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AMPAR (α-amino-3-hydroxy-5-methylisoxazole-4-propionate glutamate receptor) stimulation in the nucleus accumbens (NAc) is critical in cocaine seeking. Here, we investigate the functional interaction between D1 dopamine receptors (D1DR) and AMPARs in the NAc, and explore how A1 adenosine receptor (A1AR) stimulation may reduce dopamine-induced facilitation of AMPARs and cocaine seeking. All animals were trained to self-administer cocaine and were tested for reinstatement of cocaine seeking following extinction procedures. The role of AMPARs in both AMPA- and D1DR-induced cocaine seeking was assessed using viral-mediated gene transfer to bi-directionally modulate AMPAR activity in the NAc core. The ability of pharmacological AMPAR blockade to modulate D1DR-induced cocaine seeking also was tested. Immunoblotting was used to determine whether stimulating D1DR altered synaptic AMPA GluA1 phosphorylation (pGluA1). Finally, the ability of an A1AR agonist to modulate D1DR-induced cocaine seeking and synaptic GluA1 receptor subunit phosphorylation was explored. Decreasing AMPAR function inhibited both AMPA- and D1DR-induced cocaine seeking. D1DR stimulation increased AMPA pGluA1(S845). Administration of the A1AR agonist alone decreased synaptic GluA1 expression, whereas coadministration of the A1AR agonist inhibited both cocaine- and D1DR-induced cocaine seeking and reversed D1DR-induced AMPA pGluA1(S845). These findings suggest that D1DR stimulation facilitates AMPAR function to initiate cocaine seeking in D1DR-containing direct pathway NAc neurons. A1AR stimulation inhibits both the facilitation of AMPAR function and subsequent cocaine seeking, suggesting that reducing AMPA glutamate neurotransmission in direct pathway neurons may restore inhibitory control and reduce cocaine relapse.
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http://dx.doi.org/10.1038/npp.2013.96 | DOI Listing |
Neuropsychopharmacology
December 2024
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
The accumulation of GluA2-lacking Ca-permeable AMPARs (CP-AMPARs) in the medium spiny neurons (MSNs) of the nucleus accumbens (NAc) is required for the expression of incubation of cocaine craving. The exchange protein directly activated by cAMP (Epac) is an intracellular effector of cAMP and a guanine nucleotide exchange factor for the small GTPase Rap1. Epac2 has been implicated in the trafficking of AMPA receptors at central synapses.
View Article and Find Full Text PDFBiol Psychiatry Cogn Neurosci Neuroimaging
December 2024
Department of Psychiatry and Behavioral Sciences, Medical University of South Carolina, Charleston, SC; Department of Neurosciences, Medical University of South Carolina, Charleston, SC; Department of Translational Neuroscience, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC.
Background: Cue-induced craving precipitates relapse in drug and alcohol use disorders. Theta burst stimulation (TBS) to the left frontal pole of the medial prefrontal cortex (MPFC) has previously been shown to reduce drinking and brain reactivity to alcohol cues. This randomized, double-blind, sham-controlled target-engagement study aimed to assess whether TBS has similar effects in individuals with cocaine use disorder (CUD).
View Article and Find Full Text PDFPsychopharmacology (Berl)
December 2024
Department of Population Health Sciences, Unit of Animals in Science and Society, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands.
Rationale: Substance use disorder (SUD) is a chronic relapsing brain disorder that is characterised by loss of control over substance use. A variety of rodent models employing punishment setups have been developed to assess loss of control over substance use, i.e.
View Article and Find Full Text PDFAbstinence from cocaine use has been shown to elicit a progressive intensification or incubation of cocaine craving/seeking that is posited to contribute to propensity for relapse. While the mechanisms underlying incubation of cocaine seeking remain elusive, considerable evidence suggests that abstinence from cocaine promotes mesolimbic dopamine adaptations that contribute to exaggerated cocaine seeking. Consequently, preventing these dopamine adaptations may reduce incubation of cocaine seeking and thereby reduce the likelihood of relapse.
View Article and Find Full Text PDFPharmacol Biochem Behav
November 2024
Division on Substance Use Disorders, New York State Psychiatric Institute and Department of Psychiatry, Columbia University Irving Medical Center, 1051 Riverside Drive, Unit 120, New York, NY 10032, USA.
Individuals seeking treatment for their cocaine use often report depressive systems and nearly half meet criteria for major depressive disorder (MDD). This descriptive study aimed to assess the effects of the antidepressant venlafaxine alone and in combination with gabapentin on depressive symptoms, subjective effects of cocaine, and cocaine self-administration in depressed and non-depressed people who use cocaine. The effects of medication condition on mood and on the effects of smoked cocaine were compared between a group of clinically depressed people who use cocaine (n = 5) and a control group of non-depressed people who use cocaine (n = 5) using laboratory-based measures.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!