Monoaminergic Psychomotor Stimulants: Discriminative Stimulus Effects and Dopamine Efflux

Abstract

The present studies were conducted to investigate the relationship between discriminative stimulus effects of indirectly acting monoaminergic psychostimulants and their ability to increase extracellular levels of dopamine (DA) in the nucleus accumbens (NAcb) shell. First, the behavioral effects of methamphetamine (MA), cocaine (COC), 1-[2-[bis(4-fluorophenyl-)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909), d-amphetamine, and methylphenidate were established in rats trained to discriminate intraperitoneal injections of 0.3 mg/kg MA from saline. In other studies, in vivo microdialysis was used to determine the effects of MA, COC, and GBR 12909 on extracellular DA levels in the NAcb shell. Results show that all drugs produced dose-related and full substitution for the discriminative stimulus effects of 0.3 mg/kg MA. In microdialysis studies, cumulatively administered MA (0.3-3 mg/kg), COC (3-56 mg/ kg), and GBR 12909 (3-30 mg/kg) produced dose-dependent increases in DA efflux in the NAcb shell to maxima of approximately 1200 to 1300% of control values. The increase in DA levels produced by MA and COC was rapid and short-lived, whereas the effect of GBR 12909 was slower and longer lasting. Dose-related increases in MA lever selection produced by MA, COC, and GBR 12909 corresponded with graded increases in DA levels in the NAcb shell. Doses of MA, COC, and GBR 12909 that produced full substitution increased DA levels to approximately 200 to 400% of control values. Finally, cumulatively administered MA produced comparable changes in DA levels in both naive and 0.3 mg/kg MA-trained rats. These latter results suggest that sensitization of DA release does not play a prominent role in the discriminative stimulus effects of psychomotor stimulants.

A preclinical evaluation of the discriminative and reinforcing properties of lisdexamfetamine in comparison to d-amfetamine, methylphenidate and modafinil

“…In this model, D-amfetamine and methylphenidate both dose-dependently generalised to the discriminative cue elicited by intraperitoneal injection of D-amfetamine. This finding is consistent with the cross-generalisation of the discriminative cues of these two stimulants as determined in both rats (Witkin et al, 1991;Gosden et al, 1996;Craft and Stratmann, 1996;Kollins et al, 2001;Stadler et al, 2001;Desai et al, 2010) and human subjects (Martin et al, 1971;Smith and Davis, 1977;Heishman and Henningfield, 1991;Rush et al, 1998).…”

Drug Discrimination in Methamphetamine-Trained Rats: Effects of Cholinergic Nicotinic Compounds

“…The dopaminergic drugs d-AMP and the enantiomers of MA engendered dose-dependent and full or nearly full substitution for d-MA. These results are consistent with previous findings in d-MA-trained rats, pigeons, and squirrel monkeys (Sasaki et al, 1995;Tidey and Bergman, 1998;Munzar and Goldberg, 2000;Czoty et al, 2004;Desai et al, 2010). The two enantiomers of MA had similar discriminative stimulus effects; however, the levorotatory enantiomer, l-MA, was approximately 5-fold less potent than d-MA, presumably reflecting its greater potency in stimulating presynaptic DA release.…”

“…For example, directly and indirectly acting DA agonists have been shown to mimic, and DA receptor antagonists to attenuate, the discriminative stimulus effects of d-MA and cocaine (Callahan et al, 1997;Tidey and Bergman, 1998;Munzar and Goldberg, 2000). Moreover, a close correspondence has been reported between the discriminative stimulus effects of d-MA and cocaine and their ability to increase extracellular concentrations of DA in the nucleus accumbens shell of rats or the caudate nucleus of squirrel monkeys, findings that further contribute to our current understanding of DA's role in their subjective effects (Czoty et al, 2004;Desai et al, 2010).…”

Preference for Distinct Functional Conformations of the Dopamine Transporter Alters the Relationship between Subjective Effects of Cocaine and Stimulation of Mesolimbic Dopamine

“…The study of these subjective effects in the laboratory is often accomplished with drug-discrimination procedures, and several previous studies have indicated that the discriminative-stimulus effects of drugs are closely related to their subjective effects in humans (2, 3). The subjective, reinforcing, and discriminative-stimulus effects of psychomotor stimulants in humans and laboratory animals are thought to involve increased DA transmission in the mesolimbic system (4-8). In human subjects, a relationship between the subjective-effects of cocaine and dopamine (DA) transporter (DAT) occupancy in striatal areas has been demonstrated (9).…”