]

    Mephedrone (4-methylmethcathinone; 4-MMC) is a novel recreational drug similar to methylenedioxymethamphetamine (MDMA) and amphetamine. Several adverse effects have been reported, but little is known about its sub-acute effects. To study sub-acute effects of mephedrone over a period of 9 days. Recreational mephedrone users were recruited and followed over a time period of 9 days. It was recorded whether participants consumed mephedrone or not within the period of testing; those who did were compared to those who did not. Forty-six regular mephedrone users (22 males, 24 females) participated, 21 participants voluntarily opted to consume mephedrone 1-3 days after baseline and 25 opted to abstain. Participants were assessed at baseline on a multitude of measures and provided daily reports on cognition, sleep, mood, physical problems, mephedrone cravings and substance use on each subsequent day of the study. The study controlled for psychopathology, sleep, past and current substance use, impulsivity and demographics. Those who consumed mephedrone reported persistent negative mood, physical problems and fatigue, compared to those who did not-after controlling for baseline group differences in sleep and subsequent alcohol and cannabis use. The results provide the first prospective evidence of the duration and extent of specific undesirable sub-acute effects of mephedrone in regular recreational users and indicate sub-acute effects of mephedrone on mood, fatigue and physical symptoms.

  • 11.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIAAA, MD USA.
    Damadzic, Ruslan
    NIAAA, MD USA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Lilly Research Labs, IN USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Correction: The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation (vol 233, nr 12, pp. 2355–2363, 2016)2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 21-22, p. 3825-3825Article in journal (Other academic)
    Abstract [en]

    n/a

  • 12.
    Karlsson, Camilla
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rehman, Faazal
    NIH, MD 20892 USA.
    Damdazic, Ruslan
    NIH, MD 20892 USA.
    Atkins, Alison Lynn
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Schank, Jesse R.
    University of Georgia, GA 30602 USA.
    Gehlert, Donald R.
    Eli Lilly and Co, IN 46285 USA.
    Steensland, Pia
    Karolinska Institute, Sweden.
    Thorsell, Annika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Linköping University, Center for Social and Affective Neuroscience (CSAN). Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    The melanin-concentrating hormone-1 receptor modulates alcohol-induced reward and DARPP-32 phosphorylation2016In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 233, no 12, p. 2355-2363Article in journal (Refereed)
    Abstract [en]

    Melanin-concentrating hormone (MCH) is involved in the regulation of food intake and has recently been associated with alcohol-related behaviors. Blockade of MCH-1 receptors (MCH1-Rs) attenuates operant alcohol self-administration and decreases cue-induced reinstatement, but the mechanism through which the MCH1-R influences these behaviors remains unknown. MCH1-Rs are highly expressed in the nucleus accumbens shell (NAcSh) where they are co-expressed with dopamine (DA) receptors. MCH has been shown to potentiate responses to dopamine and to increase phosphorylation of DARPP-32, an intracellular marker of DA receptor activation, in the NAcSh. In the present study, we investigated the role of the MCH1-R in alcohol reward using the conditioned place preference (CPP) paradigm. We then used immunohistochemistry (IHC) to assess activation of downstream signaling after administration of a rewarding dose of alcohol. We found that alcohol-induced CPP was markedly decreased in mice with a genetic deletion of the MCH1-R as well as after pharmacological treatment with an MCH1-R antagonist, GW803430. In contrast, an isocaloric dose of dextrose did not produce CPP. The increase in DARPP-32 phosphorylation seen in wildtype (WT) mice after acute alcohol administration in the NAcSh was markedly reduced in MCH1-R knock-out (KO) mice. Our results suggest that MCH1-Rs regulate the rewarding properties of alcohol through interactions with signaling cascades downstream of DA receptors in the NAcSh.

  • 13.
    Karlsson, Louise
    et al.
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Hiemke, Christoph
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Carlsson, Björn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Josefsson, Martin
    Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Artillerigatan 12, Sweden.
    Ahlner, Johan
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Bengtsson, Finn
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Diagnostics, Department of Clinical Pharmacology.
    Schmitt, Ulrich
    Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University of Mainz, Germany .
    Kugelberg, Fredrik C
    Linköping University, Department of Medical and Health Sciences, Clinical Pharmacology. Linköping University, Faculty of Health Sciences.
    Effects on enantiomeric drug disposition and open-field behavior after chronic treatment with venlafaxine in the P-glycoprotein knockout mice model2011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 215, no 2, p. 367-377Article in journal (Refereed)
    Abstract [en]

    Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

  • 14.
    Karlsson, Rose-Marie
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Choe, Jessica S.
    National Institute of Mental Health, NIH, Bethesda, MD, USA .
    Cameron, Heather A
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Crawley, Jacqueline N
    National Institute of Mental Health, NIH, Bethesda, MD, USA.
    Holmes, Andrew
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    The neuropeptide Y Y1 receptor subtype is necessary for the anxiolytic-like effects of neuropeptide Y, but not the antidepressant-like effects of fluoxetine, in mice2008In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 195, no 4, p. 547-557Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Neuropeptide Y (NPY) is implicated in the pathophysiology of affective illness. Multiple receptor subtypes (Y1R, Y2R, and Y5R) have been suggested to contribute to NPY's effects on rodent anxiety and depression-related behaviors.

