Psychomotor stimulants like amphetamine produce locomotion and support self-administration in humans and laboratory animals. Repeated exposure to these drugs produces long-term enhancements, termed sensitization, in their ability to produce these effects. Understanding the neuronal events that lead to and the neuroadaptation that underlie sensitization may thus have particular bearing for understanding the escalation of drug use that is characteristic of the transition from casual experimentation with drugs to drug craving and abuse. ? ? The dopamine projections to the nucleus accumbens are known, via their impact on other neurotransmitter systems, to be critical for the production of locomotor and self-administration behaviors by amphetamine. This, together with the fact that repeated exposure to amphetamine sensitizes its ability to increase extracellular dopamine in the nucleus accumbens, suggests an important relation between sensitized dopamine neuron reactivity and the enhanced pursuit and self-administration of drugs observed in sensitized animals. ? ? Using a model of enhanced drug self-administration in the sensitized rat, the proposed experiments will examine different ways in which the expression of these sensitized responses aimed at obtaining amphetamine can be prevented. The experiments will focus on identified intracellular signaling pathways using calcium/calmodulin-dependent protein kinase II (CaMKII), as well as conditioned inhibitors, environmental stimuli specifically unpaired with the drug. Their contribution to dopaminergic and glutamatergic neuroadaptation underlying enhanced amphetamine self-administration and reinstatement will specifically be assessed. ? ? Because both CaMKII and conditioned inhibitors selectively regulate the expression of sensitized but not acute responding to amphetamine, they each may represent an attractive target for the inhibition of enhanced amphetamine self-administration and reinstatement. ? ?
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