Christina N. Lessov

Behavioral sensitization to ethanol: genetics and the effects of stress.

Some aspects of drug abuse syndromes may be influenced by sensitization to some drug effects. This enhancement of drug effect has been associated with prior drug exposure and with exposure to stressful stimuli. It has been postulated that sensitization to psychomotor stimulant drug effects influences sensitivity to drug reward. The drugs of abuse best characterized for sensitization phenomena include cocaine, amphetamine, and morphine. In general, ethanols molecular mechanisms of action have been difficult to define relative to drugs with known receptor or transporter binding sites and, likewise, ethanol sensitization has been less thoroughly examined. Evidence supporting the existence of behavioral sensitization to ethanol, for genetic differences in the occurrence of ethanol sensitization, and for the influence of corticosterone on the development of ethanol sensitization is reviewed herein. There appear to be different genetic determinants of acute drug sensitivity and sensitization. Cross-sensitization between stress and ethanol suggest a potential role for hypothalamic-pituitary-adrenal (HPA) axis associated changes in ethanol sensitization, consistent with mechanisms likely contributing to sensitization to other abused drugs. Furthermore, glucocorticoid receptors appear to mediate both ethanol- and stress-induced sensitization to ethanol. A biological link between drug reward and drug sensitization involving HPA axis hormones may exist and, thus, study of the sensitization process may elucidate mechanisms relevant to drug abuse.

Voluntary ethanol drinking in C57BL/6J and DBA/2J mice before and after sensitization to the locomotor stimulant effects of ethanol

Abstract. Rationale: Drug-induced sensitization has been associated with enhanced drug self-administration and may contribute to drug addiction. Objectives: We investigated the possible association between sensitization to the locomotor stimulant effects of ethanol (EtOH) and voluntary EtOH consumption. Methods: Mice of the EtOH-avoiding DBA/2J (D2) and EtOH-preferring C57BL/6J (B6) inbred strains were offered the choice of an EtOH solution versus tap water (EtOH-experienced) or just water (Naïve), and voluntary consumption was measured. Mice from each condition then received repeated EtOH or saline injections, and locomotor responses were measured. Subsequently, all mice were offered the choice of EtOH versus water, and voluntary consumption was again measured. A subsequent study examined relative susceptibility of D2 and B6 mice to EtOH-induced locomotor sensitization. Results: Voluntary EtOH consumption induced locomotor sensitization to an EtOH challenge in B6 mice. D2 mice consumed little EtOH, but developed sensitization with repeated EtOH treatments as expected. EtOH consumption was not altered in EtOH-sensitized D2 mice. Unexpectedly, B6 mice developed significant sensitization, and following sensitization, the EtOH-experienced EtOH-sensitized group consumed more EtOH than their EtOH-experienced saline-treated (non-sensitized) counterparts. In an independent study, B6 mice required between three and five EtOH injections to express sensitization, whereas for D2 mice, between one and three EtOH exposures were sufficient. Conclusions: Development of sensitization to the locomotor stimulant effects of EtOH may be associated with increased EtOH consumption in mice with high initial avidity for EtOH. In the same mice, voluntary EtOH consumption can also produce behavioral sensitization to the effects of EtOH.

Attenuation of Ethanol-Induced Conditioned Taste Aversion in Mice Sensitized to the Locomotor Stimulant Effects of Ethanol

This study examined the effect of repeated ethanol (EtOH) injections that induced behavioral sensitization on subsequent acquisition of EtOH- and lithium chloride (LiCl)-induced conditioned taste aversion (CTA). CTA acquisition was assessed in independent groups of EtOH-sensitized and nonsensitized genetically heterogeneous female mice after injections of saline; 1, 2, or 4 g/kg EtOH; or 2 or 4 mEq/kg LiCl. Saline and 1 g/kg EtOH did not induce CTA. Four g/kg EtOH and 4 mEq/kg LiCl induced similar levels of CTA in EtOH-sensitized and nonsensitized groups. CTA induced by 2 g/kg EtOH and 2 mEq/kg LiCl was attenuated in EtOH-sensitized mice compared with nonsensitized counterparts. Thus, a sensitizing regimen of EtOH preexposure resulted in both a decrease in EtOH and LiCl aversion and an increase in EtOH locomotor sensitivity; such changes could ultimately contribute to enhanced EtOH intake and potentially to EtOH abuse.