The general effects of cocaine are not well understood at the molecular level. What is known is that the dopamine D 1 receptor plays an important role. Here we show that a key mechanism may be cocaine's blockade of the histamine H 3 receptor-mediated inhibition of D 1 receptor function. This blockade requires the 1 receptor and occurs upon cocaine binding to 1 -D 1 -H 3 receptor complexes. The cocainemediated disruption leaves an uninhibited D 1 receptor that activates G s , freely recruits ␤-arrestin, increases p-ERK 1/2 levels, and induces cell death when over activated. Using in vitro assays with transfected cells and in ex vivo experiments using both rats acutely treated or self-administered with cocaine along with mice depleted of 1 receptor, we show that blockade of 1 receptor by an antagonist restores the protective H 3 receptor-mediated brake on D 1 receptor signaling and prevents the cell death from elevated D 1 receptor signaling. These findings suggest that a combination therapy of 1 R antagonists with H 3 receptor agonists could serve to reduce some effects of cocaine.

Exposure to certain acute and chronic stressors results in an immediate behavioral and physiological response to the situation followed by a period of days when cross-sensitization to further novel stressors is observed. Cross-sensitization affects to different behavioral and physiological systems, more particularly to the hypothalamus-pituitary-adrenal (HPA) axis. It appears that the nature of the initial (triggering) stressor plays a major role, HPA cross-sensitization being more widely observed with systemic or high-intensity emotional stressors. Less important appears to be the nature of the novel (challenging) stressor, although HPA cross-sensitization is better observed with short duration (5-15 min) challenging stressors. In some studies with acute immune stressors, HPA sensitization appears to develop over time (incubation), but most results indicate a strong initial sensitization that progressively declines over the days. Sensitization can affect other physiological system (i.e. plasma catecholamines, brain monoamines), but it is not a general phenomenon. When studied concurrently, behavioral sensitization appears to persist longer than that of the HPA axis, a finding of interest regarding long-term consequences of traumatic stress. In many cases, behavioral and physiological consequences of prior stress can only be observed following imposition of a new stressor, suggesting long-term latent effects of the initial exposure.

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