Chronic cocaine enhances serotonin autoregulation and serotonin uptake binding

Abstract

Repeated cocaine intoxication can result in the development of behavioral sensitization in animals and psychosis in humans, phenomena that have been associated with alterations in dopamine (DA) function. Using electrophysiologic and autoradiographic techniques, modifications of central serotonin (5-hydroxytryptamine; 5-HT) systems were investigated in rats treated with a regimen of cocaine administration that produced behavioral sensitization. The inhibitory response of single 5-HT neurons in the dorsal raphe (DR) to (-)-cocaine, the 5-HT uptake inhibitor fluoxetine or the 5-HT1A agonist 8-hydroxy-2-[di-N-propylamino]tetralin (8-OHDPAT) was significantly enhanced in cocaine-treated rats. Furthermore, several brain areas that contain either cell bodies (DR) or terminals for 5-HT (medial and sulcal prefrontal cortex, frontal cortex) showed cocaine-induced elevations in [3H]imipramine-labeled 5-HT uptake sites, while [3H]-8-OHDPAT-labeled 5-HT1A receptors were decreased only in the central medial amygdala. These results suggest that modifications of autoregulatory mechanisms secondary to alterations of 5-HT uptake processes may contribute to the development of cocaine sensitization.

Effects of Cocaine and MDMA Self-Administration on Serotonin Transporter Availability in Monkeys

“…In the present study, a history of cocaine SA was associated with higher levels of SERT, extending preclinical rodent studies (Cunningham et al, 1992) to nonhuman primates and to PET imaging. Acutely abstinent cocainedependent patients (Jacobsen et al, 2000) or cocaine overdose victims (Mash et al, 2000) also had higher SERT binding in anterior and posterior striatal regions compared Figure 1 SERT availability in the caudate nucleus, putamen and anterior cingulate cortex (ACC) in monkeys with extensive histories of cocaine or MDMA self-administration (SA) or food reinforcement (Control).…”

“…However, previous preclinical and clinical studies would argue against this point since differences were reported in cocaineexposed rodents (Cunningham et al, 1992) and humans (Jacobsen et al, 2000;Mash et al, 2000). Also, one potential reason why we did not detect significantly lower levels of SERT availability in select ROI in the monkeys selfadministering MDMA could be related to their prior exposure to cocaine, which may have increased SERT availability prior to the predicted MDMA-induced reductions.…”

Dissociable Roles for the Dorsal and Median Raphé in the Facilitatory Effect of 5-HT1A Receptor Stimulation upon Cocaine-Induced Locomotion and Sensitization

“…One possible mechanism for this blunting is that repeated DPAT may have augmented the elevation in 5-HT1A autoreceptor function produced by repeated cocaine administration. In support of this, electrophysiological recordings (eg Cunningham et al, 1992) as well as autoradiographic (Cunningham et al, 1992;Perret et al, 1998), behavioral (King et al, 1993), and biochemical studies (Levy et al, 1994;Parsons et al, 1995Parsons et al, , 1996Baumann and Rothman, 1998) indicate that repeated cocaine administration sensitizes 5-HT1A autoreceptor function, at least following short periods of cocaine withdrawal.…”

“…These effects on extracellular serotonin are consistent with the pharmacological blockade of serotonin reuptake by cocaine (Koe, 1976) and the potential involvement of impulse-modulating somatodendritic serotonin 1A (5-hydroxytryptophan (5-HT)1A) receptors (eg Marwah, 1986, 1987;Lakoski, 1988, 1990). Accordingly, behavioral, biochemical, and electrophysiological evidence indicates alterations in 5-HT1A autoreceptor function following withdrawal from repeated cocaine (Cunningham et al, 1992;Johnson et al, 1993;King et al, 1993;Lakoski, 1988, 1990). Also, cocaineinduced locomotor sensitization is potentiated by the systemic administration of the 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT) and inhibited by the systemic administration of 5-HT1A antagonist WAY 100635 (De La Garza and Cunningham, 2000;Muller et al, 2003).…”

Animal models of drug addiction: Where do we go from here?

“…In addition, although chronic cocaine does not alter basal levels of cortical 5-HT (Baumann, Raley, Partilla, & Rothman, 1993;Johnson, Fiorella, & Rabin, 1993), it does cause regionally specific alterations in 5-HT uptake binding (Belej, Maji, Sioutis, Barros, & Nobrega, 1996;Burchett & Bannon, 1997;Cunningham, Paris, & Goeders, 1992) and decreased 5-HT turnover rates in the frontal cortex (Dworkin, Co, & Smith, 1995). Most importantly, these changes are dose dependent and many persist long after the cessation of drug use.…”