Effects of subchronic amphetamine or amfonelic acid on rat brain dopaminergic and serotonergic function

Repeated doses of direct or indirect CNS stimulants are known to cause behavioral hypersensitivity. The biochemical basis for hypersensitization remains unclear. Since the dopaminergic system uses a large storage pool that is only slowly mobilized to releasable sites, a change in this relationship may underlie the biochemical changes leading to increased responsiveness to stimulants. To test this hypothesis, rats were first tested with low doses of 2.5 mg/kg amphetamine or 1.0 mg/kg amfonelic acid (AFA) for their locomotor response, then 5.0 mg/kg amphetamine or 2.5 mg/kg AFA were injected daily for 7 days and the rats retested with the lower doses of amphetamine or AFA, respectively. Both drugs produced hypersensitivity, but the cataleptic response to acute dopamine (DA) receptor blockade by haloperidol was unaltered. The ability of haloperidol to increase DA metabolism was unaltered and the ability of acute AFA to synergize with haloperidol was similar in the striatum of stimulant and saline treated rats, but reduced in the medial prefrontal cortex of both AFA and d-amphetamine treated rats. Additional rats had DA2 receptor sensitivity measured in the striatum and frontal cortex, but no significant differences were found. Only amphetamine caused a significant decrease in frontal cortex serotonin type 2 receptors. Since there was no alteration in the ability of AFA to increase neurogenic release of DA in the striatum and a decrease occurred in prefrontal cortex, an increase in the storage to functional pool exchange in the nigrostriatal and mesocortical DA containing neurons seems unlikely. In contrast, both the amphetamine and AFA treatment groups had their brain 5HT and 5HIAA levels reduced by about 50%. This suggests that changes in other transmitter systems may have a permissive effect allowing exaggerated responses to excessive DA release.