Chronic cocaine exposure: Behavioral response and expression of 5-HT2A receptors

Some of the adverse effects associated with abstinence from chronic cocaine usage are similar to the psychiatric symptoms of affective illness. Some of these symptoms include dysphoria, agitation, anxiety and alterations in sleep and appetite (Gawin and Kleber, 1986, 1988). Since in the treatment of affective illness these symptoms are responsive to medications which regulate specific receptors in the serotonergic system, I studied the influence chronic cocaine exposure and abstinence has on the expression and behavioral responses of the 5-HT2A receptor. First, the specific binding parameters of [3H]ketanserin were assessed in the hippocampus and frontal cortex of rat brain tissue. These studies revealed relatively high affinity binding in both areas. The dissociation constants averaged 1.40 +/− 0.05 nM for the frontal cortex and 2.88 +/− 0.22 nM for the hippocampus. The density of the binding sites for the frontal cortex and hippocampus averaged 567 +/− 35 and 233 +/− 53 f moles/mg protein respectively. Additional receptor binding experiments conducted at various time points during and following cocaine exposure via subcutaneously implanted cocaine- or vehicle-containing Silastic capsules revealed no treatment-related differences in receptor density. Since previous studies have reported that various stressors (chronic forced swim test, restraint stress, or food restriction) may increase either the level of 5-HT in various brain areas, 5-HT2A receptor density, or behavioral responses to 5-HT2A receptor agonists. I also examined the interaction between the stress of minor surgery (associated with the capsule implantation), food restriction, and chronic cocaine treatment on head-twitch responses (HTRs) to the 5-HT2A agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), in rats. Circulating cocaine concentrations were 116 +/− 11 ng/ml (low dose) and 330 +/− 75 ng/ml (high dose) at the end of the 3-day treatment period. Food restriction occurred through pair-feeding of control animals to high-dose cocaine-treated subjects that showed a transient drug-induced anorexia. Untreated rats subjected to surgery and food restriction exhibited a significantly elevated HTR at 3 days post-surgery compared to untreated animals given the same dose of DOI. This enhanced sensitivity to DOI subsequently declined in a time-dependent manner. High- but not low-dose cocaine treatment unexpectedly attenuated the stress-induced increase in DOI-elicited HTRs. Since the 5HT2A binding data revealed no treatment-related differences in receptor density, the result suggest that these alterations in behavioral responsiveness may reflect changes in 5-HT2A signal transduction mechanisms