Local cerebral metabolic effects of the novel cocaine analog, WF-31: comparisons to fluoxetine.

The effects of the acute administration of the selective serotonin uptake inhibitor, fluoxetine, on rates of local cerebral glucose utilization in rats were compared to those of the novel cocaine analog, [2beta-propanoyl-3beta-(4-isopropylphenyl)-tropane, WF-31, which has greater affinity for serotonin than dopamine transporters, using the quantitative autoradiographic 2-[14C]deoxyglucose method. Locomotor activity was assessed simultaneously. Fluoxetine administration resulted in dose-dependent decreases in locomotor behavior, as well as widespread reductions in rates of metabolic activity in brain areas including raphe nuclei, dorsal and ventral striatum, amygdala, hippocampus, limbic cortex, and thalamus. These effects were largely concentrated in brain regions containing high densities of serotonin transporters as revealed by in vitro autoradiography. In contrast, the acute administration of WF-31 produced more discrete changes in metabolic activity that were localized within the raphe nuclei and in portions of the hippocampal formation. Blockade of WF-31's dopaminergic effects by pretreatment with the antagonist, alpha-flupenthixol, resulted in a pattern of metabolic changes that closely resembled that observed with fluoxetine. These data suggest that the alterations in functional activity produced by both fluoxetine and WF-31 are largely the result of actions on serotonergic systems.

Effects of chronic cocaine administration on dopamine transporter mRNA and protein in the rat.

Male Sprague-Dawley rats were administered cocaine (10, 15 or 25 mg/kg) or vehicle, i.p., once daily for 8 consecutive days and killed 1 h after the last injection. Acute cocaine administration produced dose-dependent increases in spontaneous locomotor activity. These levels of activity were further enhanced by 8 days of chronic treatment, indicating the emergence of behavioral sensitization. Chronic cocaine administration resulted in dose-dependent decreases in the density of dopamine transporter (DAT) mRNA in both the substantia nigra pars compacta and ventral tegmental area as shown by in situ hybridization histochemistry. Changes in DAT binding sites were assessed using [3H]mazindol quantitative autoradiography. In contrast to the levels of mRNA, there were few changes in the number of [3H]mazindol binding sites. Although the density of binding sites was unaltered in most regions, [3H]mazindol binding was increased in the anterior nucleus accumbens. This study extends previous findings by demonstrating the dose-dependent nature of the changes in DAT mRNA that accompanies chronic cocaine administration. The levels of DAT binding sites within the dorsal and ventral striatum, however, were largely unchanged. This mismatch suggests that cocaine may differentially influence the gene expression of DAT in the ventral midbrain as compared to the density of DAT binding sites in the basal forebrain.