The effects of putative 5-hydroxytryptamine receptor active agents on D-amphetamine self-administration in controls and rats with 5,7-dihydroxytryptamine median forebrain bundle lesions

Animals in which 5,7-dihydroxytryptamine (5,7-DHT) was bilaterally injected into the median forebrain bundle (MFB) and sham lesioned animals were allowed access to an apparatus which delivered, upon lever pressing, intravenous D-amphetamine injections. MFB lesioned rats achieved stable self-injections patterns and self-administered more drug per test session than controls. A number of agents known to either directly or indirectly affect 5-hydroxytryptamine (5-HT) receptor function were administered prior to D-amphetamine access. The responses to these pretreatments in lesioned vs non-lesioned rats were markedly different. Pretreatment with L-tryptophan reduced the number of D-amphetamine self-injections in sham lesioned rats but had no effect in MFB lesioned animals. Fluoxetine pretreatment, likewise, reduced responding in non-lesioned rats and had no observable effect in lesioned animals. Quipazine markedly reduced self-injection in control rats but was not evaluated in the lesioned group. The putative 5-HT antagonists utilized, cyproheptadine and methysergide, unpredictably reduced self-injection frequency of non-lesioned animals in a dose related manner. When MFB lesioned animals were pretreated with cyproheptadine, rapid bursts of lever pressing were observed and 3 of 6 animals thus treated died as a result (presumably amphetamine overdose). In the remaining animals, methysergide produced a similar marked increase in self-injection rate. While these data may suggest that, in some instances, non-serotonergic mechanisms are involved, for the most part it would appear that 5-HT containing neurons are of major import in some aspect of D-amphetamine self-administration.