Abstract

Relapse is the hallmark of drug addiction disorder. Drug seeking and uncontrolled intake of drugs of abuse during abstinence is a limitation for successful treatment of this disorder. Negative affective consequences (dysphoria and anhedonia) characterize the early abstinence from psychostimulants, and the withdrawal symptoms precipitate relapse. An upregulation of the kappa opioid neurotransmission has been associated with the development of the negative symptomatology during early abstinence. A significant induction of dynorphin, the endogenous ligand of the kappa opioid receptor (KOR), is observed in the Nucleus Accumbens and dorsal striatum after both, an acute and chronic amphetamine administration. Consistent with these observations, it has been suggested that blockade of the KOR would attenuate the relapse during drug abstinence. Interestingly, we have preliminary results showing that the systemic administration of the KOR antagonist norbinaltorphimine (norBNI) attenuates the expression of amphetamine sensitization. Behavioral sensitization, a progressive and persistent increase in locomotor activity, induced by the repeated administration of psychostimulants is a preclinical model of addiction in rodents. This sensitized behavioral response is accompanied by an increased dopamine (DA) release in the NAc. Neuroplastic changes are thought to underlie pathological drug craving, culminating in relapse to drug seeking, even after abstinence periods. The kappa opioid system exerts a tonic inhibitory control on DA extracellular levels and modulates the behavioral sensitization induced by psychostimulants. In contrast to the acute effect, the repeated treatment with the KOR agonist U-69593 increases stimulated- DA release in the NAc evidencing that KOR repeated activation sensitizes DA neurotransmission. Surprisingly, we showed that repeated treatment with U-69593, during early abstinence, reverses the sensitized DA release in the NAc, but not the expression of locomotor sensitization induced by amphetamine. These data indicates that a sensitized DA releases in the NAc does not underlie the expression of amphetamine-induced behavior. Consistent with our results, recently it has been demonstrated that during the repeated use of cocaine emerges a sensitized DA release in the dorsolateral striatum that is accompanied by a decrease in DA releasability in the NAc. Taken together, these results show that during the repeated use of psychostimulants a dopaminergic sensitization transition from the NAc to the dorsal striatum takes place, which is responsible for the maintenance of addictive-type behaviors. Then, it might be suggested that an increase in the kappa opioid system activity due to repeated administration of psychostimulants underlies this neuronal transition as a consequence of a differential modification in the pre-sinaptic control of DA extracellular levels in mesolimbic and nigrostriatal terminals: while the repeated activation of KOR attenuates the stimulated-DA release in the NAc, facilitates the stimulated-DA release in the dorsal striatum. The hypothesis of this proposal is that the psychostimulant-induced sensitization depends on the dorsolateral striatum kappa opioid system. We propose that the blocking KOR in the dorsolateral striatum reverts the expression of amphetamine sensitization through a decrease of DA releasability in the dorsolateral striatum. The aims are: 1- To study the effect of systemic blocking of KOR on DA neurotransmission in the dorsolateral striatum of freely moving rats after a challenge injection of amphetamine in sensitized rats; 2- To study the effect of blocking KOR directly in the dorsolateral striatum on DA neurotransmission in the striatum of freely moving rats after a challenge injection of amphetamine in sensitized rats; 3-Using quantitative microdialysis experiments to study the mechanism underlying KOR-mediated DA release facilitation in dorsolateral striatum in amphetamine sensitized rats