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RSA 2004 Abstracts
MUSC (Medical University of South Carolina)
ETHANOL SENSITIVITY AND NMDA RECEPTOR FUNCTION IN MICE LACKING THE HOMER1 GENE
C.T. Smothers, K.K. Szumlinski, K.D. Lominac, L.D. Middaugh, P.F. Worley, P.W. Kalivas, J.J. Woodward
Dept. of Physiology and Neuroscience and Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC.
It has been shown that N-methyl-D-aspartate (NMDA) receptors are sensivitive to pharmacologically relevant concentrations of ethanol. However, the molecular elements that modulate the ethanol sensitivity of NMDA receptors has yet to be fully elucidated. Molecular scaffolding proteins have been shown to play prominent roles in synaptic development, synaptic plasticity and other neuroadaptive processes. A family of scaffolding proteins called, Homer, have been implicated in influencing spine maturation and linking metabotropic glutamate receptors with ionotropic receptors. Previous data has shown that in Homer2 deletion mice the NMDA current density in 2 week cultured hippocampal neurons is less than that observed in wild-type mice. In this study, we examined the behavioral and electrophysiological responses to ethanol in Homer1 deletion mice. Behaviorally, a genotypic difference was observed in righting reflex times to a 5 g/kg dose of ethanol. The righting times were longer for Homer1 knock-out mice (144.2 +/- 9.1 min; n = 8), in comparsion to wild-type mice (82.8 +/- 11.6 min; n = 7). In two-week old cultured hippocampal neurons the NMDA current density was similar in Homer1 knock-out and wild-type animals. No differences in ethanol inhibition of NMDA currents were observed between knock-out and wild-type hippocampal neurons. This data suggest that different mechanisms are involved in the neuroadaptive processes which underlie synaptic signaling and the actions of ethanol in mice with deletions of specific Homer genes. Supported in part by AA09986 and AA00238 to JJW; DA-11742 to PFW; P50-AA10761 to LDM; MH-40817 and DA-03906 to PWK; and INIA to KKS.
DISSOCIATION BETWEEN HOMER1 AND HOMER2 FUNCTION IN VIVO: ETHANOL PREFERENCE AND GROUP1 MGLUR FUNCTION
K.K. Szumlinski, K.D. Lominac, J.K. Walker, L.D. Middaugh, P.R. Worley, P.W. Kalivas
Dept. of Physiology and Neuroscience and Center for Drug and Alcohol Programs, Medical University of South Carolina, Charleston, SC.
The Homer family of scaffolding proteins are encoded by three genes (Homer1, Homer2 and Homer3) and are critical regulators of glutamate transmission within the mesocorticolimbic system. Earlier behavioural studies using mice with a null deletion of Homer2 revealed a marked aversion to higher ethanol doses as revealed by ethanol consumption and conditioned place preference. The increased aversiveness to ethanol reported for Homer2 knock-out (KO) mice was associated with reduced NMDA and Group1 mGluR function. To determine whether or not Homer proteins may be differentially involved in ethanol reward, the present study assessed ethanol preference and consumption between wild-type (WT) mice and Homer1 KO mice under 24-hr free-access conditions in the home cage. In contrast to the stark genotypic difference in ethanol preference and consumption reported for Homer2 KO mice, no statistically significant genotypic difference was observed between Homer1 KO and WT mice with respect to either behavioural variable. Interestingly, Homer1 deletion also failed to influence the capacity of the Group1 mGluR agonist, DHPG, to increase glutamate levels in the nucleus accumbens. These data indicate that, in contrast to Homer2 deletion, Homer1 deletion does not influence sensitivity to unconditioned ethanol reward under free-access conditions, nor does it alter Group1 mGluR function. Thus, Homer2 regulation of Group1 mGluR signaling appears to be more critical in determining individual sensitivity to the rewarding effects of ethanol. Supported in part by P.R.W DA-11742 to PFW; P50-AA10761 to LDM; MH-40817 and DA-03906 to PWK; and INIA to KKS.
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