Serotonergic modulation of the discriminative-stimulus effects of cocaine in squirrel monkeys

Abstract

In order to investigate the potential modulatory role of serotonin on the discriminative-stimulus effects of cocaine, two groups of squirrel monkeys were trained to discriminate 0.3 mg/kg or 1.0 mg/kg cocaine and saline under a two-lever drug-discrimination procedure. Substitution of a range of cocaine doses (0.03-1.7 mg/kg) occasioned orderly, dose-dependent increases in cocaine-lever responding. When administered alone, the non-selective serotonin direct agonist, quipazine, also occasioned increases in cocaine-lever responding which were more pronounced in subjects trained with the lower cocaine dose. When quipazine was administered in combination with cocaine, there was an increase in cocaine-lever responding, indicating an additive effect. The serotonin uptake inhibitor, fluoxetine, occasioned saline-lever responding when administered alone. However, in combination with cocaine, fluoxetine enhanced the discriminative effects of cocaine in subjects trained at the lower cocaine dose. The 5-HT2-selective antagonists, ketanserin and ritanserin, did not occasion cocaine-lever responding when administered alone. In combination with cocaine, ketanserin attenuated the discriminative effects of cocaine in most subjects, and ritanserin attenuated the discriminative effects of cocaine in subjects trained at the higher dose. These results indicate that the discriminative-stimulus effects of cocaine may be increased by direct- and indirect-acting serotonin agonists and attenuated by serotonin antagonists in squirrel monkeys.

Drug Discrimination in Methamphetamine-Trained Monkeys: Effects of Monoamine Transporter Inhibitors

“…Unlike the DAT inhibitors, the SERT inhibitor clomipramine did not substitute for MA. This result agrees with data from previous studies of SERT inhibitors in MA-or cocaine-trained animals (Cunningham and Callahan, 1991;Spealman, 1993;Terry et al, 1994;Schama et al, 1997;Tidey and Bergman, 1998;. Like clomipramine, the NET inhibitor desipramine did not engender MA-like stimulus effects, again consistent with the results of previous studies in MAtrained animals (Tidey and Bergman, 1998;.…”

“…These results are comparable to those previously reported for the SERT inhibitor citalopram in cocaine-trained monkeys (Spealman, 1993; but see Schama et al, 1997). However, they differ markedly from previous results in rats showing that, with few exceptions, SERT inhibitors enhance the discriminative stimulus effects of cocaine (Simon and Appel, 1997;Callahan and Cunningham, 1997;Kleven and Koek, 1998;.…”

“…In the present and previous studies, for example, SERT inhibitors, including clomipramine or fluoxetine, did not reproduce, and even attenuated the discriminative stimulus effects of dopaminergic psychomotor stimulants in monkeys trained with the relatively high doses of 0.3 mg/kg MA and 1.0 mg/kg cocaine (Spealman, 1993). Yet, the SERT inhibitor fluoxetine previously has been shown to accentuate the discriminative stimulus effects of cocaine in monkeys trained with a lower cocaine dose (0.3 mg/kg; Schama et al, 1997). Although the role of training dose in such effects of SERT inhibitors needs to be documented more fully, these results suggest, overall, that NET and SERT mechanisms play limited, modulatory roles in the discriminative stimulus effects of cocaine or MA.…”

Serotonin 5-HT2 Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…For example, indirect 5-HT agonists such as SERT inhibitors or 5-HT releasers have been found to attenuate the behavioral-stimulant effects (Spealman, 1993;Howell and Byrd, 1995), reinforcing effects (Kleven and Woolverton, 1993;Glowa et al, 1997;Czoty et al, 2002;Negus et al, 2007), and reinstatement effects (Ruedi-Bettschen et al, 2010;Howell and Negus, 2014) of cocaine in nonhuman primates. Interestingly, some SERT inhibitors (e.g., fluoxetine, citalopram), which evoked saline-responding when administered alone, enhanced the discriminative stimulus effects of cocaine in both monkeys (Spealman, 1993;Schama et al, 1997) and rats (Cunningham and Callahan, 1991;Callahan and Cunningham, 1997). Although the differential mechanisms underlying these observations remain to be fully explored, further studies employing in vivo microdialysis techniques in awake squirrel monkeys revealed that the altered behavioral effects of cocaine after serotonergic pretreatments correlated with reductions in cocaine-induced DA increases within the striatum (Czoty et al, 2002).…”

Cocaine-Like Discriminative Stimulus Effects of Heroin: Modulation by Selective Monoamine Transport Inhibitors

“…For example, norepinephrine transporter (NET) inhibitors have been shown to substitute at least partially for the DS effects of cocaine, whereas the ␣-1 norepinephrine (NE) antagonist prazosin attenuated the DS effects of cocaine (Johanson and Barrett, 1993;Spealman, 1995). In contrast, serotonin transporter (SERT) inhibitors consistently have been shown to lack significant cocaine-like DS effects in monkeys (Kleven et al, 1990;Spealman, 1993;Schama et al, 1997). Variable effects of SERT inhibitors on the DS effects of cocaine in monkeys have been reported, with a study from our laboratory showing that the selective SERT inhibitor citalopram attenuated the DS effects of cocaine (Spealman, 1993;cf.…”