Afferent-specific AMPA receptor subunit composition and regulation of synaptic plasticity in midbrain dopamine neurons by abused drugs.
Ventral tegmental area (VTA) dopamine (DA) neurons play a pivotal role in processing reward-related information and are involved in drug addiction and mental illness in humans. Information is conveyed to the VTA in large part by glutamatergic afferents that arise in various brain nuclei, including the pedunculopontine nucleus (PPN). Using a unique rat brain slice preparation, we found that PPN stimulation activates afferents targeting GluR2-containing AMPA receptors (AMPAR) on VTA DA neurons, and these afferents did not exhibit long-term depression (LTD). In contrast, activation of glutamate afferents onto the same DA neurons via stimulation within the VTA evoked EPSCs mediated by GluR2-lacking AMPARs that demonstrated LTD or EPSCs mediated by GluR2-containing AMPA receptors that did not express LTD. Twenty-four hours after single cocaine injections to rats, GluR2-lacking AMPARs were increased at both PPN and local VTA projections, and this permitted LTD expression in both pathways. Single injections with the main psychoactive ingredient of marijuana, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), increased GluR2-lacking AMPA receptors and permitted LTD in only the PPN pathway, and these effects were prevented by in vivo pretreatment with the cannabinoid CB1 receptor antagonist AM251. These results demonstrate that cocaine more globally increases GluR2-lacking AMPA receptors at all glutamate synapses on VTA dopamine neurons, whereas Delta(9)-THC selectively increased GluR2-lacking AMPA receptors at subcortical PPN synapses. This suggests that different abused drugs may exert influence over distinct sets of glutamatergic afferents to VTA DA neurons which may be associated with different reinforcing or addictive properties of these drugs.
Electrophysiology Research Section, Cellular Neurobiology Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA.
Cameron H
CH
Good
Carl R
CR
Lupica
D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology*; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D013287:Illicit Drugs / Q000494:pharmacology; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D036881:Long-Term Synaptic Depression / Q000187:drug effects; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000187:drug effects*; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D045042:Pedunculopontine Tegmental Nucleus / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism
D018765:Dopamine Uptake Inhibitors; D013287:Illicit Drugs; D011619:Psychotropic Drugs; D018091:Receptors, AMPA; D013759:Dronabinol; D003042:Cocaine; C104722:glutamate receptor ionotropic, AMPA 2; D004298:Dopamine