Dopamine dynamics associated with, and resulting from, schedule-induced alcohol self-administration: analyses in dopamine transporter knockout mice

Abstract

Preclinical and clinical evidence suggest an association between alcoholism and the primary regulator of extracellular dopamine concentrations, the dopamine transporter (DAT). However, the nature of this association is unclear. We determined if ten days of voluntary alcohol self-administration followed by withdrawal could directly alter DAT function, or if genetically-mediated changes in DAT function and/or availability could influence vulnerability to alcohol abuse. Heterozygous (DAT+/-) and homozygous mutant (DAT-/-) and wildtype (DAT+/+) mice were allowed to consume 5% alcohol in a schedule-induced polydipsia (SIP) task. In vivo fixed potential amperometry in anesthetized mice was used to (1) identify functional characteristics of mesoaccumbens dopamine neurons related to genotype, including dopamine autoreceptor (DAR) sensitivity, DAT efficiency, and DAT capacity, (2) determine if any of these characteristics correlated with alcohol drinking observed in DAT+/+ and DAT+/- animals, and (3) determine if SIP-alcohol self-administration altered DAR sensitivity, DAT efficiency, and DAT capacity by comparing these characteristics in wildtype (DAT+/+) mice that were SIP-alcohol naïve, with those that had undergone SIP-alcohol testing. DAT-/- mice consumed significantly less alcohol during testing and this behavioral difference was related to significant differences in DAR sensitivity, DAT efficiency, and DAT capacity. These functional characteristics were correlated to varying degrees with g/kg alcohol consumption in DAT+/+ and DAT+/- mice. DAR sensitivity was consistently reduced and DAT efficiency was enhanced in SIP-alcohol experienced DAT+/+ mice in comparison to naïve animals. These results indicate that DAR sensitivity is reduced by SIP-alcohol consumption and that DAT efficiency is modified by genotype as well as SIP-alcohol exposure. DAT capacity appeared to be strictly associated with SIP-alcohol consumption.

Poor inhibitory control and neurochemical differences in high compulsive drinker rats selected by schedule-induced polydipsia

“…Because of its characteristics of 'excessiveness' and 'persistence', SIP has been used as a model for compulsive responding in OCD, schizophrenia, alcohol abuse and predisposition to drug addiction (Gilpin et al 2008;Hawken et al 2011;Mittleman et al 2003Mittleman et al , 2011Myracle et al 2005; for review, Platt et al 2008;Rosenzweig-Lipson et al 2007;Schechter et al 2008;Wayner 2002). Moreover, chronic psychiatric inpatients frequently engage in psychogenic polydipsia (de Leon et al 1994(de Leon et al , 2002.…”

Schedule-induced polydipsia as a model of compulsive behavior: neuropharmacological and neuroendocrine bases

“…Moreover, in SIP, the substitution of water for ethanol solution-induced equivalent levels of consumption has been considered as a promising behavioral model of alcohol abuse, relating directly to the induction of compulsive alcohol drinking (Gilpin et al 2008;Mittleman et al 2003Mittleman et al , 2011Singer et al 1982;Singer and Wallace 1984;Wayner 2002). Schedule induction and ethanol polydipsia provide an opportunity to investigate the development of drinking typologies that lead to chronic, excessive voluntary alcohol consumption in animals (Colotla 1981;Falk and Tang 1988), as well as the neural substrates and pharmacology of alcohol addiction (Escher and Mittleman 2006;Mittleman et al 2011).…”

“…Because of its characteristics of "excessiveness" and "persistence," growing evidence points to schedule-induced polydipsia (SIP) as a candidate model for the study of neuropsychiatric disorders presenting with compulsive behavior such as OCD, schizophrenia (Hawken et al 2011;Rosenzweig-Lipson et al 2007;Schechter et al 2008;Woods-Kettelberger et al 1997; for review, see Platt et al 2008), and alcohol abuse (Gilpin et al 2008;Mittleman et al 2003Mittleman et al , 2011Wayner 2002). The SIP model is characterized by the development of an adjunctive behavior of excessive drinking in food-deprived animals exposed to intermittent food-reinforcement schedules (Falk 1961(Falk , 1971.…”

Applications of schedule-induced polydipsia in rodents for the study of an excessive ethanol intake phenotype

“…Destruction of dopamine terminals within the mesolimbic dopamine circuitry (i.e., nucleus accumbens and olfactory tubercle) in rats via bilateral 6-hydroxydopamine lesions prevented acquisition of water SIP (Robbins & Koob, 1980). Mice with a genetically engineered deletion of the dopamine transporter (DAT) exhibited a diminished acquisition of ethanol SIP with access to a 5% solution (Mittleman et al, 2011), although earlier work with a two-bottle choice procedure showed that neither male nor female DAT knockout mice displayed differences in ethanol consumption versus wild-type controls when a comparable 4% solution was offered (Hall, Sora, & Uhl, 2003). The apparent disparity between these observations may reflect the differential roles of dopaminergic signaling in the context of non-regulatory (SIP) versus regulated (two-bottle choice) ethanol consumption, similar to differences noted for adjunctive versus deprivation-induced water drinking following destruction of dopamine terminals within the mesolimbic pathway (Robbins & Koob, 1980).…”