    OBJECTIVES: To further elucidate the role of Y1R in (1) NPY's anxiolytic-like effects and (2) fluoxetine's antidepressant-like and neurogenesis-inducing effects.

    METHODS: Mice lacking Y1R were assessed for spontaneous anxiety-like behavior (open field, elevated plus-maze, and light/dark exploration test) and Pavlovian fear conditioning, and for the anxiolytic-like effects of intracerebroventricularly (icv)-administrated NPY (elevated plus-maze). Next, Y1R -/- were assessed for the antidepressant-like effects of acute fluoxetine in the forced swim test and chronic fluoxetine in the novelty-induced hypophagia test, as well as for chronic fluoxetine-induced hippocampal neurogenesis.

    RESULTS: Y1R -/- exhibited largely normal baseline behavior as compared to +/+ littermate controls. Intraventricular administration of NPY in Y1R -/- mice failed to produce the normal anxiolytic-like effect in the elevated plus-maze test seen in +/+ mice. Y1R mutant mice showed higher immobility in the forced swim test and longer latencies in the novelty-induced hypophagia test. In addition, Y1R -/- mice responded normally to the acute and chronic effects of fluoxetine treatment in the forced swim test and the novelty-induced hypophagia test, respectively, as well as increased neuronal precursor cell proliferation in the hippocampus.

    CONCLUSIONS: These data demonstrate that Y1R is necessary for the anxiolytic-like effects of icv NPY, but not for the antidepressant-like or neurogenesis-inducing effects of fluoxetine. The present study supports targeting Y1R as a novel therapeutic target for anxiety disorders.

  • 15.
    Robinson, J. E.
    et al.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Fish, E. W.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Krouse, M. C.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Heilig, Marcus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Malanga, C. J.
    University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism2012In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 220, no 1, p. 215-224Article in journal (Refereed)
    Abstract [en]

    RATIONALE: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.

    OBJECTIVE: This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.

    METHODS: Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline.

    RESULTS: Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX.

    CONCLUSIONS: The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

  • 16.
    Schank, Jesse R.
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Pickens, Charles L.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Rowe, Kelly E.
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Cheng, Kejun
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Thorsell, Annika
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Rice, Kenner C.
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Shaham, Yavin
    National Institute on Drug Abuse, NIH, Bethesda, MD, USA.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA.
    Stress-induced reinstatement of alcohol-seeking in rats is selectively suppressed by the neurokinin 1 (NK1) antagonist L8224292011In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 218, no 1, p. 111-119Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Genetic inactivation or pharmacological antagonism of neurokinin 1 (NK1) receptors blocks morphine and alcohol reward in rodents, while NK1 antagonism decreases alcohol craving in humans. The role of the NK1 system for relapse-like behavior has not previously been examined.

    OBJECTIVE: Divergence between human and rodent NK1 receptors has limited the utility of NK1 antagonists developed for the human receptor species for preclinical studies of addiction-related behaviors in rats. Here we used L822429, an NK1 antagonist specifically engineered to bind at high affinity to the rat receptor, to assess the effects of NK1 receptor antagonism on alcohol-seeking behaviors in rats.

    METHODS: L822429 (15 and 30 mg/kg) was used to examine effects of NK1 receptor antagonism on operant self-administration of 10% alcohol in 30-min daily sessions, as well as intermittent footshock stress- and cue-induced reinstatement of alcohol-seeking after extinction of lever responding.

    RESULTS: At the doses used, L822429 did not significantly affect alcohol self-administration or cue-induced reinstatement, but potently and dose dependently suppressed stress-induced reinstatement of alcohol seeking, with an essentially complete suppression at the highest dose. The effect of L822429 on stress-induced reinstatement was behaviorally specific. The drug had no effect on conditioned suppression of operant responding following fear conditioning, locomotor activity, or self-administration of a sucrose solution.

    CONCLUSIONS: To the degree that the reinstatement model provides a model of drug relapse, the results provide support for NK1 antagonism as a promising mechanism for pharmacotherapy of alcoholism, acting through suppression of stress-induced craving and relapse.

