Discriminative stimulus properties of the serotonin agonist MK 212

Abstract

In an attempt to clarify the role of 5-hydroxytryptamine (5-HT) in the discriminative stimulus properties of MK 212 (6-chloro-2[1-piperazinyl]pyrazine), male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg of this compound from saline. While the putative 5-HT agonists fenfluramine and m-chlorophenylpiperazine (MCPP) mimicked MK 212 in a dose-related manner, d-lysergic acid diethylamide (LSD), 8-hydroxy-2(di-n-propylamino)tetralin (8-OHDPAT), 5-methoxy-N,N-dimethyltryptamine (5-MeODMT), quipazine, Ru 24969, and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) failed to substitute completely. The 5-HT1/5-HT2 antagonists BC 105, metergoline, and methysergide completely blocked the MK 212 cue, while the selective 5-HT2 antagonists ketanserin and pirenperone, the dopamine antagonists haloperidol and spiperone, and the beta-noradrenergic antagonist propranolol were without effect. The substitutions of fenfluramine and MCPP for MK 212 support a role for 5-HT in the MK 212 cue; however, the lack of substitution of many other 5-HT agonists is difficult to explain. The complete antagonism by 5-HT1/5-HT2 but not by selective 5-HT2, antagonists suggests the possibility that 5-HT1 receptors mediate the stimulus properties of MK 212. Further research is needed to support this hypothesis and to investigate the relative role of 5-HT and other neurotransmitters in the stimulus effects of MK 212.

Hyperlocomotive and Discriminative Stimulus Effects of Cocaine Are Under the Control of Serotonin2C(5-HT2C) Receptors in Rat Prefrontal Cortex

“…Neurochemical studies of MK 212 have demonstrated that this piperazine analog exhibits its highest affinity (K i Ϸ 32-490 nM) for 5-HT 2C R and displays full efficacy to stimulate the 5-HT 2C R (Kennett, 1993;Porter et al, 1999;Cussac et al, 2002). In vivo analyses indicate that systemic administration of MK 212 evokes hyperthermia and hypophagia (Clineschmidt, 1979), oral dyskinesias (Eberle-Wang et al, 1996), penile erections (Berendsen et al, 1990), hypomotility (Lucki et al, 1989), and discriminative stimulus effects (Cunningham et al, 1986), all of which are blocked preferentially by 5-HT 2C R antagonists. In contrast, MK 212 has a much lower affinity for 5-HT 2A R (K i Ϸ 17,400 nM; Kennett, 1993;Porter et al, 1999) and does not evoke behavioral effects consistent with an efficacy to stimulate 5-HT 2A R (e.g., Lucki et al, 1989;Fiorella et al, 1995).…”

Contribution of Serotonin (5-Hydroxytryptamine; 5-HT) 5-HT2 Receptor Subtypes to the Hyperlocomotor Effects of Cocaine: Acute and Chronic Pharmacological Analyses

“…All drugs were injected in a volume of 1 ml/kg. The doses of drugs were chosen based upon their functional selectivity at a particular 5-HT 2 R (Cunningham et al, 1986;RinaldiCarmona et al, 1992;Schreiber et al, 1995;Kennett et al, 1997;Gobert et al, 2000); the affinity profiles for each of the 5-HT 2 R ligands are presented in Table 1.…”

Discriminative stimulus effects of serotonin agonists, neutral antagonists, and inverse agonists in pigeons: perspectives on intrinsic efficacy measurements in vivo

“…Thereafter, five of these pigeons were retrained to discriminate an injection of 1.0 mg/kg of MK212 from saline. This training dose was based on the potency of MK212 to produce discriminative stimulus in rats (Cunningham et al 1986) and to substitute for the discriminative stimulus effects of mCPP in rats (Fiorella et al 1995b;Gommans et al 1998). Two additional pigeons failed to acquire a threechoice discrimination among injections of 0.1 mg/kg methysergide, saline, and 1.0 mg/kg WAY-163,909 in another experiment and these pigeons were retrained to discriminate 1.0 mg/kg MK212 from saline.…”

“…Drug discrimination procedures have been used previously to determine the mechanisms of action for a range of psychoactive drugs (Hayes and Kelly 1985;Negus and Fantegrossi 2008), distinguish low and high efficacy opioid agonists (Young et al 1992;Zhang et al 2000), and separate GABA inverse agonists from neutral antagonists (Leidenheimer and Schechter 1991;McMahon and France 2005;Rowan and Lucki 1992;Takada et al 1986). Previous operant drug discrimination studies have established 5-HT 2C receptor agonists such as MK212 (Cunningham et al 1986), mCPP (Callahan and Cunningham 1994;Fiorella et al 1995b;Gommans et al 1998), and R0 60-0175 (Dekeyne et al 1999) and antagonists such as pizotifen (Minnema et al 1984), mianserin (Kelley et al 1995), clozapine (Hoenicke et al 1992), and ketanserin (Smith et al 1995), as discriminative stimuli in rats, mice, or pigeons. The profiles of a 5-HT 2A receptor agonist, neutral antagonist, and inverse agonist were compared using drug discrimination procedures (Li et al 2009) but patterns of drug discrimination responding for 5-HT 2C receptor agonists, neutral antagonists, and inverse agonists have not been examined.…”