The 5-Hydroxytryptamine2A Receptor Antagonist R-(+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol (M100907) Attenuates Impulsivity after Both Drug-Induced Disruption (Dizocilpine) and Enhancement (Antidepressant Drugs) of Differential-Reinforcement-of-Low-Rate 72-s Behavior in the Rat

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 327; no. 3; pp. 891 - 897
• Main Authors: Ardayfio, Paul A., Benvenga, Mark J., Chaney, Stephen F., Love, Patrick L., Catlow, John, Swanson, Steven P., Marek, Gerard J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2008
• Subjects: Animals; Antidepressive Agents - pharmacology; Behavior, Animal - drug effects; Dizocilpine Maleate - pharmacology; Fluorobenzenes - pharmacology; Piperidines - pharmacology; Rats; Receptor, Serotonin, 5-HT2A - drug effects; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Reinforcement, Psychology; Serotonin Antagonists - pharmacology
• ISSN: 0022-3565; 1521-0103; 1521-0103
• DOI: 10.1124/jpet.108.143370

Previous work has suggested that N-methyl-d-aspartate (NMDA) receptor antagonism and 5-hydroxytryptamine (5-HT)2A receptor blockade may enhance and attenuate, respectively, certain types of impulsivity mediated by corticothalamostriatal circuits. More specifically, past demonstrations of synergistic “antidepressant-like” effects of a 5-HT2A receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT2A receptor blockade with respect to response inhibition as an important prefrontal cortical executive function relating to motor impulsivity. To examine the dynamic range over which 5-HT2A receptor blockade may exert effects on impulsivity, [R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol] (M100907) was examined both alone and in combination with the psychotomimetic NMDA receptor antagonist dizocilpine [e.g., (-)-5-methyl-10,11-dihydro-5 H-dibenzo[a,d]cyclohepten-5,10-imine maleate; MK-801] and two different antidepressants, the tricyclic antidepressant desmethylimipramine (DMI) and the monoamine oxidase inhibitor tranylcypromine in rats performing under a DRL 72-s schedule. MK-801 increased the response rate, decreased the number of reinforcers obtained, and exerted a leftward shift in the inter-response time (IRT) distribution as expected. A dose of M100907 that exerted minimal effect on DRL behavior by itself attenuated the psychotomimetic effects of MK-801. Extending previous M100907-fluoxetine observations, addition of a minimally active dose of M100907 to low doses of DMI and tranylcypromine enhanced the antidepressant-like effect of the antidepressants. Therefore, it may be that a tonic excitation of 5-HT2A receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range.