Cocaine- and ethanol-induced behavioral sensitization: the similarities and differences in the locomotor activity and protein kinase phosphorylation

Abstract

Behavioral sensitization is a progressive enhancement in the locomotor-stimulating effects of a drug following repeated exposure, and it can serve as a model for drug addiction or psychosis. The purpose of the current study was to compare between the cocaine- and ethanol-induced behavioral sensitization in the locomotor and protein kinases activities. In the part I, (1) I examined the locomotor activity and phosphorylation of some protein kinases in response to the representative CNS stimulant cocaine, and (2) aimed to determine whether these effects were mediated by dopamine (DA) D1 or D2 receptors. In the part II, (3) I aimed to test whether another kind of abused drug, CNS depressant ethanol could also induce the behavioral sensitization, and (4) investigated whether the cross-sensitization occurs between the two substances. Both substances are well-known abused drugs and it is supposed that all abused drugs have common mechanisms of action. In addition, I also investigated the protein kinase phosphorylation.

In the cocaine-sensitized state following repeated treatment, the behavioral responsiveness to cocaine was augmented. The sensitized state was accompanied by alteration in AMPK phosphorylation, and this alteration was accentuated by further challenge with cocaine. The phosphorylation levels of the upstream kinases LKB1 and CaMK4 were congruent with the changes in AMPK phosphorylation. AKT and GSK3β phosphorylations were affected by the sensitization but not responded to the acute challenge. On the contrary, ERK1/2 and MEK1/2 phosphorylations were only affected by acute cocaine treatment but not by the sensitization itself. The directions of alteration were different between the brain regions. In the frontal cortex, the phosphorylations were increased for all molecules examined. However, in the dorsal striatum, the phosphorylations of AMPK and GSK3β pathway kinases were decreased, while ERK1/2 and MEK1/2 phosphorylations were increased.

Acute locomotor-activating effects of cocaine were blocked by either SCH23390 or haloperidol. In the frontal cortex, the effects of cocaine on the kinase phosphorylation were accentuated by haloperidol and abolished by SCH23390. In the dorsal striatum, the effect of cocaine was enhanced by SCH23389 but blocked by haloperidol.

Ethanol-induced behavioral sensitization was observed at low-dose (0.5 g/kg), but not at high-dose (2 g/kg). At the sensitizing dose, the acute behavioral effect of ethanol was not observed, while the neural activity assessed by Egr-1 expression was increased. In the ethanol-sensitized state, the phosphorylations of AMPK, LKB1, CaMK4, AKT/ GSK3β and MEK1/2/ERK1/2 were increased in the frontal cortex but decreased it in the dorsal striatum when challenged with ethanol (0.5 g/kg, E-E).

The cross-sensitization between the cocaine and ethanol were observed. In ethanol-sensitized state, locomotor response to cocaine was accentuated, and the phosphorylation of AMPK and its upstream kinases LKB1 and CaMK4, AKT/GSK3β signaling pathway were also accentuated by cocaine challenge (S-C vs. E-C). MEK1/2/ERK1/2 signaling pathway was only enhanced in the frontal cortex but not in the dorsal striatum by cocaine challenge in the ethanol-sensitized state. In cocaine-sensitized state, a challenge with ethanol elicited an increase in the locomotor activity. But it could not enhance the phosphorylation of AMPK and its upstream kinases LKB1 and CaMK4, AKT/GSK3β signaling pathway in both regions. The MEK1/2/ERK1/2 signaling pathway was only accentuated in the frontal cortex.

Taken together, in the cocaine-sensitized state, the alterations of the protein kinases phosphorylations and the behavioral responsiveness to acute cocaine were augmented. The opposite direction the dorsal striatum and frontal cortex induced by cocaine in the phosphorylation of AMPK and AKT/GSK3β systems could be explained by the differential activations of DA D1 and D2 receptors in these brain regions. However, the phosphorylations of ERK and MEK in both regions might be mediated directly by dopamine receptor and protein kinase A (PKA) pathway. Ethanol induced behavioral sensitization at a low-dose, while the acute inhibitory behavioral response was not observed. The cross-sensitization between the ethanol and cocaine was observed, and it could suggest an underlying common mechanism for drug dependence regardless of the primary target of the brain. However, there were differences between the ethanol- and cocaine-sensitization in the profile of kinase phosphorylation. Dopamine-mediated signaling would be the common pathway, but the difference would be mediated by the action of ethanol on the glutamate-GABA system.