Abstract
The localization of 5-hydroxytryptamine4(5-HT4) receptors suggests their role in the regulation of dopamine (DA) neurotransmission, a speculation that has been supported by neurochemical studies. Mesolimbic DA systems play a prominent role in mediating the behavioral effects of the abused psychostimulant cocaine, and the intent of the present study was to assess the role of 5-HT4 receptors in the control of spontaneous and cocaine-induced activity. Systemic administration of the 5-HT4 receptor partial agonist 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]1-propanone hydrochloride (RS 67333; 0.0001–1 mg/kg) or the 5-HT4receptor antagonist 4-amino-5-chloro-2-methoxy-benzoic acid-(diethylamino)ethyl ester hydrochloride (SDZ 205,557; 0.0001–1 mg/kg) did not significantly alter spontaneous activity, whereas SDZ 205,557 significantly attenuated cocaine-induced horizontal activity and rearing. To test the hypothesis that cocaine-elicited behaviors were modulated by 5-HT4 receptors in the nucleus accumbens (NAc) shell, two separate groups of male rats were implanted with bilateral cannulas aimed at the NAc shell. Intra-NAc shell microinjections of either RS 67333 (1 or 3 μg/0.2 μl/side) or SDZ 205,557 (1–5 μg/0.2 μl/side) did not alter spontaneous activity observed after a systemic saline injection but did significantly attenuate the hyperactivity induced by systemic cocaine injection (10 mg/kg). These results support an involvement of 5-HT4receptors, particularly those in the NAc shell, in the locomotor stimulatory effects of cocaine. Furthermore, these data suggest that 5-HT4 receptors may regulate behavioral processes dependent on mesolimbic DA pathways and may provide a novel target for the development of medications useful in the treatment of both drug dependence and psychiatric disorders.
Footnotes
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Send reprint requests to: Kathryn A. Cunningham, Ph.D., Department of Pharmacology and Toxicology, The University of Texas Medical Branch, Galveston, TX 77555-1031. E-mail: cunningham{at}utmb.edu
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↵1 This work was supported by National Institute on Drug Abuse Grants DA05708, DA06511 (to K.A.C.), and DA05879 (to L.R.M.). Portions of these data were presented at the 28th Annual Meeting of the Society for Neuroscience, 1998, Los Angeles.
- Abbreviations:
- DA
- dopamine
- 5-HT
- 5-hydroxytryptamine (serotonin)
- NAc
- nucleus accumbens
- RS 67333
- 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-butyl-4-piperidinyl]1-propanone hydrochloride
- SDZ 205,557
- 4-amino-5-chloro-2-methoxy-benzoic acid-(diethylamino)ethyl ester hydrochloride
- Received February 3, 1999.
- Accepted July 2, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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