The Selective Serotonin2A Receptor Antagonist, MDL100,907, Elicits a Specific Interoceptive Cue in Rats

Abstract

Employing a two-lever, food-reinforced, Fixed Ratio 10 drug discrimination procedure, rats were trained to recognize the highly-selective serotonin (5-HT) 2A receptor antagonist, MDL100,907 (0.16 mg/kg, i.p.) Drug discrimination procedures have been extensively used in the characterization of psychoactive agents, including drugs interacting with 5-HT reuptake sites (Millan et al. 1999b) and agonists at 5-HT 1A (Schreiber et al. 1995b) and 5-HT 3 (Glennon et al. 1992) receptors. Although it has proven difficult to differentiate the roles of closely-related 5-HT 2A , 5-HT 2B and 5-HT 2C receptors (Glennon 1991), it was suggested that discriminative stimulus (DS) properties of several 5-HT 2 agonists and hallucinogens, such as mescaline (Appel and Callahan 1989), lysergic acid diethylamide (LSD) (Fiorella et al. 1995) and quipazine (Friedman et al. 1984), are mediated by 5-HT 2A receptors. Further, use of the highly selective 5-HT 2A receptor antagonist, MDL100,907 (Kehne et al. 1996), demonstrated that 5-HT 2A receptors mediate DS properties of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI), a further hallucinogen (Schreiber et al. 1994). In contrast, DS properties of the 5-HT 2 ligand, m-chlorophenylpiperazine (mCPP), appear to be mediated by 5-HT 2C receptors (Callahan and Cunningham 1994; see Gommans et al. 1998), and employing the 5-HT 2B/2C antagonist, SB206,553, and the selective 5-HT 2C antagonist, SB242,084, it was shown that 5-HT 2C receptors likewise mediate DS properties of the novel, mixed 5-HT 2C/2B agonist, RO60,0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine; Dekeyne et al. 1999).Interest in 5-HT 2A receptors has been reinforced by evidence that their blockade may contribute to the distinctive functional profile of the "atypical" antipsychotic, clozapine, and, possibly, other novel agents employed

Discriminative Stimulus Effects of 1-(2,5-Dimethoxy-4-methylphenyl)-2-aminopropane (DOM), Ketanserin, and (R)-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-pipidinemethanol (MDL100907) in Rats

“…Different groups of eight rats each were trained to discriminate between saline and either 0.56 mg/kg DOM, 1.0 mg/kg ketanserin, or 0.1 mg/kg MDL100907 while responding under a fixed ratio (FR) schedule of food presentation. The training doses of DOM, ketanserin, and MDL100907 were based on published reports of these drugs when they were used as training drugs or to antagonize drugs presumed to be acting at 5-HT 2A receptors (Schreiber et al, 1994;Dekeyne et al, 2002;Smith et al, 2002;Li et al, 2007). Daily sessions consisted of a 30-min timeout period, during which the chamber was dark and lever presses had no programmed consequence, followed by a response period, during which stimulus lights above both levers were illuminated and an FR 5 schedule of food presentation was active.…”

“…Several laboratories have established stimulus control with DOM (e.g., Glennon et al, 1983). Stimulus control also has been established with MDL100907 (Dekeyne et al, 2002), although this discrimination has not been used to explore possible inverse agonism by MDL100907; and stimulus control has been established between ketanserin and another drug (e.g., quipazine; Smith et al, 1995Smith et al, , 2002, although there are no reports of a discrimination between ketanserin and vehicle.…”

Discriminative stimulus properties of the “atypical” antidepressant, mirtazapine, in rats: a pharmacological characterization

“…A role of 5-HT 2A receptor blockade in the DS properties of mirtazapine also appears unlikely inasmuch as SB242,084, SB243,213, and S32006 all possess low affinity for 5-HT 2A receptors, and the highly selective antagonist at 5-HT 2A receptors, MDL100,907 and SR46349-B, failed to significantly substitute for mirtazapine. Nonetheless, it would be interesting to evaluate whether mirtazapine substitutes for a DS elicited by MDL100,907 itself and whether it blocks the interoceptive actions of the agonist, DOI, which are elicited via stimulation of 5-HT 2A receptors (Schreiber et al 1994;Dekeyne et al 2002). …”

“…Third, both mianserin and mirtazapine abolished a DS elicited by the α 2 -AR agonist, S18616 (Dekeyne and Millan 2006). Fourth, mianserin antagonized a DS elicited by the 5- CLZ Clozapine, SSRI selective 5-HT reuptake inhibitor, NARI noradrenaline reuptake inhibitor, Ant antagonist, PAG partial agonist HT 2A agonist, DOI (Yamamoto et al 1991;Smith et al 1990Smith et al , 2002Schreiber et al 1994) and substituted for the 5-HT 2A receptor antagonist, MDL100,907 (Dekeyne et al 2002;Dekeyne A and Millan MJ, unpublished observation). Finally, mianserin shared the DS properties of the 5-HT 1A agonist, flesinoxan (Herremans et al 1999).…”

Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines

“…The efficacy of M100907 as an antagonist of hallucinogen-induced stimulus control in the rat was first demonstrated by Schreiber et al (1994) for DOI and has now been extended to include, among others, LSD, 5-MeO-DMT, and DOM. An interesting complication was added by Dekeyne et al (2002Dekeyne et al ( , 2003 who observed that M100907 can establish stimulus control in the rat and suggested that the effect is mediated by antagonism of 5-HT 2A receptors with possible involvement of alpha 1 adrenoceptors and other yet to be identified mechanisms.…”