Discriminative stimulus effects of ethanol and 3α-hydroxy-5α-pregnan-20-one in relation to menstrual cycle phase in cynomolgus monkeys ( Macaca fascicularis )

Abstract

The present study was designed to characterize the discriminative stimulus effects of ethanol and the neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) in nonhuman primates as a function of menstrual cycle phase. Female cynomolgus monkeys (Macaca fascicularis) were trained in a two-lever procedure to discriminate 1.0 g/kg ethanol (IG, 30 min pretreatment) from water using food reinforcement. A cumulative dosing procedure was used to assess changes in the potency of ethanol and an endogenous anxiolytic steroid in the follicular versus the luteal phase of the menstrual cycle. Plasma progesterone and allopregnanolone levels were determined within 24 h of testing to verify phase of menstrual cycle. The monkeys were more sensitive to the discriminative stimulus effects of ethanol and the ethanol-like effects of the endogenous neuroactive steroid allopregnanolone during the luteal phase of the menstrual cycle. These findings suggest that changes in the endogenous levels of ovarian-derived progesterone and allopregnanolone alter sensitivity to the discriminative stimulus effects of ethanol.

Effects of menstrual cycle phase on the reinforcing effects of phencyclidine (PCP) in rhesus monkeys

“…The contribution of genomic and non-genomic effects of the steroid hormones with regard to NMDA receptors (McEwen, 2002(McEwen, ,1996 adds to the complexity of potential interactions of estrogen and progesterone with the pharmacological effects of PCP related to its reinforcing effects. Furthermore, progesteronederived neurosteroids, such as pregnanolone and allopregnanolone, are behaviorally active (Grant et al, 1997;Mathis et al, 1996) positive neuromodulators of NMDA receptors (Bowlby, 1993;Irwin et al, 1994;Wu et al, 1991). Allopregnanolone itself has been shown to modulate NMDA-stimulated dopamine release in a progesterone-and estrogen-dependent manner (Cabrera et al, 2002).…”

Alteration of voluntary ethanol and saccharin consumption by the neurosteroid allopregnanolone in mice

“…For example, ALLOP and other neurosteroids that are positive modulators of GABA A receptors produce EtOH-like discriminative stimulus effects in rats and monkeys (Ator et al 1993;Bienkowski and Kostowski 1997;Grant et al 1997;Bowen et al 1999). Conditioned place preference, drug discrimination, and self-administration studies suggest that these neurosteroids possess abuse liability in primates and rodents (Finn et al 1997a;Vanover 1997;Rowlett et al 1999;Sinnott et al 2002).…”

Cortical 3α-hydroxy-5α-pregnan-20-one levels after acute administration of Δ9-tetrahydrocannabinol, cocaine and morphine

“…Allopregnanolone substitutes for ethanol in discriminative stimulus paradigms (Grant et al 1996;Engel and Grant 2001). The reinforcing effect of allopregnanolone varies with menstrual cycle (Grant et al 1997) and is demonstrable only in males of some species (Sinnott et al 2002a). Allopregnanolone administration increases ethanol self-administration (Janak et al 1998) and ethanol reinstatement (Nie and Janak 2003) under some conditions.…”