| 1. |
- Alsiö, Johan, et al.
(författare)
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The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat : a cross-site study
- 2015
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 232:21-22, s. 4017-4031
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 2. |
- Aziz, Abdul Maruf Asif, et al.
(författare)
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The nociceptin/orphanin FQ receptor agonist SR-8993 as a candidate therapeutic for alcohol use disorders: validation in rat models
- 2016
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 233:19-20, s. 3553-3563
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Björk, Karl, et al.
(författare)
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β-Arrestin 2 knockout mice exhibit sensitized dopamine release and increased reward in response to a low dose of alcohol
- 2013
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 230:3, s. 439-449
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Tidskriftsartikel (refereegranskat)abstract
- RationaleThe 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.ObjectivesHere, 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.MethodsAlcohol-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.ResultsIn 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.ConclusionsOur 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.
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| 4. |
- Brooks, Samantha J., et al.
(författare)
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The impact of cognitive training in substance use disorder : the effect of working memory training on impulse control in methamphetamine users
- 2017
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 234:12, s. 1911-1921
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Cippitelli, Andrea, et al.
(författare)
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Neuropeptide Y (NPY) suppresses yohimbine-induced reinstatement of alcohol seeking
- 2010
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 208:3, s. 417-426
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Cippitelli, Andrea, et al.
(författare)
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Suppression of alcohol self-administration and reinstatement of alcohol seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats
- 2010
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Ingår i: Psychopharmacology. - : Springer. - 0033-3158 .- 1432-2072. ; 211:4, s. 367-375
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
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| 8. |
- Ekström, Johan G., et al.
(författare)
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Effects of blue light and caffeine on mood
- 2014
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 231:18, s. 3677-3683
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Tidskriftsartikel (refereegranskat)abstract
- Both short wavelength (blue) light and caffeine have been studied for their mood enhancing effects on humans. The ability of blue light to increase alertness, mood and cognitive function via non-image forming neuropathways has been suggested as a non-pharmacological countermeasure for depression across a range of occupational settings. This experimental study compared blue light and caffeine and aimed to test the effects of blue light/placebo (BLU), white light/240-mg caffeine (CAF), blue light/240-mg caffeine (BCAF) and white light/placebo (PLA), on mood. A randomised, controlled, crossover design study was used, in a convenience population of 20 healthy volunteers. The participants rated their mood on the Swedish Core Affect Scales (SCAS) prior to and after each experimental condition to assess the dimensions of valence and activation. There was a significant main effect of light (p = 0.009), and the combination of blue light and caffeine had clear positive effects on core effects (ES, ranging from 0.41 to 1.20) and global mood (ES, 0.61 +/- 0.53). The benefits of the combination of blue light and caffeine should be further investigated across a range of applications due to the observed effects on the dimensions of arousal, valence and pleasant activation.
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| 9. |
- Engel, Jörgen, 1942, et al.
(författare)
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Blockade of growth hormone secretagogue receptor 1A signaling by JMV 2959 attenuates the NMDAR antagonist, phencyclidine-induced impairments in prepulse inhibition
- 2015
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Ingår i: Psychopharmacology. - : Springer Science and Business Media LLC. - 0033-3158 .- 1432-2072. ; 232:23, s. 4285-4292
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Tidskriftsartikel (refereegranskat)abstract
- Schizophrenic-spectrum patients commonly display deficits in preattentive information processing as evidenced, for example, by disrupted prepulse inhibition (PPI), a measure of sensorimotor gating. Similar disruptions in PPI can be induced in rodents and primates by the psychotomimetic drug phencyclidine (PCP), a noncompetitive inhibitor of the NMDA receptor. Mounting evidence suggests that the hunger hormone ghrelin and its constitutively active receptor influences neuronal circuits involved in the regulation of mood and cognition. In the present series of experiments, we investigated the effects of ghrelin and the growth hormone secretagogue receptor (GHS-R1A) neutral antagonist, JMV 2959, on acoustic startle responses (ASR), PPI, and PCP-induced alterations in PPI. Intraperitoneal (i.p.) administration of ghrelin (0.033, 0.1, and 0.33 mg/kg) did not alter the ASR or PPI in rats. Conversely, i.p. injection of JMV 2959 (1, 3, and 6 mg/kg), dose dependently decreased the ASR and increased PPI. Pretreatment with JMV 2959 at a dose with no effect on ASR or PPI per se, completely blocked PCP-induced (2 mg/kg) deficits in PPI while pretreatment with the highest dose of ghrelin did not potentiate or alter PPI responses of a sub-threshold dose of PCP (0.75 mg/kg). These findings indicate that the GHS-R1A is involved in specific behavioral effects of PCP and may have relevance for patients with schizophrenia.
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