Neurochemical and behavioral evidence supporting (+)-AJ 76 as a potential pharmacotherapy for cocaine abuse.

Abstract

In vivo microvoltammetry was used to detect synaptic concentrations of dopamine (DA) and serotonin (5-HT) from nucleus accumbens (NAcc) in awake, freely moving, male, Sprague Dawley laboratory rats, while their locomotor behavior was monitored, simultaneously, in an open-field paradigm; the purpose was to evaluate the pharmacology of the D3-preferring, dopamine (DA) autoreceptor antagonist, (+)-AJ 76 [cis-(+)-1S, 2R-5-methoxy-1-methyl-2-(n-propylamino)-tetralin HCL] and its potential use as a pharmacotherapy for cocaine abuse. Results showed that (1). (+)-AJ 76 significantly increased synaptic concentration of DA above baseline (p < 0.001); a small but significant decrease in synaptic concentration of 5-HT was seen (p < 0.001), although a significant increase occurred during the time course, at the 20 minute mark (p < 0.05). Analysis of the two hour data also showed that both locomotor and central locomotor activity were not affected; however, temporally related increases in both behaviors were significant at 10, 20 and 30 minutes (p < 0.05). In a second and separate study, (2). cocaine increased synaptic concentrations of DA (p < 0.001) and 5-HT (p < 0.001), and locomotor activity (p < 0.001) above baseline, but central locomotion was not affected, except for specific temporal enhancements at 10, 20, 30, 50, 60 and 90 min. (p < 0.05). In a third and separate study, (3). an (+)-AJ 76/cocaine study, (+)-AJ 76 was administered five minutes before cocaine. The results showed that synaptic DA concentration was significantly increased over baseline values (p < 0.001) but that synaptic DA was lower than cocaine-induced synaptic DA (p < 0.001). No significant difference in synaptic 5-HT occurred after (+)-AJ 76/cocaine treatment, but temporally related increases over baseline occurred from 10 to 40 min. (p < 0.05). Synaptic 5-HT concentrations after (+)-AJ 76/cocaine were not significantly different from those induced by cocaine per se. (+)-AJ 76/cocaine treatment significantly increased locomotor activity (p < 0.001); central locomotor behavior was not affected, however, time course data showed significant increases at 10, 20, 40, 50 and 80 min. (p < 0.05). The major finding from the present studies, is that +(-) AJ 76/cocaine treatment produced synaptic concentrations of DA from NAcc which were lower than those due to cocaine per se, while no differential effect on synaptic 5-HT concentration, locomotor or central locomotor behavior occurred. Therefore, these data support the hypothesis that (+)-AJ 76 may be useful for the treatment of cocaine addiction or abuse.