Alcohol Consumption Decreases Oxytocin Neurons in the Anterior Paraventricular Nucleus of the Hypothalamus in Prairie Voles.

BACKGROUND: Alcohol use disorders are associated with dysfunctional social relationships and stress responses. The neuropeptides oxytocin (OT) and vasopressin (AVP) are known to orchestrate or mediate many aspects of social behavior, stress responses, and ingestive behaviors. Because of the overlap between the effects of alcohol and the roles of OT and AVP, we sought to determine whether alcohol consumption altered expression of OT and AVP in the paraventricular nucleus (PVN) of the hypothalamus, one of the key sites for OT and AVP synthesis. METHODS: Pair-housed adult male prairie voles were allowed to consume 15% ethanol versus water in the home cage continuously (Continuous-Access [CA] group) or every other day for 4 hours (Intermittent-Access [IA] group). Control animals never had access to alcohol. After 7 weeks, animals were sacrificed and their brains were removed and immunohistochemical analysis of OT- and AVP-immunopositive neurons was performed. RESULTS: OT-immunopositive neurons were significantly decreased in the anterior PVN in the CA but not IA group, relative to Control animals, suggesting that continuous alcohol consumption decreases the number of OT neurons. There was no effect of alcohol consumption on posterior PVN OT neurons, and no effect on PVN AVP neurons. CONCLUSIONS: These data show that continuous-access voluntary alcohol consumption is associated with decreased OT neurons in the anterior PVN, suggesting that alcohol-induced alterations in the OT system should be investigated as a mechanism for alcohol-related changes in social behavior, stress responses, and exacerbation of alcohol use disorders.

Voluntary locomotor activity mitigates oxidative damage associated with isolation stress in the prairie vole (Microtus ochrogaster).

Organismal performance directly depends on an individual's ability to cope with a wide array of physiological challenges. For social animals, social isolation is a stressor that has been shown to increase oxidative stress. Another physiological challenge, routine locomotor activity, has been found to decrease oxidative stress levels. Because we currently do not have a good understanding of how diverse physiological systems like stress and locomotion interact to affect oxidative balance, we studied this interaction in the prairie vole (Microtus ochrogaster). Voles were either pair housed or isolated and within the isolation group, voles either had access to a moving wheel or a stationary wheel. We found that chronic periodic isolation caused increased levels of oxidative stress. However, within the vole group that was able to run voluntarily, longer durations of locomotor activity were associated with less oxidative stress. Our work suggests that individuals who demonstrate increased locomotor activity may be better able to cope with the social stressor of isolation.

Oxytocin prevents dysregulation of the acute stress response and glucocorticoid-induced oxidative stress in chronically isolated prairie voles.

Chronic social isolation can lead to dysregulation of many physiological and psychological processes, including the ability to respond to acute stressors. Previous work in our lab reported that six weeks of social isolation in prairie voles (Microtus ochrogaster) caused increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia, and that oxytocin treatment prevented all of these changes. Following these results, we investigated how chronic social isolation with and without oxytocin treatment affected glucocorticoid (CORT) and oxidative stress responses to an acute stressor, a 5-min resident-intruder (R-I) test at the end of the social isolation period. To investigate the effect of a brief acute stressor on CORT and oxidative stress, baseline blood samples were collected following six weeks of social isolation, 24-hrs before the R-I test. Two more blood samples were collected 15-min after the end of the R-I test, and again 25-min later to measure peak and recovery responses, respectively. Isolated animals had higher baseline, peak, recovery, and integrated levels of CORT and reactive oxygen metabolites (ROMs, a measure of oxidative stress), compared to animals that did not experience isolation. Importantly, oxytocin treatment throughout the isolation period prevented these elevations in CORT and ROMs. No significant changes were observed in total antioxidant capacity (TAC). Levels of CORT and ROMs at the peak and recovery time points were positively correlated. These data show that acute stress in chronically isolated prairie voles, then, is associated with increased glucocorticoid-induced oxidative stress (GiOS), and that oxytocin mitigates isolation-induced dysregulation of glucocorticoid and oxidative stress acute stress responses.

Oxytocin administration prevents cellular aging caused by social isolation.

