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.

Accumulating evidence suggests that acetylcholine nicotinic mechanisms may contribute to the abuse‐related effects of methamphetamine (MA). In the present study, effects of indirect dopamine (DA) agonists, (d‐amphetamine, L‐MA, cocaine, GBR 12909, methylphenidate), full [nicotine (NIC), anabasine (ANA), (+)‐epibatadine, (−)‐epibatadine, isoarecolone] and partial [varenicline (VAR)] nicotinic agonists, and other cholinergic compounds (atropine, scopolamine, rivastigmine, donepezil) were examined in rats that discriminated 0.3 mg/kg i.p. MA from saline. All indirect DA agonists fully substituted for MA in a dose‐related manner. Among cholinergic agonists, NIC fully substituted for MA in a dose‐dependent manner, whereas other nicotinic agonists produced partial MA‐like responding. Other cholinergic compounds, failed to substitute for MA. In additional experiments, nicotinic agonists were examined in squirrel monkeys that discriminated 0.1 mg/kg i.m. MA from saline. NIC fully substituted for MA, whereas ANA and VAR produced partial MA‐lever responding. These results are consistent with the idea that nicotinic activity plays a role in the abuse‐related effects of MA, and may provide a mechanism for anti‐stimulant medication development (supported by ARRA‐NIH‐NIDA DA026548‐01A1).

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Results from GTPγS binding and other in vitro assays suggest that cannabinoid (CB) receptor agonists range in efficacy from partial to full agonists. The present studies compared the in vivo effects of a proposed CB1 full agonist, AM4054, and three potential CB1 partial agonists, BAY 59‐3074, an aminoalkylindole (AAI3), and Δ9‐tetrahydrocannabinol (Δ9THC) in female rats. During 6 hr sessions post‐injection AM4054 and BAY 59‐3074 reduced core body temperature by more than 40C and doses required to decrease temperature by 3oC were 0.13 and 6.7 mg/kg, respectively; neither Δ9THC nor AAI3 decreased temperature by more than 2oC. In a rat tail‐flick assay, AM4054, Δ9THC and BAY 59‐3074 all had antinociceptive effects over 6 hr sessions, with respective ED50 values of 0.13, 6.0, and 7.7 mg/kg; AAI3 produced small, but significant, increases in tail flick latency. Similarly, AM4054, Δ9THC and BAY 59‐3074 all had diuretic effects, and the average doses required to yield 15 g/kg urine within 2 hrs were 0.05, 5.3, and 4.9 mg/kg, respectively; AAI3 did not have diuretic effects. All four drugs tested decreased operant responding for sweetened milk at 1‐3 hrs after injection; the respective ED50 values for AM4054, Δ9THC, BAY 59‐3074, and AAI3 were: 0.04, 6.4, 3.8, and 10.2 mg/kg. These data indicate that CB1 agonists may be differentiated according to their profile of behavioral effects in rats. (Supported by PHS Grants DA19205, 15723)