The stimulatory and inhibitory components of cocaine's actions on the 5-HTP-induced 5-HT(2A) receptor response

Document Type

Article

Publication Title

Pharmacology Biochemistry and Behavior

Abstract

Previously we have shown that cocaine attenuates the 5-HT(2A) receptor-mediated head-twitch response (HTR) in mice produced by the 5-HT(2A/C) direct agonist (±)-1(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). This inhibition appears to be due to cocaine-induced indirect stimulation of the inhibitory serotonergic 5-HT(1A) and noradrenergic α2 receptors via the inhibition of reuptake of synaptic serotonin (5-HT) and norepinephrine (NE), respectively. In the present study, we investigated the effects of cocaine, its phenyltropane analogue WIN 35428, and the selective 5-HT (sertraline), NE (nisoxetine) and dopamine (DA) (GBR 12935) reuptake inhibitors on the 5-hydroxytryptophan (5-(HTP)-induced HTR. We utilized two experimental protocols where cocaine or the cited drugs were administered either after (protocol 1) or prior (protocol 2) to 5-HTP injection. Cocaine in both protocols produced a dose-dependent enhancement in the 5-HTP-induced HTR (ED50 4.68 ± 1.21 and 3.55 ± 1.31, respectively). Sertraline was more potent (ED50 2.64 ± 1.1 and 2.1 ± 1.54, respectively) in enhancing the induced behavior and dose by dose produced greater (3 to 10 times) HTRs than cocaine. On the other hand, nisoxetine dose dependently and completely attenuated the induced behavior (ID50 3.33 ± 1.32 and 1.72 ± 1.34, respectively), whereas GBR 12935 only at high doses (ID50 15.34 ± 1.52 and 11.91 ± 1.3, respectively) decreased the induced response. The inability of cocaine to induce as many HTRs as sertraline appears to lie in its ability to also indirectly stimulate the inhibitory 5-HT(1A) and α2 receptors because the stimulant caused greater enhancement in the 5-HTP-induced HTRs in the presence of their corresponding antagonists [S(-)-UH 301 and yohimbine, respectively]. WIN 35428 was more potent (ED50 2.87 ± 1.3 and 1.79 ± 1.1 for protocols 1 and 2, respectively) in stimulating the 5-HTP-induced HTR and produced a bell-shaped dose-response curve. The results indicate that cocaine enhances the 5-HTP-induced HTR via the inhibition of synaptic 5-HT reuptake. The stimulant also simultaneously attenuates the induced behavior by indirect simulation of the serotonergic 5-HT(1A) and noradrenergic α2 receptors via inhibition of reuptake of the corresponding monoamines.

First Page

387

Last Page

396

DOI

10.1016/S0091-3057(96)00108-6

Publication Date

1-1-1996

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