title: Amphetamine self-administration attenuates dopamine D2 autoreceptor function.
abstract: Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drug-seeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [(35)S]GTPγS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gαi2, whereas striatal D2/D3 receptors were coupled equally to Gαi2 and Gαo for signaling. Importantly, AMPH abolished the interaction between Gαi2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gαi2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction.
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Erin S
authors: ES
authors: Calipari
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Haiguo
authors: H
authors: Sun
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Khalil
authors: K
authors: Eldeeb
authors: Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Deborah J
authors: DJ
authors: Luessen
authors: Department of Otolaryngology, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Xin
authors: X
authors: Feng
authors: 1] Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA [2] The Center for Neurobiology of Addiction Treatment, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Allyn C
authors: AC
authors: Howlett
authors: 1] Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA [2] The Center for Neurobiology of Addiction Treatment, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Sara R
authors: SR
authors: Jones
authors: 1] Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC, USA [2] The Center for Neurobiology of Addiction Treatment, Wake Forest University School of Medicine, Winston Salem, NC, USA.
authors: Rong
authors: R
authors: Chen
mesh_terms: D000661:Amphetamine / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D058999:Drug-Seeking Behavior / Q000187:drug effects; D008297:Male; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D012646:Self Administration; D015398:Signal Transduction; D066328:Ventral Striatum / Q000187:drug effects / Q000378:metabolism
chemical_list: D017660:Autoreceptors; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D000661:Amphetamine; D004298:Dopamine