Cocaine-like discriminative stimulus effects of “norepinephrine-preferring” monoamine releasers: time course and interaction studies in rhesus monkeys

Abstract

Rationale The therapeutic potential of monoamine releasers with prominent dopaminergic effects is hindered by their high abuse liability. Objectives The present study examined the effects of several novel ‘norepinephrine (NE)-preferring’ monoamine releasers relative to nonselective monoamine releasers, d-amphetamine and d-methamphetamine, in rhesus monkeys trained to discriminate cocaine. NE-preferring releasers were approximately 13-fold more potent for NE compared to dopamine release and ranged in potency for serotonin release (PAL-329<l-methamphetamine<PAL-169). Methods Adult rhesus macaques were trained to discriminate 0.4 mg/kg, IM cocaine on a 30-response fixed ratio schedule of food reinforcement. Substitution studies determined the extent to which test drugs produced cocaine-like discriminative-stimulus effects and their time course. Drug interaction studies determined whether pretreatment with test drugs altered the discriminable effects of cocaine. Results Results show that cocaine, d-amphetamine, and d-methamphetamine dose-dependently substituted for cocaine with similar potencies. Among the ‘NE-preferring’ releasers, PAL-329 and l-methamphetamine also dose-dependently substituted for cocaine but differed in potency. PAL-169 failed to substitute for cocaine up to a dose that disrupted responding. When administered prior to cocaine, only d-amphetamine and PAL-329 significantly shifted the cocaine dose-effect function leftward indicating enhancement of cocaine’s discriminative stimulus effects. Conclusions These data suggest that greater potency for NE relative to dopamine release (up to 13-fold) does not interfere with the ability of a monoamine releaser to produce cocaine-like discriminative effects but that increased serotonin release may have an inhibitory effect. Further characterization of these and other ‘NE-preferring’ monoamine releasers should provide insight into their potential for the management of cocaine addiction.

The dopamine, serotonin and norepinephrine releasing activities of a series of methcathinone analogs in male rat brain synaptosomes

“…While most of the focus of these compounds has been on their DAT and SERT activity, the noradrenergic properties of methcathinones might also play a significant role in their pharmacology (Hysek et al 2011;Rothman et al 2001). NE releasers have been shown to affect cocaine selfadministration (Banks et al 2014;Kohut et al 2017) and drugs elevating NE do not appear to be reinforcing (Wee and Woolverton 2004). In our experience with rat brain synaptosomes, NET release potencies generally vary in a similar fashion as DAT release potencies and compounds tend to be slightly more potent as NE releasers (unpublished).…”

A genetic deletion of the serotonin transporter differentially influences the behavioural effects of MDMA

“…Studies in Rhesus monkeys, likewise, indicate that dopamine is more relevant for the discriminative stimulus of AMPH (Kamien and Woolverton, 1989). Thus, although a role for noradrenaline cannot be fully excluded (Kohut et al, 2017), the majority of the studies favour a more prominent role of dopamine (Schmidt and Weinshenker, 2014). Irrespective of the potential role of the DAT and NET, it is important to realise that the relative contribution of the DAT and NET would be similar in SERT +/+ and SERT −/− rats.…”

Limited modulation of the abuse-related behavioral effects of d-methamphetamine by disulfiram.

“…The present experiments were conducted in monkeys that previously were trained to discriminate cocaine (0.4 mg/kg, intramuscularly; IM) from saline under an FR30/TO10-s schedule of reinforcement (Kohut, Jacobs, Rothman, Partilla, Bergman, & Blough, 2017). Briefly, response keys were differentially associated with the pre-component injection of saline or cocaine.…”