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- HT4 receptor 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-HT4 receptors, 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 300-307 |
| Number of pages | 8 |
| Journal | Journal of Pharmacology and Experimental Therapeutics |
| Volume | 291 |
| Issue number | 1 |
| State | Published - Oct 1999 |
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ASJC Scopus subject areas
- Pharmacology
Cite this
Antagonism of 5-hydroxytryptamine4 receptors attenuates hyperactivity induced by cocaine : Putative role for 5-hydroxytryptamine4 receptors in the nucleus accumbens shell. / McMahon, Lance R.; Cunningham, Kathryn.
In: Journal of Pharmacology and Experimental Therapeutics, Vol. 291, No. 1, 10.1999, p. 300-307.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Antagonism of 5-hydroxytryptamine4 receptors attenuates hyperactivity induced by cocaine
T2 - Putative role for 5-hydroxytryptamine4 receptors in the nucleus accumbens shell
AU - McMahon, Lance R.
AU - Cunningham, Kathryn
PY - 1999/10
Y1 - 1999/10
N2 - 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- HT4 receptor 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-HT4 receptors, 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.
AB - 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- HT4 receptor 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-HT4 receptors, 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.
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M3 - Article
C2 - 10490917
AN - SCOPUS:0032872358
VL - 291
SP - 300
EP - 307
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 1
ER -