title: Increased gabaergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in mu-opioid receptor knockout mice.
abstract: There is general agreement that dopaminergic neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex play a key role in drug reinforcement. The activity of these neurons is strongly modulated by the inhibitory and excitatory input they receive. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperpolarization of these GABAergic neurons, thereby causing a disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptors upon GABA neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement. We studied mu-opioid receptor signaling in relation to cocaine reinforcement in wild-type and mu-opioid receptor knockout mice using a cocaine self-administration paradigm and in vitro electrophysiology. Cocaine self-administration was reduced in mu-opioid receptor knockout mice, suggesting a critical role of mu-opioid receptors in cocaine reinforcement. The frequency of spontaneous inhibitory post-synaptic currents onto dopaminergic neurons in the ventral tegmental area was increased in mu-opioid receptor knockout mice compared with wild-type controls, while the frequency of spontaneous excitatory post-synaptic currents was unaltered. The reduced cocaine self-administration and increased GABAergic input to VTA dopaminergic neurons in mu-opioid receptor knockout mice supports the notion that suppression of GABAergic input onto dopaminergic neurons in the VTA contributes to mu-opioid receptor modulation of cocaine reinforcement.
authors.affiliation: Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Centre Utrecht, Stratenum, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Mathon
authors.forename: H M B
authors.initials: HM
authors.lastname: Lesscher
authors.forename: M A F M
authors.initials: MA
authors.lastname: Gerrits
authors.forename: A
authors.initials: A
authors.lastname: Kamal
authors.forename: J E
authors.initials: JE
authors.lastname: Pintar
authors.forename: A G P
authors.initials: AG
authors.lastname: Schuller
authors.forename: B M
authors.initials: BM
authors.lastname: Spruijt
authors.forename: J P H
authors.initials: JP
authors.lastname: Burbach
authors.forename: M P
authors.initials: MP
authors.lastname: Smidt
authors.forename: J M
authors.initials: JM
authors.lastname: van Ree
authors.forename: G M J
authors.initials: GM
authors.lastname: Ramakers
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000235:genetics*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013569:Synapses / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D017450:Receptors, Opioid, mu; D005680:gamma-Aminobutyric Acid; D003042:Cocaine; D004298:Dopamine