Inhibition of cocaine self-administration by fluoxetine or D-fenfluramine combined with phentermine Andrew C. Glatz, Michelle Ehrlich, Richard S. Bae, Michelle J. Clarke, Patricia A. Quinlan, Emily C. Brown, Pedro Rada, Bartley G. Hoebel* Department of Psychology, Princeton University, Princeton, NJ 08544, USA Received 2 February 2001; received in revised form 6 August 2001; accepted 15 August 2001 Abstract Instrumental responding for intravenous cocaine in rats at 85% of free-feeding weight was significantly decreased 50% by D-fenfluramine plus phentermine (D-Fen/Phen, 5 mg/kg of each for 1 day). A similar effect was obtained in normal-weight rats self- administering a cocaine — heroin mixture. Treating normal-weight animals with fluoxetine (5 mg/kg) for 4 days also significantly decreased cocaine self-administration by half, and then adding phentermine caused an additional decrease in cocaine intake. Animals that were well trained to self-administer drug did not self-administer intravenous D-Fen/Phen or Flu/Phen. The present results confirm that serotonergic drugs can decrease cocaine, or cocaine/heroin, self-administration in rats, and that phentermine adds to the effect. Based on related research with the same dose of D-Fen/Phen, it is suggested that effectiveness in reducing cocaine reinforcement is due in part to a satiating effect in which dopamine and acetylcholine are released in the nucleus accumbens. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Cocaine; Self-administration; D-Fenfluramine; Fenfluramine; Phentermine; Fluoxetine; Speedball; Heroin; Rat 1. Introduction There has been a long search for treatments that effec- tively and safely reduce self-administration of addictive drugs such as cocaine. In the rat model, serotonergic drugs have been sometimes shown to reduce intravenous self- administration of cocaine. This has been demonstrated with a serotonin precursor L-tryptophan (Carroll et al., 1990b; McGregor et al., 1993) and the reuptake blocker fluoxetine (Carroll et al., 1990a; Peltier and Schenk, 1993; Richardson and Roberts, 1991); although negative results were also reported (Porrino et al., 1989; Tella, 1995) and clinical efficacy of fluoxetine was questioned (Grabowski et al., 1995). Serotonin depleters and receptor blockers can decrease cocaine seeking under some conditions (Schenk, 2000; Tran-Nguyen et al., 1999). This suggested that sero- tonergic drugs by themselves are of limited use. The question addressed here is how to make them more effective. Drugs of abuse act in part on a system that reinforces eating behavior (Di Chiara et al., 1993; Hoebel, 1985; Hoebel and Hernandez, 1990; Hoebel et al., 1999; Wise, 1998). Therefore, researchers have hypothesized that appe- tite suppressants might help to inhibit drug intake (Rada and Hoebel, 2000b). The combination of D,L-fenfluramine, which is largely serotonergic (Garattini et al., 1986), and phentermine that is partly dopaminergic and noradrenergic, and perhaps indirectly serotonergic as well (Baumann et al., 2000, Mendlin et al., 1999; Rowland et al., 2000) increases extracellular monoamines in various parts of the brain (Balcioglu and Wurtman, 1998; Shoaib et al., 1997) and proved especially potent for appetite reduction and weight loss in therapy for obesity (Weintraub, 1992). The combina- tion also reduced cocaine intake in animals (Glowa et al., 1997; Rothman et al., 1998) and may reduce cocaine-related symptoms in humans (Hitzig, 1993; Kampman et al., 2000), but this combination was reported to have toxic side effects in rats (Harvey and McMaster, 1977; Lew et al., 1997) and humans (Teramae et al., 2000). Other drug combinations and multifunction drugs were then tested in a variety of contexts in attempts to inhibit the appetite for food or drugs, e.g., D-fenfluramine (D-Fen) plus phentermine (Ehrlich et al., 0091-3057/01/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII:S0091-3057(01)00657-8 * Corresponding author. Tel.: +1-609-258-4463; fax: +1-609-258- 1113. E-mail address: hoebel@princeton.edu (B.G. Hoebel). www.elsevier.com/locate/pharmbiochembeh Pharmacology, Biochemistry and Behavior 71 (2002) 197– 204