Abstract
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-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-HT2A receptors modulates impulsivity and function of corticothalamostriatal circuits over an extensive dynamic range.
Footnotes
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.143370.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; DRL, differential reinforcement-of-low rate; 5-CSRTT, five-choice serial reaction time task; M100907, R-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol; IRT, inter-response time; SSRI, selective serotonin reuptake inhibitor; NMDA, N-methyl-d-aspartate; MK-801, dizocilpine or (-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; DMI, desmethylimipramine or desipramine; ANOVA, analysis of variance; veh, vehicle; mPFC, medial prefrontal cortex; (R)-CPP, 3-[(R)-2-carboxypiperazin-4-yl]-propyl-1-phosphoric acid.
- Received July 9, 2008.
- Accepted September 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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