Long-term administration of psychostimulant drugs produces enduring changes in behavior. It is likely that the long-term changes in brain function associated with prolonged drug exposure are important to addictive behavior. The molecular mechanisms underlying the persistent alteration in brain function associated with prolonged psychostimulant exposure are poorly understood. The behavioral effects of the psychostimulant amphetamine are dependent on activation of dopamine receptors within the striatum and limbic forebrain. Repeated administration of psychostimulants to rodents produces alterations in nuclear proteins which may underlie long-lasting changes in behavior. The A2a subtype of adenosine receptor is expressed in and regulates responsiveness of D2-expressing striatal and limbic forebrain neurons, and modulates the behavioral and nuclear responses of acute amphetamine. The A1 adenosine receptor also modulates AMPH-induced behavior, but the anatomical basis of this A1 effect is not understood. We hypothesize that striatal and limbic forebrain A2a and A1 adenosine receptors are sites where the acute effects of AMPH and enduring changes in brain function following chronic AMPH can be regulated. The expression of striatal and limbic forebrain A2a and A1 receptors will be characterized and the roles that these adenosinergic receptors play in modulating the behavioral and nuclear effects of acute and chronic AMPH administration will be investigated. These experiments will begin to identify nuclear mechanisms underlying this form of drug-induced neural plasticity which are vulnerable to modulation by forebrain adenosinergic receptors.
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