Adolescent social defeat alters N-methyl-D-aspartic acid receptor expression and impairs fear learning in adulthood.

Repeated social defeat of adolescent male rats results in adult mesocortical dopamine hypofunction, impaired working memory, and increased contextual anxiety-like behavior. Given the role of glutamate in dopamine regulation, cognition, and fear and anxiety, we investigated potential changes to N-methyl-D-aspartic acid (NMDA) receptors following adolescent social defeat. As both NMDA receptors and mesocortical dopamine are implicated in the expression and extinction of conditioned fear, a separate cohort of rats was challenged with a classical fear conditioning paradigm to investigate whether fear learning is altered by adolescent defeat. Quantitative autoradiography was used to measure 3H-MK-801 binding to NMDA receptors in regions of the medial prefrontal cortex, caudate putamen, nucleus accumbens, amygdala and hippocampus. Assessment of fear learning was achieved using an auditory fear conditioning paradigm, with freezing toward the auditory tone used as a measure of conditioned fear. Compared to controls, adolescent social defeat decreased adult NMDA receptor expression in the infralimbic region of the prefrontal cortex and central amygdala, while increasing expression in the CA3 region of the hippocampus. Previously defeated rats also displayed decreased conditioned freezing during the recall and first extinction periods, which may be related to the observed decreases and increases in NMDA receptors within the central amygdala and CA3, respectively. The alteration in NMDA receptors seen following adolescent social defeat suggests that dysfunction of glutamatergic systems, combined with mesocortical dopamine deficits, likely plays a role in the some of the long-term behavioral consequences of social stressors in adolescence seen in both preclinical and clinical studies.

Dysfunction in fatty acid amide hydrolase is associated with depressive-like behavior in Wistar Kyoto rats.

BACKGROUND: While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors. METHODOLOGY/PRINCIPAL FINDINGS: The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats. CONCLUSIONS/SIGNIFICANCE: These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder.

Adolescent social defeat alters markers of adult dopaminergic function.

Stressful experiences during adolescence can alter the trajectory of neural development and contribute to psychiatric disorders in adulthood. We previously demonstrated that adolescent male rats exposed to repeated social defeat stress show changes in mesocorticolimbic dopamine content both at baseline and in response to amphetamine when tested in adulthood. In the present study we examined whether markers of adult dopamine function are also compromised by adolescent experience of social defeat. Given that the dopamine transporter as well as dopamine D1 receptors act as regulators of psychostimulant action, are stress sensitive and undergo changes during adolescence, quantitative autoradiography was used to measure [(3)H]-GBR12935 binding to the dopamine transporter and [(3)H]-SCH23390 binding to dopamine D1 receptors, respectively. Our results indicate that social defeat during adolescence led to higher dopamine transporter binding in the infralimbic region of the medial prefrontal cortex and higher dopamine D1 receptor binding in the caudate putamen, while other brain regions analyzed were comparable to controls. Thus it appears that social defeat during adolescence causes specific changes to the adult dopamine system, which may contribute to behavioral alterations and increased drug seeking.

Voluntary alcohol consumption alters stress-induced changes in dopamine-2 receptor binding in Wistar-Kyoto rat brain.

