Synthetic cathinone MDPV enhances reward function through purinergic P2X7 receptor-dependent pathway and increases P2X7 gene expression in nucleus accumbens. (1st April 2019)

• Record Type: Journal Article
• Authors: Gentile, Taylor A.; Simmons, Steven J.; Tallarida, Christopher S.; Su, Shu; Rom, Slava; Watson, Mia N.; Reitz, Allen B.; Potula, Raghava; Rawls, Scott M.
• Is Part Of: Drug and alcohol dependence. Volume 197(2019)
• Page Start: 22
• Page End: 27
• Publication Date: 2019-04-01
• Subjects: Purine -- P2X7 -- Psychostimulant -- MDPV -- Cathinone -- ICSS -- ATP -- Accumbens; Drug abuse -- Periodicals; Alcoholism -- Periodicals; 616.86
• DOI: 10.1016/j.drugalcdep.2018.12.022
• Languages: English
• ISSNs: 0376-8716

Abstract

Highlights: A role for the purine P2X7 receptor system in designer cathinone (MDPV) pharmacology was investigated. P2X7antagonist A438079 reduced MDPV-induced reward in ICSS assay. MDPV exposure enhanced P2X7 gene and protein expression in nucleus accumbens. MDPV exposure enhanced ATP synthase gene and protein expression in nucleus accumbens. Abstract: Background and purpose: Purinergic P2X7 receptors are present on neurons, astrocytes and microglia and activated by extracellular ATP. Since P2X7 receptor activation releases endogenous substrates ( e.g., pro-inflammatory cytokines, dopamine, and glutamate) that facilitate psychostimulant reward and reinforcement, we investigated the hypothesis that the synthetic cathinone 3, 4-methylenedioxypyrovalerone (MDPV) produces rewarding effects that are dependent on active P2X7 receptors. Methods: Reward function was measured in male mice using intracranial self-stimulation (ICSS). MDPV (0.1, 0.3, 0.5 mg/kg, SC) and a selective P2X7 antagonist (A438079) (5, 10, 50 mg/kg, IP) were tested alone and in combination. In separate mice, gene and protein expression of P2X7 and mitochondrial adenosine triphosphate (ATP) synthase (an enzyme that catalyzes synthesis of ATP, an endogenous ligand for P2X7 receptors) in the nucleus accumbens (NAcc) were quantified following MDPV exposure (0.1, 0.5, 5 mg/kg, SC). Key results: MDPV (0.5 mg/kg, SC) facilitated ICSS as quantified by a significant reduction in brain reward threshold. A438079 (5, 10, 50 mg/kg, IP) did not affect ICSS by itself; however, for combined administration, A438079 (10 mg/kg, IP) inhibited facilitation of ICSS by MDPV (0.5 mg/kg, SC). At the cellular level, MDPV exposure increased gene and protein expression of P2X7 and ATP synthase in the NAcc. Conclusion and implication: We provide evidence that a psychostimulant drug produces reward enhancement that is influenced by P2X7 receptor activity and enhances P2X7 receptor expression in the brain reward circuit.