  • 17.
    Schroeder, Jennifer R.
    et al.
    Johns Hopkins Bayview Med Ctr, MD 21224 USA.
    Phillips, Karran A.
    NIDA, MD 21224 USA.
    Epstein, David H.
    NIDA, MD 21224 USA.
    Jobes, Michelle L.
    NIDA, MD 21224 USA.
    Furnari, Melody A.
    NIDA, MD 21224 USA.
    Kennedy, Ashley P.
    NIDA, MD 21224 USA.
    Heilig, Markus
    Linköping University, Department of Clinical and Experimental Medicine, Center for Social and Affective Neuroscience. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Local Health Care Services in Central Östergötland, Department of Psychiatry.
    Preston, Kenzie L.
    NIDA, MD 21224 USA.
    Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder2018In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 235, no 10, p. 2957-2966Article in journal (Refereed)
    Abstract [en]

    Background Preliminary evidence suggested that the PPAR gamma agonist pioglitazone reduces opioid-withdrawal symptoms, possibly by inhibiting increases in proinflammatory cytokines. Methods A randomized, placebo-controlled clinical trial was conducted utilizing two different study designs (entirely outpatient, and a combination of inpatient and outpatient) to evaluate the safety and efficacy of pioglitazone as an adjunct medication for people with opioid physical dependence undergoing a buprenorphine taper. Participants were stabilized on buprenorphine/naloxone (sublingual, up to 16/4 mg/day), then randomized to receive oral pioglitazone (up to 45 mg/day) or placebo before, during, and after buprenorphine taper. Outcome measures included the Subjective Opiate Withdrawal Scale (SOWS) and Clinical Opiate Withdrawal Scale, use of rescue medications to alleviate opioid withdrawal symptoms, and opioid-positive urine specimens. Cerebrospinal fluid (CSF) and plasma were collected during the taper in a subset of participants for measurement of proinflammatory cytokines. Results The clinical trial was prematurely terminated due to slow enrollment; 40 participants per group were required for adequate statistical power to test study hypotheses. Twenty-four participants enrolled; 17 received at least one dose of study medication (6 pioglitazone, 11 placebo). SOWS scores were higher in the pioglitazone arm than in the placebo arm after adjusting for use of rescue medications; participants in the pioglitazone arm needed more rescue medications than the placebo arm during the post-taper phase. SOWS scores were positively correlated with monocyte chemoattractant protein-1 (MCP-1) in CSF (r = 0.70, p = 0.038) and plasma (r = 0.77, p = 0.015). Participants having higher levels of plasma MCP-1 reported higher SOWS, most notably after the buprenorphine taper ended. Conclusions Results from this study provide no evidence that pioglitazone reduces opioid withdrawal symptoms during buprenorphine taper. High correlations between MCP-1 and opioid withdrawal symptoms support a role of proinflammatory processes in opioid withdrawal.

  • 18.
    Thorsell, Annika
    et al.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Schank, Jesse R.
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Singley, Erick
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Hunt, Stephen P
    University College London, UK.
    Heilig, Markus
    National Institute on Alcohol Abuse and Alcoholism, NIH; Bethesda, MD, USA.
    Neurokinin-1 receptors (NK1Rs), alcohol consumption, and alcohol reward in mice2010In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 209, no 1, p. 103-111Article in journal (Refereed)
    Abstract [en]

    RATIONALE: Reduced voluntary alcohol consumption was recently found in neurokinin-1 receptor (NK1R)-deficient (KO) mice. It remains unknown whether this reflects developmental effects or direct regulation of alcohol consumption by NK1R:s, and whether the reduced consumption reflects motivational effects.

    OBJECTIVE: The objective of this study is to obtain an expanded preclinical validation of NK1R antagonism as a candidate therapeutic mechanism in alcohol use disorders.

    METHODS: The NK1R antagonist L-703,606 and NK1R KO mice were used in models that assess alcohol-related behaviors.

    RESULTS: L-703,606 (3-10 mg/kg i.p.) dose-dependently suppressed alcohol intake in WT C57BL/6 mice under two-bottle free choice conditions but was ineffective in NK1R KO:s, demonstrating the receptor specificity of the effect. Alcohol reward, measured as conditioned place preference for alcohol, was reduced by NK1R receptor deletion in a gene dose-dependent manner. In a model where escalation of intake is induced by repeated cycles of deprivation and access, escalation was seen in WT mice, but not in KO mice. Among behavioral phenotypes previously reported for NK1R mice on a mixed background, an analgesic-like phenotype was maintained on the C57BL/6 background used here, while KO:s and WT:s did not differ in anxiety- and depression-related behaviors.

    CONCLUSIONS: Acute blockade of NK1R:s mimics the effects of NKR1 gene deletion on alcohol consumption, supporting a direct rather than developmental role of the receptor in regulation of alcohol intake. Inactivation of NK1R:s critically modulates alcohol reward and escalation, two key characteristics of addiction. These data provide critical support for NK1R antagonism as a candidate mechanism for treatment of alcoholism.

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