Muscarinic receptor blockade in the ventral tegmental area attenuates cocaine enhancement of laterodorsal tegmentum stimulation-evoked accumbens dopamine efflux in the mouse.
The reinforcing properties of cocaine have been related to increased extracellular concentrations of dopamine in the nucleus accumbens (NAc). M5 muscarinic acetylcholine receptors (mAChRs) on dopamine cells in the ventral tegmental area (VTA) facilitate mesoaccumbens dopamine transmission and are critically involved in mediating natural and drug reinforcement. We investigated the effects of pharmacological blockade of mAChRs in the VTA on cocaine's ability to enhance electrically evoked NAc dopamine efflux. Using fixed potential amperometry together with carbon fiber recording microelectrodes positioned in the NAc core, we quantified dopamine oxidation currents (dopamine efflux) evoked by brief stimulation (15 monophasic pulses at 50 Hz every 30 s) of the laterodorsal tegmentum (LDT) in urethane (1.5 g/kg, i.p.) anesthetized mice. Compared to predrug baseline responses, cocaine (5 or 10 mg/kg, i.p.) dose-dependently enhanced LDT stimulation-evoked NAc dopamine efflux, whereas the nonsubtype selective mAChR antagonist scopolamine (10 microg/0.5 microl) microinfused into the VTA diminished LDT-evoked NAc dopamine efflux. Preinfusion of scopolamine into the VTA diminished the facilitatory actions of cocaine on LDT stimulation-evoked NAc dopamine efflux, and when infused at the peak effect of cocaine attenuated LDT-evoked dopamine efflux to below predrug baseline levels. These findings suggest that LDT cholinergic inputs to dopamine neurons in the VTA, via activation of mAChRs (probably of the M5 subtype), are involved in modulating the facilitatory effects of cocaine on NAc dopamine neurotransmission. They also suggest that the development of antagonists aimed at selectively disrupting M5 receptor function may be valuable in reducing abuse liability of psychostimulants.
Lester
Deranda B
DB
Department of Psychology, The University of Memphis, Memphis, Tennessee 38152, USA.
Miller
Anthony D
AD
Blaha
Charles D
CD
D000704:Analysis of Variance; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation; D008297:Male; D051379:Mice; D008845:Microinjections; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology*; D013194:Staining and Labeling; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013681:Tegmentum Mesencephali / Q000187:drug effects* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology
D018727:Muscarinic Antagonists; D011976:Receptors, Muscarinic; D012601:Scopolamine; D003042:Cocaine; D004298:Dopamine