Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
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Neuropsychopharmacology · Oct 2013
Chronic interferon-α decreases dopamine 2 receptor binding and striatal dopamine release in association with anhedonia-like behavior in nonhuman primates.
Neuroimaging studies in humans have demonstrated that inflammatory cytokines target basal ganglia function and presynaptic dopamine (DA), leading to symptoms of depression. Cytokine-treated nonhuman primates also exhibit evidence of altered DA metabolism in association with depressive-like behaviors. To further examine cytokine effects on striatal DA function, eight rhesus monkeys (four male, four female) were administered interferon (IFN)-α (20 MIU/m(2) s.c.) or saline for 4 weeks. ⋯ Sucrose consumption was reduced during IFN-α administration and was correlated with decreased DA release at 4 weeks as measured by in vivo microdialysis. Taken together, these findings indicate that chronic peripheral IFN-α exposure reduces striatal DA release in association with anhedonia-like behavior in nonhuman primates. Future studies examining the mechanisms of cytokine effects on DA release and potential therapeutic strategies to reverse these changes are warranted.
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Neuropsychopharmacology · Oct 2013
BDNF overexpression in the ventral tegmental area prolongs social defeat stress-induced cross-sensitization to amphetamine and increases ΔFosB expression in mesocorticolimbic regions of rats.
Social defeat stress induces persistent cross-sensitization to psychostimulants, but the molecular mechanisms underlying the development of cross-sensitization remain unclear. One candidate is brain-derived neurotrophic factor (BDNF). The present research examined whether ventral tegmental area (VTA) BDNF overexpression would prolong the time course of cross-sensitization after a single social defeat stress, which normally produces transient cross-sensitization lasting <1 week. ΔFosB, a classic molecular marker of addiction, was also measured in mesocorticolimbic terminal regions. ⋯ Immunohistochemistry showed that the combination of virally enhanced VTA BDNF, stress, and AMPH resulted in increased ΔFosB in the NAc shell compared with the other groups. Thus, elevation of VTA BDNF prolongs cross-sensitization, facilitates sensitization, and increases ΔFosB in mesocorticolimbic terminal regions. As such, elevated VTA BDNF may be a risk factor for drug sensitivity.
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Neuropsychopharmacology · Oct 2013
Dissociable effects of kappa-opioid receptor activation on impulsive phenotypes in wistar rats.
The kappa-opioid receptor (KOR) is the primary target for the endogenous opioid peptide dynorphin (DYN), and KORs reside within brain circuitry underlying the complex integration of information related to different behavioral domains such as motivation, negative affect, and decision-making. Alterations in extended amygdala DYNs and KOR function following chronic alcohol exposure have been shown to mediate escalated alcohol self-administration during acute withdrawal. In addition to excessive alcohol consumption and increased negative affect, other symptoms of alcohol dependence include compromised impulse control. ⋯ Therefore, KOR activation was shown to induce an impulsive phenotype that was nor-BNI-sensitive. Dysregulation of impulsive behavior by increased DYN/KOR activity could serve to increase vulnerability for the initiation, or perpetuate existing patterns of excessive alcohol abuse and can enhance the probability of relapse in dependent individuals. Furthermore, KOR-mediated impulsivity has implications for numerous neuropsychiatric disorders.
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Neuropsychopharmacology · Oct 2013
Acute prosocial effects of oxytocin and vasopressin when given alone or in combination with 3,4-methylenedioxymethamphetamine in rats: involvement of the V1A receptor.
The neuropeptides oxytocin (OT) and vasopressin (AVP) are recognized for their modulation of social processes in humans when delivered peripherally. However, there is surprisingly little evidence for acute social effects of peripherally administered OT or AVP in animal models. On the other hand, the party drug 3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') has powerful prosocial effects in rats that appear to occur through stimulation of central OT release. ⋯ C25 did not inhibit adjacent lying induced by OT, whereas SR49059 inhibited adjacent lying induced by MDMA (5 mg/kg), OT (0.5 mg/kg), and AVP (0.01 mg/kg). Interestingly, when ineffective doses of OT and MDMA, or AVP and MDMA, were combined, a robust increase in adjacent lying was observed. These results show for the first time acute prosocial effects of peripherally injected OT and AVP in laboratory rats, and suggest a commonality of action of OT, AVP, and MDMA in stimulating social behavior that involves V1ARs.
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Neuropsychopharmacology · Oct 2013
GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine.
A single dose of the short-acting NMDA antagonist ketamine produces rapid and prolonged antidepressant effects in treatment-resistant patients with major depressive disorder (MDD), which are thought to occur via restoration of synaptic connectivity. However, acute dissociative side effects and eventual fading of antidepressant effects limit widespread clinical use of ketamine. ⋯ The results demonstrate that low, subthreshold doses of ketamine combined with lithium or a selective GSK-3 inhibitor are equivalent to higher doses of ketamine, indicating the pivotal role of the GSK-3 pathway in modulating the synaptogenic and antidepressant responses to ketamine. The possible mitigation by GSK-3 inhibitors of the eventual fading of ketamine's antidepressant effects remains to be explored.