Decrease of glycogen synthase kinase 3ß phosphorylation in the rat nucleus accumbens shell is necessary for amphetamineinduced conditioned locomotor activity.

Phosphorylation levels of glycogen synthase kinase 3ß (GSK3ß) negatively correlated with psychomotor stimulant-induced locomotor activity. Locomotor sensitization induced by psychomotor stimulants was previously shown to selectively accompany the decrease of GSK3ß phosphorylation in the nucleus accumbens (NAcc) core, suggesting that intact GSK3ß activity in this region is necessary for psychomotor stimulants to produce locomotor sensitization. Similarly, GSK3ß in the NAcc was also implicated in mediating the conditioned effects formed by the associations of psychomotor stimulants. However, it remains undetermined whether GSK3ß plays a differential role in the two sub-regions (core and shell) of the NAcc in the expression of drug-conditioned behaviors. In the present study, we found that GSK3ß phosphorylation was significantly lower in the NAcc shell obtained from rats expressing amphetamine (AMPH)-induced conditioned locomotor activity. Further, we demonstrated that these effects were normalized by treatment with lithium chloride, a GSK3ß inhibitor. These results suggest that the behavior produced by AMPH itself and a conditioned behavior formed by associations with AMPH are differentially mediated by the two sub-regions of the NAcc.

Amphetamine dephosphorylates ERM proteins in the nucleus accumbens core and lithium attenuates its effects.

The ezrin-radixin-moesin (ERM) proteins have been implicated not only in cell-shape determination but also in cellular signaling pathway. We have previously shown that cocaine decreases phosphorylation levels of these proteins in the nucleus accumbens (NAcc), an important brain area mediating addictive behaviors. Here we further revealed that the phosphorylation levels of ERM were decreased in the NAcc core, but not in the shell, by a single injection of amphetamine (AMPH) (2 mg/kg, i.p.). When lithium (100 mg/kg, i.p.) was co-administered with AMPH, the decreases of phosphorylation levels for ERM by AMPH were recovered back to basal levels in the NAcc core. Together, these results suggest that psychomotor stimulants like AMPH regulate phosphorylation levels of ERM in the NAcc core and lithium-involved signaling pathway has a regulatory role in the opposite direction in this site.

Blockade of ERK Phosphorylation in the Nucleus Accumbens Inhibits the Expression of Cocaine-induced Behavioral Sensitization in Rats.

Repeated administration of psychostimulants such as cocaine leads to the development of behavioral sensitization. Extracellular signal-Regulated Kinase (ERK), an enzyme important for long-term neuronal plasticity, has been implicated in such effects of these drugs. Although the nucleus accumbens (NAcc) is the site mediating the expression of behavioral sensitization by drugs of abuse, the precise role of ERK activation in this site has not been determined. In this study we demonstrate that blockade of ERK phosphorylation in the NAcc by a single bilateral microinjections of PD98059 (0.5 or 2.0µ g/side), or U0126 (0.1 or 1.0µg/side), into this site dose-dependently inhibited the expression of cocaine-induced behavioral sensitization when measured at day 7 following 6 consecutive daily cocaine injections (15 mg/kg, i.p.). Acute microinjection of either vehicle or PD98059 alone produced no different locomotor activity compared to saline control. Further, microinjection of PD98059 (2.0µ g/side) in the NAcc specifically lowered cocaine-induced increase of ERK phosphorylation levels in this site, while unaffecting p-38 protein levels. These results indicate that ERK activation in the NAcc is necessary for the expression of cocaine-induced behavioral sensitization, and further suggest that repeated cocaine evokes neuronal plasticity involving ERK pathway in this site leading to long-lasting behavioral changes.