Editors' ChoiceAddiction

A Scaffold for Addiction?

STKE  10 Aug 2004:
Vol. 2004, Issue 245, pp. tw284
DOI: 10.1126/stke.2452004tw284

Behavioral sensitization to cocaine, which occurs after repeated administration, involves long-lasting changes in glutamatergic transmission in the nucleus accumbens. Szumlinski et al., a group that previously showed that cocaine elicits changes in expression of genes encoding Homer scaffolding proteins [which exist in complexes with metabotropic glutamate receptors (mGluRs)], investigated the effects of Homer deletion on the response to cocaine. 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. Further, 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. However, Homer deletion (unlike cocaine withdrawal) had no effect on extracellular dopamine. Restoring Homer2 by means of an adenovirus vector reversed these effects of Homer2 knockout 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 and increased the sensitivity to extracellular cystine of cystine-glutamate exchange. As in cocaine withdrawal, Homer2 knockout increased accumbens content of activator of G protein signaling 3 (AGS3) and decreased that of the catalytic protein of the cystine/glutamate exchanger (xCT). 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.

K. K. Szumlinski, M. H. Dehoff, S. H. Kang, K. A. Frys, K. D. Lominac, M. Klugmann, J. Rohrer, W. Griffin III, S. Toda, N. P. Champtiaux, T. Berry, J. C. Tu, S. E. Shealy, M. J. During, L. D. Middaugh, P. F. Worley, P. W. Kalivas, Homer proteins regulate sensitivity to cocaine. Neuron 43, 401-413 (2004). [Online Journal]