Dual serotonin (5-HT) projections to the nucleus accumbens core and shell:Relation of the 5-HT transporter to amphetamine-induced neurotoxicity

Dopamine release in the nucleus accumbens (NAc) has been implicated as medi ating the rewarding effects of stimulant drugs; however, recent studies sug gest that 5-HT release may also contribute. In an effort to assess the role of 5-HT in drug-mediated reward, this study analyzed the serotonergic inne rvation of NAc using immunocytochemistry for 5-HT and the 5-HT transporter (SERT). We report that in control rats the NAc receives two distinct types of 5-HT axons that differ in regional distribution, morphology, and SERT ex pression. Most regions of the NAc are innervated by thin 5-HT axons that ex press SERT, but in the caudal NAc shell nearly all 5-HT axons lack SERT and have large spherical varicosities. Two weeks after methamphetamine or p-ch loroamphetamine (PCA) treatment, most 5-HT axons in dorsal striatum and NAc have degenerated; however, the varicose axons in the shell appear intact. These drug-resistant 5-HT axons that lack SERT densely innervate the caudal one-third of the accumbens shell, the same location where dopamine axons a re spared after methamphetamine. Moreover, 4 hr after PCA, the varicose axo ns in the caudal shell retain prominent stores of 5-HT, whereas 5-HT axons in the rest of the NAc are depleted of neurotransmitter. The results demons trate that two functionally different 5-HT projections innervate separate r egions of the NAc and that selective vulnerability to amphetamines may resu lt from differential expression of SERT. We postulate that action potential s conducted from the raphe nuclei can release 5-HT throughout the NAc, wher eas transporter-mediated release induced by stimulant drugs is more restric ted and unlikely to occur in the caudal NAc shell.