Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the ‘atypical’ antipsychotics, clozapine and risperidone

Schreiber, Rudy; Brocco, Mauricette; Millan, Mark J.

doi:10.1016/0014-2999(94)90643-2

Cited by 122 publications

(78 citation statements)

References 9 publications

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“…from saline in operant conditioning chambers equipped with two levers. The training dose was selected in light of the ability of MDL100,907 to abolish actions mediated by 5-HT 2A receptors in other paradigms without exerting significant effects at other receptors (Schreiber et al 1994(Schreiber et al , 1995aMillan et al 1999a;Gobert et al 2000).…”

Section: Methodsmentioning

confidence: 99%

“…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).…”

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confidence: 99%

“…Further, clozapine and several other antipsychotics block DS properties of 5-HT 2A agonists such as DOI (Palumbo and Winter 1994;Schreiber et al 1994), while 5-HT 2A receptors are, at least partially, involved in the DS properties of clozapine itself (Millan et al 1999c).…”

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

Dekeyne

2002

Neuropsychopharmacology

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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

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Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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

Dekeyne

2002

Neuropsychopharmacology

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“…On the other hand, the 5-HT 2C/2B receptor antagonist SDZ SER 082 displays 40-fold selectivity for the 5-HT 2C compared to the 5-HT 2A receptor, but similar affinity for the 5-HT 2C and 5-HT 2B receptor subtypes (Nozulak et al 1995). Studies conducted with some of these 5-HT 2 subtypeselective antagonists have indicated that 5-HT 2A rather than 5-HT 2C receptor subtypes are crucial for the discriminative stimulus effects of DOI (Schreiber et al 1994). 5-HT 2A receptor activation was also suggested to be the principal mechanism underlying the disruptive effects of DOI on prepulse inhibition and latent inhibition (Sipes and Geyer 1995;Padich et al 1996;Hitchcock et al 1997).…”

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Effect of LSD on Prepulse Inhibition and Spontaneous Behavior in the Rat A Pharmacological Analysis and Comparison between Two Rat Strains

Ouagazzal

Grottick

Moreau

et al. 2001

Neuropsychopharmacology

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The goal of the present study was to better delineate the mechanisms of action of the prototypical hallucinogen LSD. LSD (0.03, 0.1 and 0.3 mg/kg, s.c.) Delineation of the neurobiological mechanisms underlying the profound effects of hallucinogens on perception, mood, and thought processes has been the subject of great interest over the years. There is now increasing evidence that the two major classes of hallucinogens, the indolamines (e.g., LSD) and the phenethylamines (e.g., DOM and DOI) share a common site of action at 5-HT 2 receptor populations (Barnes and Sharp 1999;Aghajanian and Marek 2000). 5-HT 2 receptors consist of three distinct subtypes, namely 5-HT 2A , 5-HT 2B and 5-HT 2C (for review see Barnes and Sharp 1999). They are G-protein-coupled receptors and share a high degree of homology in their amino acid sequences. Binding and cellular studies have shown that LSD, DOI, DOM and other related hallucinogens share a high affinity for the 5-HT 2A/B/C receptor subtypes (Egan et al. 1998;Nelson et al. 1999;Porter et al. 1999).

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“…Accumulating evidence strongly suggests that hallucinogenic agents exert their stimulus control in rats primarily by activation of the 5-HT 2A receptor, with the 5-HT 2C and 5-HT 1A receptors having modulatory roles Fiorella et al, 1995a,b;Schreiber et al, 1994;Winter et al, 2000). In the first study of stimulus control in mice by a hallucinogen, Smith et al (2003) found that the 5-HT 2A and 5-HT 2C receptors played a major and minor role, respectively, in the discriminative effects of the phenethylamine hallucinogen, 2,5-dimethoxy-4-iodo-amphetamine (DOI; Shulgin and Shulgin, 1991).…”

Section: Introductionmentioning

confidence: 99%

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Krall

Richards

Rabin

et al. 2008

Pharmacology Biochemistry and Behavior

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Rationale-Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT 2A receptors, with serotonergic receptors of the 5-HT 1A and 5-HT 2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT 2A receptor density is decreased and, at a functional level, the head twitch response following the administration of DOI, an index of activation of 5-HT 2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter.Objective-Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice.Methods-SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle.Results-The visual stimulus exerted control in both genotypes. LSD induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital induced stimulus control in 80% of WT mice and 54% of knockout mice.Conclusions-Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT 1A and/or 5-HT 2A receptors underlies the absence of stimulus control by LSD.

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Blockade of the discriminative stimulus effects of DOI by MDL 100,907 and the ‘atypical’ antipsychotics, clozapine and risperidone

Cited by 122 publications

References 9 publications

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

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

Effect of LSD on Prepulse Inhibition and Spontaneous Behavior in the Rat A Pharmacological Analysis and Comparison between Two Rat Strains

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

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