Abstract:The effects of social isolation on behavior, neuroactive steroid concentrations, and GABA A receptor function were investigated in rats. Animals isolated for 30 days immediately after weaning exhibited an anxiety-like behavioral profile in the elevated plus-maze and Vogel conflict tests. This behavior was associated with marked decreases in the cerebrocortical, hippocampal, and plasma concentrations of pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone compared with those apparent for group-housed rats; in contrast, the plasma concentration of corticosterone was increased in the isolated animals. Acute footshock stress induced greater percentage increases in the cortical concentrations of neuroactive steroids in isolated rats than in group-housed rats. Social isolation also reduced brain GABA A receptor function, as evaluated by measuring both GABA-evoked Cl Ϫ currents in Xenopus oocytes expressing the rat receptors and tert-[ 35 S]butylbicyclophosphorothionate ([ 35 S]TBPS) binding to rat brain membranes. Whereas the amplitude of GABAinduced Cl Ϫ currents did not differ significantly between group-housed and isolated animals, the potentiation of these currents by diazepam was reduced at cortical or hippocampal GABA A receptors from isolated rats compared with that apparent at receptors from group-housed animals. Moreover, the inhibitory effect of ethyl-␤-carboline-3-carboxylate, a negative allosteric modulator of GABA A receptors, on these currents was greater at cortical GABA A receptors from socially isolated animals than at those from group-housed rats. Finally, social isolation increased the extent of [ 35 S]TBPS binding to both cortical and hippocampal membranes. The results further suggest a psychological role for neurosteroids and GABA A receptors in the modulation of emotional behavior and mood.

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The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.

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Social isolation of rats both reduces the cerebrocortical and plasma concentrations of 3a-hydroxy-5a-pregnan-20-one (3a,5a-TH PROG) and 3a,5a-tetrahydrodeoxycorticosterone and potentiates the positive effects of acute stress and ethanol on the concentrations of these neuroactive steroids. We now show that social isolation decreased the plasma level of adrenocorticotropin (ACTH), moreover, intracerebroventricular administration of corticotropin releasing factor (CRF) induced a marked increase in the plasma corticosterone level in both isolated and group-housed rats, but this effect was significantly greater in the isolated rats (+121%) than in the group-housed rats (+86%). In addition, in isolated rats, a low dose of dexamethasone had no effect on the plasma corticosterone concentration, whereas, a high dose significantly reduced it; both doses of dexamethasone reduced plasma corticosterone in group-housed rats. Furthermore, the corticosterone level after injection of dexamethasone at the high dose was significantly greater in the isolated animals than in the group-housed rats. These results suggest that social isolation increased sensitivity of the pituitary to CRF and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis.

3 Intraperitoneal administration of CB compounds (3 ± 50 mg kg 71 ) induced a dose-dependent increase in the concentrations of neuroactive steroids in plasma and brain. The brain concentrations of pregnenolone, progesterone, allopregnanolone and allotetrahydrodeoxycorticosterone (THDOC) showed maximal increases in 96+3, 126+14, 110+12 and 70+13% above control, respectively, 30 to 60 min after injection of CB 34 (25 mg kg 71 ). CB 34 also increased the brain concentrations of neuroactive steroids in adrenalectomized-orchiectomized rats, although to a lesser extent than in sham-operated animals, suggesting that CB compounds stimulate brain steroidogenesis independently of their e ects on peripheral tissues. 4 The increase in brain and plasma neurosteroid content induced by CB 34 was associated with a marked anticon¯ict e ect in the Vogel test. Our results indicate that the three CB compounds tested are speci®c and potent agonists at peripheral benzodiazepine receptors, and that they stimulate steroidogenesis in both the brain and periphery.