Noradrenergic Modulation of Cocaine Sensitization in Rats

Dr. Carlos Jiménez

Repeated exposure to cocaine administration results in a progressive and enduring enhancement in the motor stimulant effect induced by a subsequent drug challenge. This phenomenon, termed behavioral sensitization, forms part of the basic pathological mechanisms involved in drug addiction. Cocaine-induced sensitization is associated with neuronal adaptations in the mesolimbic area of the CNS. In this neuronal network, the ventral tegmental area (VTA) is a key structure responsible for the initiation of sensitization. Although the precise neuroadaptations that induce sensitization are not completely understood, recent studies have placed an emphasis on the role of excitatory neurotransmitters (i.e. glutamate) in this phenomenon. NE modulates glutamate-mediated excitation in several brain areas but this action has not been examined in the VTA.

Previous findings from our laboratory demonstrate that acute cocaine administration mimics noradrenergic modulation of glutamate excitation at different brain structures. Moreover, our initial results indicate that destruction of NE terminals, using DSP4, inhibits the development of cocaine sensitization. Systemic and intrategmental injections of alpha-receptor antagonists also prevented the development of cocaine sensitization. Based on these observations we propose the general hypothesis that the development of cocaine sensitization involves an enhanced noradrenergic modulation of glutamate-induced activity in the VTA. This hypothesis will be tested by the accomplishment of the following experimental aims in a period of five years. Notice that in all aims (bold italic letters) we will be comparing animals that have been subjected to the protocol of sensitization versus naïve rats. The BTF facility will be used to accomplish the sensitization protocol.