Reverse Selection for Differential Response to the Locomotor Stimulant Effects of Ethanol Provides Evidence for Pleiotropic Genetic Influence on Locomotor Response to Other Drugs of Abuse

Background: Addictive drugs share the ability to induce euphoria, which may be associated with their potential for abuse. Replicate mouse lines with high (FAST-1, FAST-2) and low (SLOW-1, SLOW-2) sensitivity to ethanol-induced psychomotor stimulation (a possible animal model for the euphoria experienced by humans) have provided evidence for common genetic influences (pleiotropy) on sensitivity to the effects of ethanol and of GABA-A receptor acting compounds on locomotor activity. Differences between FAST and SLOW mice in locomotor response to certain other drugs were found later in selection. Reverse selection produced lines (r-FAST-1, r-FAST-2, r-SLOW-1, r-SLOW-2) with similar locomotor responses to ethanol. These lines are well suited for asking whether the same alleles that influence sensitivity to ethanol are also responsible for these later arising differences in drug sensitivity. Methods: Two replicate sets of forward- and reverse-selected FAST and SLOW lines were tested for the effects of multiple doses of morphine, cocaine, methamphetamine, nicotine, and scopolamine on their locomotor behavior. We predicted that differences in drug sensitivity between the FAST and SLOW lines would be reduced or eliminated in the reverse-selected lines. Results: Differences in sensitivity to morphine, cocaine, methamphetamine, and nicotine that arose in earlier generations of the FAST-1 and SLOW-1 lines ultimately also appeared in the FAST-2 and SLOW-2 lines. However, some differences between the FAST-2 and SLOW-2 lines (those in response to cocaine and methamphetamine) were not seen until several generations after selection had been relaxed. In lines reverse-selected for sensitivity to ethanol, differences in sensitivity to the other drugs were decreased, eliminated, or even reversed. No differences in scopolamine response were found in the replicate 1 forward- or reverse-selected lines. However, a small difference in scopolamine response in the replicate 2 lines was reversed. Conclusions: Genes that influence the locomotor response to ethanol also influence locomotor response to other drugs with stimulant effects in the FAST and SLOW mice. The current data most strongly support this conclusion for sensitivity to morphine and nicotine.