Cyclo (His-Pro), d-amphetamine and striatal dopamine: a microdialysis study

Extracellular levels of dopamine (DA) and its metabolites (DOPAC and HVA) were monitored in the striatum of rats using in vivo microdialysis, in an attempt to elucidate the mechanism of cyclo (His-Pro) (histidyl-proline-diketopiperazine, CHP) on dopaminergic activity. Pretreatment with CHP (0.5 mg/kg SC) (n = 5) or the equivalent volume of saline (n = 5) was followed 30 min later by 5 mg/kg IP of d-amphetamine. Dialysate samples were collected and analyzed by high performance liquid chromatography with electrochemical detection (HPLC-EC). Following the initial increase in DA caused by d-amphetamine, DA levels of CHP-treated rats were significantly lower than saline-treated rats across time (p less than 0.05). No difference was observed for DOPAC or HVA. It is therefore unlikely that CHP interferes with the d-amphetamine-induced inhibition of DA reuptake. Other neurotransmitter systems may be involved in the CHP-induced augmentation of amphetamine's behavioral effects. Our data, as well as previous findings, suggest that attenuation of the dopaminergic response to d-amphetamine might be best explained on the basis of striatal DA depletion, possibly via tyrosine hydroxylase (TH) inhibition. This study also indicates that a dissociation may exist between the behavioral and the striatal DA response to acute amphetamine. The data support the hypothesis that amphetamine releases DA from a newly synthesized, extravesicular cytoplasmic pool, and that intracellular striatal DA is present in considerable excess relative to the extracellular DA.