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

Abstract

Past studies have suggested that progesterone-derived ovarian hormones contribute to the discriminative stimulus effects of ethanol, particularly via progesterone metabolites that have activity at γ-aminobutyric acid type A (GABAA) receptors. It is unknown whether loss of ovarian hormones in women, for example, after menopause, may be associated with altered receptor mediation of the effects of ethanol. The current study measured the substitution of allopregnanolone, pregnanolone, pentobarbital, midazolam, dizocilpine, TFMPP, and RU 24969 in female sham and ovariectomized (OVX) rats trained to discriminate 1.0 g/kg ethanol from water. The groups did not differ in the substitution of GABAA-positive modulators (barbiturates, benzodiazepines, neuroactive steroids) or the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine. Similarly, blood-ethanol concentration (BEC) did not differ between the groups, and plasma adrenocorticotropic hormone (ACTH), progesterone, pregnenolone, and deoxycorticosterone (DOC) were unchanged 30 min after administration of 1.0 g/kg ethanol or water. However, substitution of neuroactive steroids and RU 24969, a 5-HT1A/1B receptor agonist, was lower than observed in previous studies of male rats, and TFMPP substitution was decreased in OVX rats. Ovarian hormones appear to contribute to 5-HT receptor mediation of the discriminative stimulus effects of ethanol in rats.

Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol

“…Finally, the neurosteroid substitution patterns for ethanol suggest sex differences in sensitivity. For example, in contrast to earlier studies in male rats [33, 34], female rats showed only partial substitution of allopregna-nolone and pregnanolone for a 1 g/kg ethanol training dose [36]. This latter finding is consistent with earlier work demonstrating that females were less sensitive to the modulatory effects of allopregnanolone on ethanol drinking behavior when compared to males [37].…”

“…From an initial characterization of several 5-HT receptor agonists in rats, the only compound to yield full substitution for ethanol in rats was TFMPP, a relatively nonselective 5-HT 1 agonist with slightly greater affinity for the 1A isoform [65]. This finding with TFMPP was replicated in both male [21] and female [36] rats. Subsequent evaluations of multiple compounds with various 5HT receptor agonist profiles in male rats revealed that CGS 12066B and CP 94,253 (both selective for 5-HT 1B ) or mCPP and RU 24969 (both selective for 5-HT 1B/2C ) fully generalized from ethanol (1 g/kg), whereas 8-OH DPAT (5-HT 1A ) and DOI (5-HT 2A ) did not 66–68].…”

“…A parallel set of antagonism studies used subtype selective antagonists to completely block the ethanol-like effects of CP 94,253 and mCPP [67], leading to an overall conclusion that 5-HT 1B and 5-HT 2C receptors contribute to the ethanol cue. However, there are inconsistencies in the generalizability of 5-HT 1B/2C agonists to substitute for ethanol across sex and species, as RU 24969 only partially substituted for ethanol in female rats [36] and mCPP did not generalize from ethanol in mice [64]. Refinement of receptor ligands with increased selectivity for 5-HT 1 and 5-HT 2 receptor isoforms (e.g., [69, 70]) coupled with a rapid expansion of novel ligand development for 5-HT 4 receptors, which also function to regulate neurotransmission in conjunction with 5-HT 1 and 5-HT 2 receptors [71, 72], should prompt a fresh look at the involvement of metabotropic 5-HT receptors in modulating the discriminative stimulus effects of ethanol.…”

Activation of mGluR2/3 following stress hormone exposure restores sensitivity to alcohol in rats

“…This limitation may be addressed by the utilization of a three-choice (e.g., alcohol, water, lysergic acid diethylamide-LSD) drug discrimination procedure (Grant, 1999), that could behaviorally capture a qualitative shift from the stimulus being less alcohol-like, and more like another stimulus (LSD, for example). Additionally, given the complexity of the alcohol discriminative stimulus (e.g., contribution of various transmitter systems: Helms, McCracken, Heichman, & Moschak, 2013; Hodge & Cox, 1998; Kostowski & Bieńkowski, 1999; Platt & Bano, 2011) it is unlikely that manipulation of one system (glutamate) would completely block expression of the interoceptive effects of alcohol, as we had predicted.…”