Chronic stressors, such as chronic isolation in social mammals, can elevate glucocorticoids, which can affect cellular mechanisms of aging, including increased levels of oxidative stress and shortened telomere lengths. Recent work in the selectively social prairie vole (Microtus ochrogaster) suggests that oxytocin and social support may mitigate some of the negative consequences of social isolation, possibly by reducing glucocorticoid levels. We investigated the influences of isolation, social support, and daily oxytocin injections in female prairie voles. Glucocorticoid levels, oxidative damage, telomere length, and anhedonia, a behavioral index of depression, were measured throughout the study. We found that six weeks of chronic isolation led to increased glucocorticoid levels, oxidative damage, telomere degradation and anhedonia. However, daily oxytocin injections in isolated voles prevented these negative consequences. These findings demonstrate that chronic social isolation in female prairie voles is a potent stressor that results in depression-like behavior and accelerated cellular aging. Importantly, oxytocin can completely prevent the negative consequences of social isolation.

Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP.

Relapse to alcohol use after periods of abstinence is a hallmark behavioral pathology of alcoholism and a major clinical problem. Emerging evidence indicates that metabotropic glutamate receptor 5 (mGluR5) antagonists attenuate relapse to alcohol-seeking behavior but the molecular mechanisms of this potential therapeutic effect remain unexplored. The extracellular signal-regulated kinase (ERK1/2) pathway is downstream of mGluR5 and has been implicated in addiction. We sought to determine if cue-induced reinstatement of alcohol-seeking behavior, and its reduction by an mGluR5 antagonist, is associated with changes in ERK1/2 activation in reward-related limbic brain regions. Selectively-bred alcohol-preferring (P) rats were trained to lever press on a concurrent schedule of alcohol (15% v/v) vs. water reinforcement. Following 9 days of extinction, rats were given an additional extinction trial or injected with the mGluR5 antagonist MPEP (0, 1, 3, or 10mg/kg) and tested for cue-induced reinstatement. Brains were removed 90-min later from the rats in the extinction and MPEP (0 or 10mg/kg) conditions for analysis of p-ERK1/2, total ERK1/2, and p-ERK5 immunoreactivity (IR). Cue-induced reinstatement of alcohol-seeking behavior was associated with a three to five-fold increase in p-ERK1/2 IR in the basolateral amygdala and nucleus accumbens shell. MPEP administration blocked both the relapse-like behavior and increase in p-ERK1/2 IR. p-ERK1/2 IR in the central amygdala and NAcb core was dissociated with the relapse-like behavior and the pharmacological effect of mGluR5 blockade. No changes in total ERK or p-ERK5 were observed. These results suggest that exposure to cues previously associated with alcohol self-administration is sufficient to produce concomitant increases in relapse-like behavior and ERK1/2 activation in specific limbic brain regions. Pharmacological compounds, such as mGluR5 antagonists, that reduce cue-induced ERK1/2 activation may be useful for treatment of relapse in alcoholics that is triggered by exposure to environmental events.

Abstinence following alcohol drinking produces depression-like behavior and reduced hippocampal neurogenesis in mice.

Alcoholism and depression show high degrees of comorbidity. Clinical evidence also indicates that depression that emerges during abstinence from chronic alcohol use has a greater negative impact on relapse than pre-existing depression. Although no single neurobiological mechanism can account for the behavioral pathologies associated with these devastating disorders, converging evidence suggests that aspects of both alcoholism and depression are linked to reductions in hippocampal neurogenesis. Here, we report results from a novel preclinical behavioral model showing that abstinence from voluntary alcohol drinking leads to the emergence of depression-like behavior and reductions in neurogenesis. C57BL/6J mice were allowed to self-administer ethanol (10% v/v) vs H(2)O in the home cage for 28 days. Alcohol was then removed for 1 or 14 days, and mice were tested in the forced swim test to measure depression-like behavior. After 14 days, but not 1 day of abstinence from alcohol drinking, mice showed a significant increase in depression-like behavior. The significant increase in depression-like behavior during abstinence was associated with a reduction in proliferating cell nuclear antigen (PCNA) and doublecortin (DCX) immunoreactivity in the dentate gyrus of the hippocampus indicating that both the number of proliferating neural progenitor cells (NPC) and immature neurons were reduced, respectively. The number of NPCs that were labeled with bromo-deoxyuridine (BrdU) at the beginning of alcohol exposure was not altered indicating that survival of NPCs is not linked to abstinence-induced depression. Chronic treatment (14 days) with the antidepressant desipramine during abstinence prevented both the emergence of depression-like behavior and the reduction in hippocampal neurogenesis indicating that abstinence-induced depression is associated with structural plasticity in the hippocampus. Overall, the results of this study support the conclusion that profound functional (i.e. behavioral) and structural changes occur during abstinence from alcohol use and suggest that antidepressant treatment may alleviate some of these pathological neurobehavioral adaptations.