Repeated Cocaine Administration Attenuates Group I Metabotropic Glutamate Receptor-Mediated Glutamate Release and Behavioral Activation: A Potential Role for Homer

Abstract

The present study aimed to characterize a functional role for group I metabotropic glutamate receptors (mGluRs) in the nucleus accumbens and the capacity of repeated cocaine to elicit long-term changes in group I mGluR function. Reverse dialysis of the group I agonist (RS)-3,5-dihydroxyphenylglycine (DHPG) into the nucleus accumbens resulted in an increase in extracellular glutamate levels that was mediated by the mGluR1 subtype and depended on voltage-dependent Na(+) and Ca(2+) conductance. At 3 weeks after discontinuing 1 week of daily cocaine injections, the capacity of DHPG to induce glutamate release was markedly reduced. Similarly, DHPG induced an mGluR1-dependent increase in locomotor activity after microinjection into the nucleus accumbens that was significantly blunted 3 weeks after repeated cocaine administration. Signaling through group I mGluRs is regulated, in part, by Homer proteins, and it was found that the blunting of group I mGluR-induced glutamate release and motor activity after repeated cocaine was associated with a reduction in Homer1b/c protein that was selective for the medial nucleus accumbens. These data show that repeated cocaine produces an enduring inhibition of the neurochemical and behavioral consequences of stimulating mGluR1 that is accompanied by changes in the mGluR scaffolding apparatus.

Homers regulate drug-induced neuroplasticity: Implications for addiction

“…2) [229]. As observed previously in the earlier rat study by Swanson et al [169], PFC Homer1b/c levels were unchanged following withdrawal from repeated cocaine in mice; however, we observed an approximately 30% increase in PFC Homer2a/b expression (Fig. 2).…”

“…Thus, while many drugs of abuse increase corticoaccumbens IEG Homer expression, this drug effect is transient and independent of a particular mechanism of drug action. In contrast to IEG Homers, the regulation of corticoaccumbens CC-Homer expression by drugs of abuse is more complex (Table 2) [39, 157,[166][167][168][169][170] and, as will be discussed below in greater detail, may reflect a compensatory response to either the immediate or longer-term effects of drug administration upon corticoaccumbens glutamate transmission.…”

“…As the cystine-glutamate anti-porter does not contain the PPSPF necessary for Homer binding, it is likely that Homer regulation of anti-porter function is indirect. Stimulation of presynaptically localized mGluR1 receptors leads to elevations in extracellular glutamate levels within both the NAC and PFC [169,175]. While Homer2 deletion reduces the total mGluR1 protein expression within the NAC and reduces agonist-stimulated glutamate release within this region [34], recent immunoblotting studies conducted on Homer1 WT and KO mice have failed to detect genotypic differences in Group1 mGluR expression within any brain region examined (Table 3) [176].…”

“…In contrast to IEG Homer isoforms, delayed changes in CC-Homer expression are produced within limbic regions following repeated non-contingent cocaine administration that coincide with the manifestation of behavioral and neurochemical sensitization to this drug (see Table 2) [169,229]. Repeated injections of cocaine, followed by a 1-3 week period of withdrawal, augments the acute psychomotor-activating effects of the drug, a phenomenon referred to as behavioral sensitization [e.g., 19,[20][21][22].…”

“…Repeated injections of cocaine, followed by a 1-3 week period of withdrawal, augments the acute psychomotor-activating effects of the drug, a phenomenon referred to as behavioral sensitization [e.g., 19,[20][21][22]. Immunoblotting conducted on tissue from Sprague Dawley rats indicated a coincident reduction in mGluR5 and Homer1b/c protein levels at 3 weeks withdrawal from repeated cocaine administration that was selective for the medial, but not the lateral, aspect of the NAC [169]. Identical cocaine treatment to C57BL/6J mice revealed a concomitant reduction in NAC levels of Homer1b/c and Homer2a/b, indicating that CCproducts of both the Homer1 and Homer2 genes are similarly regulated within NAC by cocaine withdrawal (Fig.…”