Motivational Effects of Ethanol in DARPP-32 Knock-Out Mice

Abstract

DARPP-32 (dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein, 32 kDa) is an important component of dopaminergic function in brain areas thought to be important for drug and alcohol addiction. The present experiments characterized the acquisition of ethanol-induced conditioned taste aversion, ethanol-induced conditioned place preference, and ethanol self-administration in DARPP-32 knock-out (KO) mice compared to wild-type (WT) controls. For taste conditioning, KO and WT mice received access to 0.2 m NaCl solution followed immediately by intraperitoneal injection of 0-4 gm/kg ethanol. Ethanol produced dose-dependent conditioned taste aversion that was the same in both genotypes. For place conditioning, KO and WT mice received eight pairings of a tactile stimulus with ethanol (2 gm/kg, i.p.), and a different stimulus with saline. Ethanol produced increases in locomotor activity during conditioning, with KO mice showing higher activity levels after ethanol compared to WT mice. WT mice, but not KO mice, acquired conditioned preference for the ethanol-paired stimulus. In the self-administration procedure, KO and WT mice were trained to lever press for access to 10% v/v ethanol. Subsequently, the mice had 23 hr/d access to food, ethanol, and water. Response patterns were determined using 0-30% v/v ethanol concentrations. WT mice displayed concentration-dependent responding for ethanol. Responding on the ethanol lever by KO mice did not change as a function of ethanol concentration. Saccharin (0.2% w/v) was subsequently added to the ethanol mixture, and responding was examined at 0, 5, 10, and 20% ethanol concentrations. Ethanol responding increased in both genotypes, although WT mice showed higher rates at all concentrations.

Deletion of N-Type Calcium Channels Alters Ethanol Reward and Reduces Ethanol Consumption in Mice

“…This striking result led us to investigate the motivational effects of ethanol in Ca v 2.2 null mice. We observed that Ca v 2.2 null mice developed place preference for a low dose of ethanol (1.2 gm/kg) that is not rewarding to wild-type mice but did not develop place preference to 2 gm/kg ethanol, which was rewarding to wild-type littermates and is the standard dose used in mouse ethanol place-conditioning studies (Risinger et al, 2001;Dickinson et al, 2003). In contrast, Ca V 2.2 null mice developed conditioned taste aversion when administered 2 gm/kg ethanol, although this was reduced in magnitude when compared with wild-type animals.…”

“…Of the total time spent in the two conditioning chambers, wild-type mice spent 57% and null mice spent 53% in the black side during the habituation session. Because the magnitude of this preference for the black side was small and was not significantly different between the two genotypes ( p ϭ 0.089; two-tailed t test), we used an unbiased protocol for conditioning (Risinger et al, 2001;Dickinson et al, 2003). Mice were conditioned to ethanol (1.2, 2.0, or 2.8 gm/kg v/v in 0.9% saline, i.p.)…”

“…4 A, B), which measures an animal's preference for a context associated with administration of a drug (Tzschentke, 1998). We trained animals with 2 gm/kg ethanol, a dose that establishes strong place preference in mice (Risinger et al, 2001;Dickinson et al, 2003). Wild-type mice showed a robust place preference for ethanol ( p ϭ 0.0093; Wilcoxon signed rank test) that was completely absent in Ca v 2.2 null mice ( p Ͼ 0.05).…”

Evidence for the Role of Histamine H3 Receptor in Alcohol Consumption and Alcohol Reward in Mice

“…However, later studies have shown that the place preference can be induced to B6 mice by increasing the number of conditioning sessions with alcohol (Risinger et al, 2001;Boyce-Rustay and Risinger, 2003). Here, we used an extended protocol with six alcohol and six saline conditioning sessions, which resulted in a significant CPP in the WT animals.…”

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

“…Activation of D1 receptors prevents the dephosphorylation of the NR1 subunit via a cascade that involves phosphorylation of PKA, which in turn phosphorylates dopamine and cAMP-regulated phosphoprotein-32 kDa (DARPP-32), which then inhibits the activation of PP1 phosphatase acting on the NR1 subunit [195]. Via this cascade, D1 receptor promotion of drug reinforcement, as might arise from prior exposure to drugs of abuse, reduces the sensitivity of NMDARs to blockade by ethanol [126] and may increase the motivational effects of ethanol [179].…”