The Wistar-Kyoto (WKY) rat has been proposed as an animal model of depressive behavior and exhibits hyper-responsiveness to stressful stimulation when compared to other rat strains. We have demonstrated that WKY rats consume 200% more alcohol under naïve conditions as compared to their outbred counterparts, Wistar (WIS) rats. The present study was designed to understand the influence of stress and alcohol consumption on central dopamine type-2 (D2) receptor sites in these two behaviorally distinct rat strains. The first part of this study examined the effects of chronic stress on alcohol consumption, while the second part examined the binding of [(125)I]-Iodosulpiride to D2 receptors in control, stressed or stress and alcohol co-treated WKY compared to WIS rats. Exposure to chronic stress led to an increase in the amount of alcohol consumed by both rat strains, with WKY rats consuming significantly more alcohol than WIS rats with or without stress exposure. Quantitative autoradiography experiments showed that chronic stress increased D2 receptor binding in the caudate putamen (CPu), nucleus accumbens (NAc), substantia nigra (SN) and ventral tegmental area (VTA) of WKY rats, and reduced receptor binding in the CPu and SN of WIS rats. Compared to the stressed animals, WKY rats co-treated with stress and alcohol demonstrated a reduction in D2 receptor sites in the cell body regions (SN and VTA), while WIS rats showed no changes in receptor binding. The observed changes in D2 receptor sites may indicate altered DA neurotransmission following stress and alcohol exposure. Since stressed WKY rats consumed more alcohol, it is possible that consumption of alcohol reverses the stress-induced D2 receptor alterations in the cell body regions, suggestive of a self medicating phenotype.

Strain differences in the distribution of N-methyl-d-aspartate and gamma (gamma)-aminobutyric acid-A receptors in rat brain.

AIMS: Previous studies have shown that the Wistar-Kyoto (WKY) rat strain exhibits depressive symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias following exposure to stress. Given the involvement of excitatory glutamate and inhibitory gamma (gamma)-aminobutyric acid (GABA) signaling pathways in influencing depressive behavior, the present study investigated strain differences in the distribution of central N-methyl-d-aspartate (NMDA) and GABA(A) receptor sites in WKY compared to their inbred counterpart, Wistar (WIS) rats. MAIN METHODS: Quantitative autoradiographic analysis was used to map the binding and distribution of NMDA and GABA(A) receptors in various brain regions in WKY and WIS rats. KEY FINDINGS: Results indicated a significant difference between the two strains. Lower NMDA receptor binding was found in the anterior cingulate cortex, caudate putmen, nucleus accumbens, CA1 region of the hippocampus and the substantia nigra pars reticulata in WKY compared to WIS rats. Conversely, higher GABA(A) receptor binding was found in the amygdala, caudate putmen, dentate gyrus, CA2 and CA3 fields of the hippocampus, periaqueductal grey and substantia nigra pars reticulata in WKY compared to WIS rats. SIGNIFICANCE: Given that these two rat strains differ in their behavioural, endocrine and neurochemical profile, the observed strain differences in NMDA and GABA(A) receptor binding suggest that these two neurotransmitter systems may be involved in the depressive and stress-sensitive phenotype of the WKY rat strain.

Antidepressant drug induced alterations in binding to central dopamine transporter sites in the Wistar Kyoto rat strain.

The Wistar Kyoto (WKY) rat has been proposed as an animal model of depressive behavior. Exposing WKY rats to stress stimulation produces symptoms such as anhedonia, psychomotor retardation, ambivalence and negative memory bias. Given the role of the mesolimbic dopamine (DA) system in cognitive, emotional and motivational behaviors, we previously examined the distribution of DA transporter (DAT) sites in the brains of WKY compared to Wistar (WIS) and Sprague-Dawley (S-D) rats. WKY rats exhibited significant differences in DAT binding sites in the cell body as well as mesolimbic areas compared to the other strains. It was reasoned that these differences may lead to altered synaptic levels of DA in specific brain regions thus contributing to the behavioral differences observed in this rat strain. Thus, the present study examined whether repeated treatment with antidepressant drugs that block the uptake of DA (nomifensine and bupropion) would modify [3H]-GBR12935 binding to DAT sites in WKY rats compared to WIS and S-D rats. The results indicate that while nomifensine and bupropion increased the binding of [3H]-GBR12935 to DAT sites in the mesocorticolimbic regions in WKY rats, these drugs increased the binding of [3H]-GBR12935 to DAT sites in the cell body areas in WIS rats but not in S-D and WKY rats. The data from this study suggest that antidepressant induced alterations in DAT sites in the mesocorticolimbic brain regions may play a role in the behavioral improvement seen in WKY rats, as measured by the Open Field Test (OFT) and the Porsolt Forced Swim Test (FST).