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BEHAVIORAL PHARMACOLOGY

The 5-Hydroxytryptamine_2A Receptor Antagonist R-(+)--(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

Lilly Research Laboratories, Lilly Corporate Center, Eli Lilly and Company, Indianapolis, Indiana

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-HT_2A receptor antagonist and fluoxetine on differential-reinforcement-of-low-rate (DRL) 72-s schedule of operant reinforcement may speak to the role of 5-HT_2A 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-HT_2A receptor blockade may exert effects on impulsivity, [R-(+)--(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-5H-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-HT_2A receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range.

Address correspondence to: Dr. Gerard J. Marek, Abbott Laboratories, GPRD, Department R48B, Bldg. AP4-110, 100 Abbott Park Rd., Abbott Park, IL 60064. E-mail: gerard.marek{at}abbott.com