Discriminative stimulus effects of ethanol, pregnanolone, and dehydroepiandrosterone (DHEA) in rats administered ethanol or saline as adolescents

Abstract

Adolescent alcohol use may produce long-term changes in the receptors and neurosteroids that putatively mediate alcohol's effects and consequently contribute to alcohol abuse and dependence as an adult. To test this possibility, ethanol (0.18-1.8 g/kg) and two neurosteroids, pregnanolone (1-10 mg/kg) and dehydroepiandrosterone (DHEA, 1-100 mg/kg), were administered alone and in combination to adult, male Long-Evans rats discriminating 1 g/kg ethanol (15% v/v) under a fixed ratio (FR) 20 schedule of food presentation after adolescent treatment with 15 injections of ethanol (n=9, 2 g/kg, 20% v/v) or saline (n=7). When compared as adults, ethanol-treated adolescents (as opposed to saline-treated adolescents) had higher percentages of ethanol-lever responding at doses smaller than the training dose, and higher response rates after both control and ethanol injections. Neither pregnanolone nor DHEA substituted for ethanol in either adolescent-treated group up to doses that substantially decreased response rates. When administered with ethanol, 1 and 3.2 mg/kg of pregnanolone enhanced the discriminative stimulus effects of small ethanol doses more in saline-treated adolescents than ethanol-treated adolescents. Unlike pregnanolone, 32 and 100 mg/kg of DHEA attenuated the discriminative stimulus effects of ethanol modestly in both adolescent-treated groups. These results in adult rats suggest that adolescent ethanol administration can enhance the discriminative stimulus effects of small ethanol doses and affect the capacity of pregnanolone, but not DHEA, to interact with ethanol's discriminative stimulus effects.

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).…”

Effects of 7-keto dehydroepiandrosterone on voluntary ethanol intake in male rats

“…7-ketoDHEA (kindly provided by Dr. Henry Lardy, Department of Biochemistry and Institute for Enzyme Research, University of Wisconsin-Madison) was dissolved in a vehicle consisting of 80% (v/v) propylene glycol, 8% polyethylene glycol, and 2% benzyl alcohol. Vehicles for both drugs have been found to be behaviorally inactive in previous studies (Quinton et al, 2005; Quinton et al, 2006; Gurkovskaya and Winsauer 2009). All drugs and control injections were administered intraperitoneally 15 minutes prior to the experimental sessions.…”

Assessment of the interoceptive effects of alcohol in rats using short-term training procedures

“…These procedures have several advantages including stable and reliable performance over time, which allows for within subject testing, and the ability to utilize response rate measures as indices of drug-induced motor effects. These procedures have proved to be important tools for pharmacological and neurobiological characterization of subjective alcohol effects and abuse liability of novel psychoactive compounds (Becker and Baros, 2006; Besheer et al, 2003; Besheer et al, 2012a; Besheer et al, 2012b; Besheer et al, 2009; Besheer and Hodge, 2005; Cannady et al, 2011; Ginsburg and Lamb, 2005; Grant and Colombo, 1993; Griffin et al, 2012; Gurkovskaya and Winsauer, 2009; Helms and Grant, 2011; Helms et al, 2009; Hodge and Cox, 1998; Hodge et al, 2001; Kostowski and Bienkowski, 1999; Platt and Bano, 2011; Platt et al, 2005; Shelton and Grant, 2002); see also (Ator and Griffiths, 2003; Overton, 1987). However, a requirement of these procedures is that stable operant responding (i.e., lever responses on a specific reinforcement schedule) must be trained prior to the initiation of discrimination training.…”