The persistence of addiction relates to the ability of drugs like amphetamine to cause permanent changes in brain regions that govern memories of emotionally significant events. One such brain region is the basolateral nucleus of the amygdala (blA). Normal learning and memory processes use neurotropic factors, like BDNF and its cognate trk-B receptor, and excitatory amino acids (EAA) acting at the NMDA and AMPA subtypes to alter synaptic strength and ultimately to change cell morphology. Neurons in the blA have a high expression level of each. We hypothesize that associative learning induced by amphetamine facilitates trk-B and EAA signaling in the blA. In a place conditioning paradigm, repeated administration of relative low does of amphetamine allow rats to learn to associate the environmental cues with drug. Amphetamine-induced motor function also can be progressively enhanced (termed sensitization). As both behaviors may model aspects of addiction, this paradigm will be used to test the three hypotheses of my specific aims. Hypothesis 1: Amphetamine-induced place preference will change the trk-B levels in the blA of rats. Expression of trk-B will be measured by immunohistochemistry in rats demonstrating place preference and/or motor sensitization. Hypothesis 2: Amphetamine-induced place preference will alter trk-B and EAA receptor function in blA. Neural firing will be measured electrophysiologically in vivo. Microiontophoresis of receptor agonists and antagonists will be used to measure receptor function. Hypothesis 3: Learning will be disrupted by infusion of the trk-B antagonist K-252a into blA. Rats will be surgically implanted with bilateral cannulae and K-252a will be infused and behavioral training will proceed as in Aims 1 and 2. Furthermore, a NMDA or AMPA agonist will be infused in an attempt to reinstate place preference.
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