Sensitivity to the locomotor stimulant effects of ethanol and allopregnanolone is influenced by common genes.

Abstract

Allopregnanolone is a neuroactive steroid that, like ethanol (EtOH), has stimulant, anxiolytic, ataxic, and depressant effects. Two experiments tested the hypothesis that sensitivity to the locomotor stimulant effects of these drugs is influenced by a common set of genes. Sensitivity to the locomotor stimulant effects of allopregnanolone was determined in 24 BXD recombinant inbred (RI) strains. Strain means were positively correlated with extant means for EtOH stimulation in 20 of the same strains. Quantitative trait locus (QTL) analysis provisionally identified many loci, including several known to influence sensitivity to EtOH. Sensitivity to allopregnanolone was also measured in FAST and SLOW mice, which were selectively bred for differential locomotor response to EtOH, to determine whether selection has also altered allopregnanolone sensitivity. FAST mice were more sensitive to the stimulant effects of allopregnanolone compared with SLOW mice. These data suggest that sensitivity to the locomotor stimulant effects of these drugs is influenced by common genes.

Allopregnanolone influences the consummatory processes that govern ethanol drinking in C57BL/6J mice

“…Because systemically-administered ALLO has been previously shown to produce locomotor stimulation in B6 mice [27], it was necessary to demonstrate a dissociation between ALLO's effects on ethanol self-administration versus general locomotor activity. The absence of locomotor effects with 100 and 400 ng ALLO is congruent with the unpublished observation that doses in excess of 1 μg were required to elicit locomotor stimulation when administered intra-VTA (Phillips & Finn, unpub).…”

Alcohol-Induced c-Fos Expression in the Edinger-Westphal Nucleus: Pharmacological and Signal Transduction Mechanisms

“…In particular, 10 mg/kg 3␣5␣-P produced a modest, statistically insignificant increase in c-Fos expression, whereas the 20 mg/kg 3␣5␣-P showed a significant increase in EW c-Fos expression. This dose of 3␣5␣-P in mice is expected to produce a similar locomotor response to 2.4 g/kg ethanol (Palmer et al, 2002). Therefore, higher doses of 3␣5␣-P were not included.…”

Allopregnanolone does not influence ethanol-induced conditioned place preference in DBA/2J mice

“…ALLOP and finasteride were stirred daily, with fresh preparations made weekly; and were administered intraperitoneally (10 ml/kg for all doses). Doses were determined from previous research (Finn et al 1997a(Finn et al , 2000VanDoren et al 2000;Palmer et al 2002).…”

“…Increased EtOH self-administration following ALLOP administration may reflect either enhancement or attenuation of EtOH's reinforcing effect. As well, effects of ALLOP on activity (Finn et al 1997a;Janak et al 1998;Palmer et al 2002) may present problems in tasks dependent upon voluntary activity. In contrast, place conditioning assesses a drug's conditioning potential by measuring an animal's tendency to approach a stimulus that was previously paired with the drug in a Pavlovian conditioning paradigm.…”