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RSA 2005 Abstracts
MEDICAL UNIVERSITY OF SOUTH CAROLINA, CHARLESTON
NUCLEUS ACCUMBENS HOMER2 OVER-EXPRESSION REVERSES THE ETHANOL PHENOTYPE OF HOMER2 MUTANT MICE
E.B. Oleson, K. Welt, K.D. Lominac, P.W. Kalivas, K.K. Szumlinski
Dept. of Physiology and Neuroscience and Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SCMice with a null deletion of Homer2 exhibit marked aversion to higher ethanol doses as revealed by ethanol consumption and conditioned place preference. Moreover, Homer2 mutant mice do not exhibit behavioral adaptation following repeated ethanol administration, an effect associated with a lack of glutamate sensitization in the nucleus accumbens. To determine an active role for Homer2 in the ethanol behavioral and neurochemical phenotype of Homer2 mutant mice, an adeno-associated virus (AAV) carrying the Homer2b splice variant was infused locally into the nucleus accumbens of wild-type (WT) and Homer2 mutant mice and genotypic differences in the behavioral and neurochemical effects of repeated ethanol were assessed. Intra-accumbens AAV-Homer2 infusion shifted the dose-response function for ethanol preference to the left in both WT and mutant mice and enhanced ethanol consumption, but only in WT mice. Intra-NAC AAV-Homer2 infusion also reversed the genotypic difference in place conditioning, as well as the sensitization of locomotion, and ethanol-induced increases in extracellular glutamate produced by the repeated administration of 3 g/kg ethanol (8 injections). These data strongly indicate an active and necessary role for accumbens Homer2 expression in the neural plasticity underlying the rewarding and psychomotor-activating effects of ethanol. If relevant to humans, these data suggest that polymorphisms in Homer2 may be a genetic regulator of vulnerability to excessive alcohol consumption. Supported by NIMH grant MH-40817 and NIDA grant DA-03906 to PWK and NIAAA grant P50 AA010761 and NIAAA grant (pilot project-INIA West) to KKS.
POTENTIATION OF ALCOHOL REWARD BY ACCUMBENS HOMER2 OVER-EXPRESSION IN THE ALCOHOL-PREFERRING C57BL/6J MOUSE
K.K. Szumlinski, K.D. Lominac, P.W. KalivasDept. of Physiology and Neuroscience and The Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC
Accumulating evidence derived from behavioral studies of Homer2 KO mice implicate an active role for accumbens Homer2 expression in vulnerability to excessive alcohol consumption. To further characterize a role for Homer2 expression in excessive alcohol consumption, an adeno-associated virus (AAV) carrying Homer2b was infused into the nucleus accumbens of male C57BL/6 mice and the effects of Homer2 over-expression were assessed on measures of alcohol reward, reinforcement and changes in locomotor activity. AAV-Homer2b infused mice exhibited increased alcohol reward as revealed by a shift to the left in dose-response function for alcohol preference in a 2-bottle choice task and a shift upwards in the dose-response function for alcohol self-administration in an operant paradigm when the animals were tested under postprandial, but not preprandial, conditions. AAV-Homer2b infusion facilitated the development of tolerance to the locomotor inhibitory effects of repeated alcohol administration (8 X 2 g/kg). However, AAV-Homer2b infused mice did not express conditioned approach behavior towards the environment paired with repeated alcohol administration, a finding possibly reflecting enhanced sensitivity to the aversive properties of drug. Collectively, these data indicate that accumbens Homer2b over-expression can potentiate alcohol reward in mice with a genetic predisposition to excessive alcohol consumption. These data further the theory that polymorphisms in Homer2, and perhaps also genes encoding other Homer proteins, contribute to genetic variance in alcohol consumption. Supported by NIH grants MH-40817 and DA-03906 to PWK and NIAAA grants P50 AA010761 and INIA West (pilot project) to KKS.
SUBTLE, BUT SIGNIFICANT, DIFFERENCES IN THE EFFECTS OF MGLUR1A VERSUS MGLUR5 BLOCKADE ON MEASURES OF ETHANOL REWARD IN B6 MICE
K.D. Lominac, R. Hannun, L.D. Middaugh, K.K. SzumlinskiDept. of Physiology and Neuroscience, Dept. Psychiatry and Behavioral Science and The Charleston Alcohol Research Center, Medical University of South Carolina, Charleston, SC
The mGluR5 subtype of Group 1 metabotropic glutamate receptors (mGluRs) is implicated in mediating ethanol reward yet the role for the mGluR1a remains under-characterized. The present study compared the capacity of the selective mGluR5 antagonist MPEP and the selective mGluR1a antagonist CPCCOEt to inhibit the rewarding and reinforcing effects of ethanol in the ethanol-preferring C57BL/6J mouse. Pretreatment (30 min earlier) with either MPEP (0-30 mg/kg, IP) or CPCCOEt (0-10 mg/kg, IP) dose-dependently reduced measures related to operant responding for 12% ethanol when the mice were tested under postprandial conditions. Although both drugs reduced operant responding for water, their effects were dose-independent. Pretreatment with 10 mg/kg MPEP or CPCCOEt completely blocked the expression of place conditioning induced by 8 injections of 2 g/kg EtOH, without altering spontaneous locomotor activity. Moreover, daily pretreatment with 10 mg/kg MPEP or CPCCOEt reduced ethanol consumption in a 4-bottle choice task under 24 hr free-access conditions in the home cage. Interestingly, while MPEP decreased preference for 6% EtOH only, CPCCOEt pretreatment shifted preference from 12% to 6% EtOH, indicating a shift to the left in the EtOH preference function. Consistent with this latter finding, pretreatment with CPCCOEt, but not MPEP, facilitated the expression of motor impairment induced by 2 g/kg EtOH. Collectively, these behavioral data indicate that both mGluR1a and mGluR5 blockade can reduce EtOH reward and reinforcement in C57BL/6J mice. However, it appears that the mechanisms through which these drugs exert their effects are different; MPEP produces a reduction in the rewarding efficacy of EtOH, whereas CPCCOEt appears to enhance sensitivity to the behavioral effects of EtOH. Supported by NIAAA grants (P50-AA10761) to LDM and KKS, as well as NIAAA grant (pilot project)INIA West to KKS.
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