An emerging view on the etiology of drug addiction is that during its development and progression there is pathological usurpation of neural mechanisms of reward-related learning and memory. Support for this """"""""aberrant learning"""""""" hypothesis is provided by anatomical, electrophysiological and biochemical evidence for the activation of putative molecular mechanisms of learning and memory following drug exposure. Behavioral sensitization is one early consequence of repeated drug exposure. This includes experience dependent potentiation of some overt behaviors, but also an increase in the incentive value of drugs and associated cues. These behavioral effects are accompanied by neurochemical sensitization of dopamine release in the nucleus accumbens (NAcb). Dopamine release in this structure is thought to increase the incentive salience of cues or act as a reinforcement signal during learning. In addition to sensitization, aberrant habit formation and a consequent resistance to extinction are thought to contribute to addictive disorders. Stimulus-response habit learning is hypothesized to rely heavily upon the dopaminergic modulation of the dorsal striatum. The overall goal of this project is to assess the precise contribution of dopamine in these phenomena by monitoring phasic dopamine responses in the NAcb and dorsal striatum during the acquisition, maintenance and extinction of conditioned pavlovian approach to stimuli that predict reward.
Specific aim 1 will examine phasic dopamine activity in the NAcb and dorsal striatum throughout learning. Dopamine will be detected with subsecond temporal resolution using fast-scan cyclic voltammetry. This will allow us to dissect the neurochemical responses to specific components of the environment (conditioned vs. unconditioned stimuli) and to detect potential quantitative and/or qualitative differences in the dopaminergic response between the two structures. In particular, we will test for anatomical differences in the rates (number of trials) that dopamine responses develop to reward-predicting stimuli during acquisition and diminish during extinction. This is hypothesized to correlate with a selective role for the dorsolateral striatum in stimulus-response habits, promoting persistent activity during extinction.
Specific aim 2 will assess the influence of drug sensitization on phasic dopamine activity in the two striatal subregions (nucleus accumbens vs. dorsolateral striatum) during learning. These experiments will be conducted in animals that have been sensitized to cocaine and in those that are naive to the drug. These experiments will provide new insight into dopamine transmission during learning following drug experience, and provide a foundation to test hypotheses on aberrant learning as a basis for addiction.
