Involvement of Aldehydes in Alcohol Addiction

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This is an exploratory (R21) grant to examine the involvement of acetaldehyde (ACD) and tetrahydroisoquinolines (THIQs) in alcohol addiction. The overall hypothesis to be tested is that the formation of ACD and THIQs contribute to alcohol addiction. The goals of the present application are to examine the reinforcing effects of ACD and salsolinol (SAL) within the mesolimbic dopamine (DA) system of the rat. The following hypotheses will be tested in the present proposal: (a) ACID and SAL are reinforcing within the ventral tegmental area (VTA) of alcohol-preferring (P) rats; (b) SAL is reinforcing within the nucleus accumbens (NAC) shell of P rats; and (c) ACD and SAL potentiate ethanol reinforcement within the VTA of P rats. These hypotheses will be tested using the intracranial self-administration (ICSA) technique to examine the reinforcing actions of ACD and/or SAL within the VTA and/or NAC of P rats. Preliminary data indicate that female P rats self- administer 6 - 90 NM ACD directly into the posterior VTA. The present application will extend these findings using male P and Wistar rats. Specific aim 1 will examine the dose-response effects of ACD within the anterior VTA, as well as in regions adjacent to the VTA, to establish the site for the reinforcing effects of ACD. This aim will also examine extinction and reinstatement for the ICSA of ACD in the posterior VTA. In addition, specific aim 1 will compare the dose-response effects for the ICSA of ACD in the posterior VTA of P and Wistar rats. Specific aim 2 will examine the dose-response effects of SAL within the VTA and NAC of P rats. Specific aim 3 will examine the effects of ACD or SAL on the reinforcing effects of ethanol in the posterior VTA of P rats. In addition, this aim will examine whether conversion of ethanol to ACD may under- lie the ICSA of ethanol into the posterior VTA of P rats by co-infusing a catalase inhibitor with ethanol. The results of this study will provide information on the effects of ACD and SAL within the mesolimbic system, which could indicate a direct reinforcing effect of these compounds themselves and/or a potentiating effect of these compounds on the reinforcing properties of ethanol. Such results could provide valuable information on novel mechanisms underlying the addictive properties of alcohol and would provide a firm scientific foundation for future neurobiological studies.