Differential effects of mild repeated restraint stress on behaviors and GABA(A) receptors in male and female rats.

We previously reported that the very mild stress of individual housing influenced seizure risk and gamma-amino butyric acid (GABA(A)) receptor activity differentially between male and female rats. The aim of the present set of studies was to assess sex differences in behavioral responses to a more pronounced type of stressor, repeated restraint stress. We also wanted to determine the role of GABA(A) receptors in effects of this stressor. Our data suggest that repeated restraint stress afforded short-term protection against seizure induction in both male and female rats. Moreover, this protection was more persistent in female than male rats. This stress paradigm also elicited a reduction in general activity in male rats, whereas female rats displayed prolonged increased activity following the repeated restraint stress exposure. However, there were limited effects on anxiety-like behaviors, as determined by time spent in the open arms on the elevated plus maze. Sex differences in stress-induced increases in plasma corticosterone levels were observed, which generally correlated with sex differences in behavioral measures. There were no significant effects of the repeated restraint stress exposure on benzodiazepine/GABA(A) receptor density or affinity nor on receptor function. Taken together, these findings provide additional evidence to support the important influences of sex in responding to stress and highlight the need to consider this context when addressing the role of stress in health issues for women and men.

Sex differences in effects of mild chronic stress on seizure risk and GABAA receptors in rats.

Social stress is a common occurrence in our society that can negatively impact health. Therefore, we wanted to study the effects of a mild stressor designed to model social stress on seizure susceptibility and GABAA receptors in male and female rats. The mild chronic stress of individual housing consistently decreased bicuculline (but not pentylenetetrazol, PTZ) seizure thresholds by 10-15% in both sexes. Housing conditions did not alter the anticonvulsant activity of diazepam or ethanol, although the anticonvulsant effect of ethanol was significantly greater against PTZ-induced seizures. Experiments testing the addition of an acute restraint stress unmasked sex differences in seizure induction. The acute stress also selectively decreased the potency of GABA to modulate GABAA receptor-mediated chloride uptake in group-housed females. There were additional sex differences by housing condition for GABAA receptor-gated chloride uptake but no differences in [3H]flunitrazepam binding. We also found significant effects of sex and housing on ethanol-induced increases in corticosterone (CORT) levels. In summary, there were complex and sex-selective effects of mild chronic stress on seizure induction and GABAA receptors. Gaining a better understanding of mechanisms underlying interactions between sex and stress has important implications for addressing health concerns about stress in men and women.

Single exposure to a serotonin 1A receptor agonist, (+)8-hydroxy-2-(di-n-propylamino)-tetralin, produces a prolonged heterologous desensitization of serotonin 2A receptors in neuroendocrine neurons in vivo.

We previously demonstrated colocalization of serotonin 1A (5-HT(1A)) and serotonin 2A (5-HT(2A)) receptors in oxytocin and corticotropin-releasing factor neurons in the hypothalamic paraventricular nucleus (PVN). Because a functional imbalance between hypothalamic 5-HT(1A) and 5-HT(2A) receptors has been implicated in several neuropsychiatric disorders, in this study we investigated whether acute in vivo activation of 5-HT(1A) receptors in the PVN results in desensitization of 5-HT(2A) receptor signaling. Functional desensitization of hypothalamic 5-HT(2A) receptors was assessed via a reduction in oxytocin and adrenocorticotropin (ACTH) responses to the 5-HT(2A/2C) receptor agonist (-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl [(-)DOI]. We report here that a single systemic injection of the 5-HT(1A) receptor agonist (+)-8-hydroxy-2-(di-n-propylamino)-tetralin [(+)8-OH-DPAT] (200 microg/kg) significantly reduced the 5-HT(2A) receptor-mediated oxytocin responses for at least 72 h. Direct intraparaventricular injection of (+)8-OH-DPAT (0.2 nmol) 24 h before a submaximal dose of (-)DOI (0.35 mg/kg) significantly inhibited the 5-HT(2A) receptor-mediated increases in both oxytocin and ACTH (-39 and -16%, respectively). In addition, the (+)8-OH-DPAT-induced desensitization of the 5-HT(2A) receptor-mediated oxytocin but not the ACTH response was inhibited in rats pretreated with either a systemic (0.1 mg/kg) or intraparaventricular (10 nmol) injection of the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY100635). This is the first in vivo demonstration of a prolonged heterologous intracellular desensitization of 5-HT(2A) receptors after acute activation of 5-HT(1A) receptors. These findings may provide insight into the long-term heterologous interactions between 5-HT(1A) and 5-HT(2A) receptor signaling that could occur in response to antidepressants, antipsychotics, or drugs of abuse that target these receptor subtypes.