Effects of a novel tamoxifen‐analogue (6c) on methamphetamine induced neurotoxicity

Abstract

The use and abuse of psychostimulants have been associated with countless adverse effects (including addiction, neurotoxicity and death) and billions of dollars of damage to the global economy. Yet, to date, there is no effective pharmacotherapeutic. Amphetamine has been shown to activate the β-isoform of protein kinase C (PKC), which phosphorylates the dopamine transporter (DAT) at N-terminal serines and threonines to increase extracellular dopamine. Recently, a novel PKC inhibitor (6C) has been developed to attenuate or block amphetamine use and addiction. Prior studies have shown that the administration of 6C with amphetamine inhibited amphetamine monoamine release, hyperlocomotion and self-administration.1 Although the neurotoxicity accompanying the acute and chronic use of amphetamine and methamphetamine are well characterized, no treatment exists for the neurotoxicity associated with their use. To assess the potential of 6C to impact psychostimulant-induced neurotoxicity (and extend its therapeutic efficacy in psychostimulant abuse), female mice received a single injection of 0 (vehicle) or 6 mg/kg of 6C subcutaneously 2 h prior to a binge-like regimen of 5 mg/kg of methamphetamine or saline during which mice were injected with 5 mg/kg of methamphetamine or saline (IP) every 2 h for a total of four injections. Two days following injections, mice were euthanized by decapitation for brain removal. The striatum was dissected from both sides of the brain. Each side of the striatum was frozen separately using dry ice and stored at −80°C until analysis occurred. As shown in Figure 1, 6C significantly reduced methamphetamine-induced neurotoxicity when probing for DAT and tyrosine hydroxylase (TH) (western/immunoblot analysis) and DA levels (HPLC). To assess any generalization of these effects of 6C on psychostimulant intake and neurotoxicity, similar analyses will be made with a new class of beta ketone analogues of amphetamine, the synthetic cathinones, whose reinforcing effects are mediated by neurochemical mechanisms similar to and different from those of amphetamine2. 1. C. Carpenter, A. G. Zestos, R. Altshuler, R. J. Sorenson, B. Guptaroy, H. D. Showalter, R. T. Kennedy, E. Jutkiewicz and M. E. Gnegy, Neuropsychopharmacology, 2017, 42, 1940-1949. 2. A. L. Riley, K. Nelson, P. To, R. López-Arnau, P. Xu, D. Wang, Y. Wang, H-W. Shen, D. Kuhn, M. Angoa-Perez, J. Anneken, D. Muskiewicz, and F. Hall. Neuroscience & Biobehavioral Reviews, 2020, 110, 150-173.