Interactions between cocaine and (-)-DS 121: studies with 2-deoxyglucose autoradiography and microdialysis in the rat brain.
(-)-DS 121 [S-(-)-3-(3-cyanophenyl)-N-n-propyl piperidine], a dopamine autoreceptor preferring antagonist, has been shown to stimulate locomotor activity and induce conditioned place preference. However, the drug fails to facilitate intracranial self-stimulation or substitute for cocaine in cueing experiments, and it blocks cocaine self-administration. In the present study using 2-deoxyglucose autoradiography, (-)-DS 121 (at 50 but not 15 mg/kg i.p.) significantly and selectively increased local cerebral glucose utilization in the olfactory cortex, medial and lateral septum, hippocampal areas, substantia nigra pars reticulata, caudate, and mammillary body. Local cerebral glucose utilization was depressed in caudal areas of the cortex. Interestingly, however, both doses of (-)-DS 121 blocked the increases in local cerebral glucose utilization produced by 5 mg/kg i.v. cocaine. The present study also evaluated the effects of (-)-DS 121 of extracellular striatal dopamine levels using microdialysis in freely moving rats. By itself, 15 mg/kg of (-)-DS 121 increased extracellular striatal dopamine levels to approximately 300% of controls. Cocaine (5 mg/kg i.v.) produced a 370% increase in striatal dopamine levels. When rats were pretreated with (-)-DS 121, a subsequent dose of cocaine augmented the increase in extracellular striatal dopamine to 870% of controls. The results support the contention that (-)-DS 121 possesses weak cocaine-mimetic effects and that its antagonism of cocaine's subjective effects are due to interactions with dopamine at postsynaptic sites. It is hypothesized that, like other preferential autoreceptor antagonists, (-)-DS 121 may be useful as a pharmacotherapy in drug addiction.
Koch
S
S
Wayne State University School of Medicine, Department of Psychiatry and Behavioral Neuroscience, Detroit, MI 48202, USA.
Piercey
M F
MF
Galloway
M P
MP
Svensson
K A
KA
D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects; D003042:Cocaine / Q000494:pharmacology*; D003847:Deoxyglucose; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D004347:Drug Interactions; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D007275:Injections, Intravenous; D008297:Male; D017551:Microdialysis; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D018492:Dopamine Antagonists; D018765:Dopamine Uptake Inhibitors; D009570:Nitriles; D010880:Piperidines; C094012:3-(3-cyanophenyl)-N-n-propylpiperidine; D003847:Deoxyglucose; D003042:Cocaine; D004298:Dopamine