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BEHAVIORAL PHARMACOLOGY

Relationship between the Serotonergic Activity and Reinforcing Effects of a Series of Amphetamine Analogs

Department of Psychiatry and Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi (S.W., K.G.A., W.L.W.); Department of Psychology, West Virginia University, Morgantown, West Virginia (K.G.A.); Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, Maryland (M.H.B., R.B.R.); and Center for Organic and Medicinal Chemistry, Science and Engineering Group, RTI International, Research Triangle Park, North Carolina (B.E.B.)

It has been reported that among drugs with mixed actions on central nervous system monoamine systems, increased serotonergic activity is associated with decreased potency as a reinforcer. The present experiment was designed to examine this relationship for amphetamine analogs that varied in serotonin releasing potency and to evaluate whether serotonergic actions can affect reinforcing efficacy. Compounds PAL 313 and 314 are para- and meta-methylamphetamine, respectively. PAL 303 and 353 are para- and meta-fluoroamphetamine, respectively. All compounds had similar potencies as in vitro releasers of dopamine (DA) and norepinephrine (NE) but differed in potency for 5-hydroxytryptamine (serotonin) (5-HT) release [EC₅₀ (nanomolar) PAL 313 = 53.4; PAL 314 = 218; PAL 303 = 939; PAL 353 = 1937]. When made available to rhesus monkeys (Macaca mulatta)(n = 4) for self-administration under a fixed-ratio 25 schedule, all were positive reinforcers with biphasic dose-response functions (0.003–1.0 mg/kg) and were equipotent. PAL 313 was self-administered at a lower rate than the other compounds, which were indistinguishable. Under a progressive-ratio schedule (n = 5), all drugs were positive reinforcers. Dose-response functions increased to a maximum or were biphasic (0.01–1.0 mg/kg), and drugs were equipotent. At maximum, PAL 313 maintained less responding than other PAL drugs, which maintained similar maxima. Thus, all compounds were positive reinforcers under both schedules, consistent with their potent DA actions. Responding was lower when 5-HT potency was higher and comparable with DA and NE potency. The results suggest that the mechanism for this effect involves a decrease in reinforcing potency and efficacy among monoamine releasing agents when 5-HT releasing potency is increased relative to DA.

Address correspondence to: Dr. William L. Woolverton, Division of Neurobiology and Behavior Research, Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, 2500 N. State St., Jackson, MS 39216-4505. E-mail: wwoolverton{at}psychiatry.umsmed.edu

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