Neurokinin 3 receptor activation potentiates the psychomotor and nucleus accumbens dopamine response to cocaine, but not its place conditioning effects.
Neurokinin(3) receptors (NK(3)-Rs) have been implicated in psychomotor activity and reinforcement mechanisms. Recently, we showed that NK(3)-R antagonism blocked the psychostimulant properties of cocaine both in rats and in primates. Here, using in vivo microdialysis in the nucleus accumbens (NAc) of freely moving rats, we investigated the effect of the NK(3)-R agonist senktide (0.2 and 0.4 mg/kg s.c.) on the cocaine-evoked increase in dopamine. Cocaine (10 mg/kg i.p.) increased dopamine levels to 404 and 480% of baseline in the core and shell of the NAc, respectively. Pretreatment with senktide at a dose of 0.2 mg/kg potentiated this effect to 666 (core) and 869% (shell) of baseline, without having any effect on dopamine when given alone. Behavioural measurements revealed that 0.2 mg/kg senktide also potentiated the cocaine-induced increase in horizontal and vertical activity. Senktide alone induced a short-lasting increase in activity that was not accompanied by any alterations of the neurochemical parameters. In conditioned place preference (CPP) experiments, senktide pretreatment did not alter CPP induced by cocaine (5 and 10 mg/kg i.p.), and had no effect when given alone. Likewise, cocaine-conditioned locomotor activity was not affected by the NK(3)-R agonist. However, as in the microdialysis studies, cocaine-induced (5 and 10 mg/kg i.p.) hyperactivity was potentiated by senktide, and there was evidence for a facilitation of sensitization to the hyperlocomotor effects of cocaine by senktide. These data provide evidence that NK(3)-Rs are involved in the control of the hyperlocomotor and NAc DA response to cocaine, but not in cocaine-induced CPP.
Jocham
Gerhard
G
Institute of Physiological Psychology and Center for Biological and Medical Research, University of Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany.
Lauber
Andrea C
AC
Müller
Christian P
CP
Huston
Joseph P
JP
de Souza Silva
M Angélica
MA
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003042:Cocaine / Q000494:pharmacology*; D003213:Conditioning, Psychological / Q000187:drug effects* / Q000502:physiology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018042:Receptors, Neurokinin-3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013373:Substance P / Q000031:analogs & derivatives / Q000494:pharmacology
D018765:Dopamine Uptake Inhibitors; D010446:Peptide Fragments; D018042:Receptors, Neurokinin-3; D015102:3,4-Dihydroxyphenylacetic Acid; C054724:senktide; D013373:Substance P; D003042:Cocaine; D004298:Dopamine