| Description |
Drugs of abuse, including ethanol, have rewarding and aversive effects, and the balance between them determines drug intake. Although the role of rewarding effects in drug intake has been characterized from a behavioral, neuroanatomical and neurobiological standpoint, the neural mechanisms and neural circuitry underlying aversion to drugs of abuse has not been investigated. The purpose of my dissertation was to dissect the neural circuitry underlying aversion to ethanol. The lateral habenula (LHb) plays an important role in learning driven by aversive outcomes, likely due to the negative modulation of midbrain monoaminergic systems. However, the role of the LHb in regulating ethanol intake is not known. To begin characterizing the role of the LHb in ethanol-directed behaviors, I studied voluntary ethanol consumption, operant self-administration, yohimbine-induced reinstatement of ethanol-seeking, and conditioned taste aversion (CTA) in sham- and LHb-lesioned rats. I found that lesions of the LHb increase the rate of escalation of ethanol intake, increase operant ethanol-seeking, block yohimbine-induced reinstatement of ethanol-seeking, and attenuate ethanol-induced conditioned aversion. My results suggest that the LHb contributes to multiple facets of ethanol-directed behaviors, likely by mediating learning driven by the aversive effects of ethanol. I further investigated the afferents and efferents of the LHb that may be critical for ethanol-associated iv behaviors. I found that the lesions of the rostromedial tegmental nucleus (RMTg), a major efferent target of the LHb, increased voluntary ethanol consumption and accelerated extinction of ethanol-induced CTA. Thus, the LHb and RMTg play complementary roles in regulation of voluntary ethanol intake, most likely by mediating persistence of ethanol-induced aversive effects. With regard to the afferents of the LHb, my results show that the projection from the lateral hypothalamus (LH) to the LHb is critical for regulation of voluntary ethanol intake. Thus, I propose that the LH-LHb-RMTg circuit may be critical in regulation of ethanol intake. |
