THE PHARMACOLOGY AND NEURAL CIRCUITRY OF SENSITIZATION TO PSYCHOSTIMULANTS

Behavioral sensitization to amphetamine-like psychostimulants is manif est as a progressive increase in drug-induced anxiety and paranoia whi ch can culminate in psychopathologies, such as paranoid psychosis and panic attacks. Sensitization may also mediate the facilitation of drug relapse in addicts by increasing the reinforcing value of acute drug administration. The primary animal model for psychostimulant-induced p sychopathologies involves repeated, non-contingent administration of d rug to rodents, which can produce a progressive and enduring augmentat ion in motor activity and increased susceptibility to drug self-admini stration. Because of the mature literature implicating mesoaccumbens d opamine transmission in the acute motor and reinforcing effects of amp hetamine-like stimulants, investigation into the neural basis of behav ioral sensitization has focused on this projection. Over the last deca de, with a few exceptions, the neurochemical and molecular literature that has emerged from this effort is replete with inconsistencies. In contrast, the presence of behavioral sensitization is a highly replica ble event. It is proposed that behavioral sensitization arises from an alteration in the neural circuitry that subserves the translation of motivationally relevant stimuli into adaptive motor responses. The mes oaccumbens dopamine projection is embedded in this circuit and an endu ring change in dopamine transmission may alter the functional state of the circuit to produce behavioral sensitization. However, combination s of alterations in other connections within the circuit can also supp ort behavioral sensitization. The specific changes in the circuit that promote behavioral sensitization are under the control of experimenta l parameters, such as the drug employed, dosage regimen, withdrawal pe riod and the presence of conditioning cues. Thus, the profile of neuro chemical alterations observed after exposure to repeated psychostimula nts may vary depending upon the experimental protocol and strain of an imals, even though all laboratories report the presence of behavioral sensitization.