Monoaminergic psychomotor stimulants: discriminative stimulus effects and dopamine efflux.
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.
Desai
Rajeev I
RI
Preclinical Pharmacology Laboratory, McLean Hospital/Harvard Medical School, Belmont, Massachusetts 02478, USA.
Paronis
Carol A
CA
Martin
Jared
J
Desai
Ramya
R
Bergman
Jack
J
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D015306:Biogenic Monoamines / Q000502:physiology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003042:Cocaine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000494:pharmacology; D008774:Methylphenidate / Q000494:pharmacology; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects*; D009714:Nucleus Accumbens / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule
D015306:Biogenic Monoamines; D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; D008774:Methylphenidate; D008694:Methamphetamine; C043425:vanoxerine; D003042:Cocaine; D004298:Dopamine