Sex-dependent behavioral effects of the neurosteroid allopregnanolone (3alpha,5alpha-THP) in neonatal and adult rats after postnatal stress.

The neuroactive steroid allopregnanolone (3a-hydroxy-5a-pregnan-20-one, 3alpha,5alpha-THP) has been shown to be involved in the central nervous system's response to stress. This experiment investigated whether response to the neuroactive steroid allopregnanolone, a positive modulator of the GABA(A) receptor, would be altered in neonatal or adult rats previously exposed to a chronic stressor-daily maternal separation during the first week of life. Subjects were then tested either as neonates or adults. In neonates, allopregnanolone decreased the number of ultrasonic vocalizations after brief maternal separation. Previously separated subjects vocalized less and were less active than controls, but were not more sensitive to allopregnanolone on either measure. In adulthood, subjects with a prior history of maternal separation had a greater grooming response to a novel environment after a 10-min cold water swim test than nonseparated subjects. Allopregnanolone reduced grooming, but, again, there was no difference due to stress history. A significant effect of gender was noted in the adult subjects--females were largely responsible for the effects reported. These results suggest that early maternal separation stress can produce an habituation response in neonates and a long-term sensitization response to later novel stress in adults. However, because the behavioral effects of allopregnanolone were not differentially influenced by this early stress history, the neuroactive steroid/GABA(A) receptor complex may not be the major mediator of these early stress sequela. Results indicating that females were more responsive to allopregnanolone than males are discussed in light of previous findings.

In vivo microdialysis assessment of extracellular serotonin and dopamine levels in awake monkeys during sustained fluoxetine administration.

Fluoxetine (FLU) rapidly enhances extracellular (EC) serotonin (5-HT) in rodent brain, whereas the antidepressant effects of this drug in humans are typically not observed for 2-3 weeks. Thus, the effects of chronic oral FLU administration on neocortical and hippocampal EC 5-HT, and on caudate EC 5-HT and dopamine (DA), were examined in awake monkeys (Macaca fascicularis) using in vivo microdialysis (10.0 mg/kg; 3, 7, 14, and 21 days). On day 3, 5-HT was significantly increased above baseline levels in hippocampus (HC) and caudate. There was a trend for an increase in neocortex EC 5-HT levels. However, by day 7 5-HT remained significantly elevated only in HC, although 5-HT levels elsewhere had not completely returned to baseline. In contrast, levels of the 5-HT metabolite, 5-HIAA, were significantly reduced in all brain regions at all time points. Caudate DA levels tended to be decreased throughout FLU treatment. Local FLU and K(+) infusion were also used at various times during chronic systemic FLU administration to evaluate changes in functional synaptic regulation. In general, these results, along with the significant decrease in 5-HIAA levels and the tendency for basal EC 5-HT levels to remain modestly elevated only in HC during sustained FLU administration, suggest a reduction in releasable pools of 5-HT. Taken together with the trend for a decrease in caudate EC DA levels, these results do not appear to support the current hypothesis regarding the mechanism of action of SSRI antidepressants-that monoaminergic neurotransmission is progressively augmented during chronic treatment.