Overlapping, but not identical, discriminative stimulus effects of the neuroactive steroid pregnanolone and ethanol

Abstract

Many behavioral effects of neuroactive steroids are mediated by GABA(A) receptors; however, other receptors might be involved. Ethanol has a complex mechanism of action, and many of the same receptors have been implicated in the effects of neuroactive steroids and ethanol. The goal of this study was to determine whether actions of neuroactive steroids and ethanol at multiple receptors result in similar discriminative stimulus effects. Rats discriminated 5.6 mg/kg of pregnanolone while responding under a fixed-ratio 20 schedule of food presentation. Pregnanolone, flunitrazepam and pentobarbital produced >80% pregnanolone-lever responding. In contrast, neither morphine nor the negative GABA(A) modulator beta-CCE substituted for pregnanolone up to doses that markedly decreased response rates. Ethanol substituted only in some rats; in other rats, ethanol produced <20% pregnanolone-lever responding up to rate-decreasing doses. Thus, substitution of positive GABA(A) modulators, and not morphine or beta-CCE, for pregnanolone in all rats suggests that positive modulation of GABA(A) receptors is important in the discriminative stimulus effects of pregnanolone. Although pregnanolone might have actions at other receptors, in addition to actions at GABA(A) receptors, substitution of ethanol for pregnanolone only in some rats suggests that the mechanisms of action of pregnanolone and ethanol overlap, but are not identical.

Discriminative stimulus effects of pregnanolone in rats: role of training dose in determining mechanism of action

“…During this period of testing, rate-decreasing effects were evident following administration of the training dose in each rat discriminating 7.5 mg/kg from vehicle. This apparent increased sensitivity to pregnanolone has been observed previously when large training doses of pregnanolone were used (rate-decreasing effects: Gerak et al 2008; seizures: Shannon et al 2005). When these rate-decreasing effects were observed, the training dose was temporarily decreased to 5.6 mg/kg and the frequency of vehicle training sessions was increased.…”

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

“…Given the opposing ways in which pregnanolone and DHEA interact with the GABA A receptor complex, however, pregnanolone would likely serve more as a “substitution” therapy than DHEA. Consistent with this notion are data from this laboratory and others demonstrating that pregnanolone and other 3α-hydroxy neurosteroids have largely overlapping discriminative stimulus effects with ethanol (Bowen, Purdy, & Grant, 1999; Gerak, Moerschbaecher, & Winsauer, 2008; Ginsburg & Lamb, 2005), whereas DHEA and its sulfated form do not (Bienkowski & Kostowski, 1997; Gurkovskaya & Winsauer, 2009). There are also published data indicating that pregnanolone has reinforcing and discriminative stimulus effects in monkeys similar to the barbiturates, another class of drugs that positively modulate the GABA A receptor complex (Rowlett et al, 1999).…”

Ovarian hormones and the heterogeneous receptor mechanisms mediating the discriminative stimulus effects of ethanol in female rats

“…However, additional receptor subtypes not tested include sigma receptors and metabotropic glutamate receptors (Besheer et al , 2006). For example, previous studies reported bidirectional substitution of ethanol and pregnanolone in some rats (Bowen et al , 1999; Gerak et al , 2008), and a sigma receptor agonist fully substituted for pregnanolone (Engel et al , 2001), and for ethanol (Hundt et al , 1998). Variation in endogenous hormones could therefore affect the contribution of these receptor subtypes not included in the current study, particularly sigma receptors.…”