A Scaffold for Addiction?

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Science  20 Aug 2004:
Vol. 305, Issue 5687, pp. 1081
DOI: 10.1126/science.305.5687.1081b

Behavioral sensitization to cocaine, which occurs following repeated administration, involves long-lasting changes in glutamatergic transmission in the nucleus accumbens. Cocaine elicits changes in the expression of genes encoding Homer scaffolding proteins [which exist in complexes with metabotropic glutamate receptors (mGluRs)], and Szumlinski et al. have now investigated the effects of Homer deletion. Mice lacking Homer1 or Homer2 showed enhanced sensitivity to cocaine-induced place conditioning (preference for environments associated with cocaine administration), as well as an enhanced locomotor response to cocaine. Furthermore, these mice had decreased basal extracellular glutamate concentration in the nucleus accumbens compared to wild-type mice (as occurs with repeated cocaine administration) and, like rats in withdrawal from repeated cocaine administration, showed increased extracellular glutamate following cocaine exposure. Restoring Homer2 reversed the effects on conditioning and on the behavioral and neurochemical response to cocaine. Homer2 knockout also led to more rapid development of cocaine self-administration and, as in cocaine-sensitized animals, attenuated the increase in extracellular glutamate produced by a mGluR1 agonist. Thus, lack of Homer2 mimics many aspects of the sensitization seen with withdrawal from repeated cocaine administration, leading the authors to propose that Homer proteins may play a key role in cocaine addiction. — EMA

Neuron 43, 401 (2004).

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