The overall objectives of this project are to study the phenomenology and the biochemical and neuroanatomical substrates of behavioral sensitization. This model is used to study the evolution of behavioral pathology and the role of conditioning or context-dependency in such behaviors. Environmental and pharmacological interventions are investigated in an attempt to alter the course of sensitization development and expression. Significant findings to date include demonstration of the following: 1) a novel-two day cocaine sensitization paradigm which is entirely conditioned or context-dependent; 2) a second sensitization paradigm, using a three-day training regimen, which produces longer-lasting conditioned sensitization than the above paradigm; 3) the requirement of intact dopamine function for the development, but not expression of context-dependent sensitization; 4) a role for the amygdala and nucleus accumbens in the two-day conditioned sensitization; 5) cross-sensitization between cocaine and the NMDA antagonist MK-801, and between cocaine and procaine (a local anesthetic that is self-administered by primates), but not between cocaine and lidocaine (which is not self-administered) or cocaine and caffeine; 6) blockade of the development of sensitization by MK-801, lithium, nimodipine, clonidine and diazepam, but not by carbamazepine, proglumide (CCK antagonist), or alpha-helical CRF (CRF antagonist); 7) blockade of the expression of conditioned sensitization by clonidine, diazepam, and nimodipine.
