Psychoactive bath salts (PABS) are dangerous cocktails of designer cathinones that are gaining a foothold in the illicit drug scene. The cathinones possess abuse liability and toxicity and share pharmacological features with cocaine and commonly abused amphetamine derivatives. Mephedrone (4-methylmethcathinone, MEPH) and MDPV (methylenedioxypyrovalerone) are two designer cathinones that remain popular with drug abusers in the UK and US, respectively, despite legislation to criminalize their possession. The hazards of PABS have been derived mostly from anecdotal reports and surveys. Limited preclinical work has established that MEPH and MDPV are rewarding and reinforcing but exert distinct effects on monoamines; MEPH is a non-selective transporter substrate that stimulates monoamine release, and MDPV is a potent dopamine and norepinephrine transport blocker. A gap in the neuropharmacological profiles of designer cathinones is the lack of knowledge about their interactions with glutamate systems. Established psychostimulants, notably cocaine, produce dysregulation of brain reward glutamate systems that underlies their abuse potential, especially as it relates to relapse. Furthermore, several promising candidates to manage psychostimulant addiction modulate glutamate transporter and receptor activity. Results from studies proposed herein will fill this gap in knowledge by providing the first comprehensive information about the role of the corticolimbic glutamate system, especially extracellular glutamate and the glutamate transport system, in the neuropharmacological effects of PABS. The hypothesis to be tested is that designer cathinones (MEPH and MDPV) disrupt glutamate function in the NAcc core of rats and produce reinforcing and drug-seeking properties in a rat model of self-administration (SA) that are attenuated by modulators of glutamate transporter subtype 1 (GLT-1) and cysteine-glutamate exchange (i.e. system Xc ). System Xc is the major source of basal glutamate whereas GLT-1 clears extrasynaptic -- glutamate, and dysfunction of both transporters during withdrawal from a chronic cocaine regimen facilitates relapse to cocaine seeking. Our hypothesis linking glutamate and PABS is supported by evidence that GLT-1 transporter expression is reduced during withdrawal from a chronic designer cathinone regimen and that a glutamate receptor antagonist reduces hyperactivity produced by repeated, intermittent synthetic cathinone exposure. A combination of neurochemical and behavioral approaches will test the hypothesis in the following Specific Aims: 1) Identify changes in extracellular glutamate levels and glutamate transporter function in the NAcc core across stages of MEPH and MDPV exposure and 2) Investigate the extent to which activators of GLT-1 (CTX) and system Xc- (N-acetylcysteine) affect intravenous MEPH and MDPV self-administration (SA). The expected positive impact of our results is the identification of the glutamate system, especially GLT-1 and system Xc-, as a mediator of the neuropharmacological effects of substituted cathinones found in PABS.
No FDA-approved medications to manage cocaine abstinence or relapse are available despite more than 50 years of psychostimulant research that has identified some of the biological substrates underlying cocaine's addictive properties. This surprising gap in therapy suggests that important biological substrates underlying the abuse liability of cocaine remain to be discovered. We now propose the first comprehensive investigation of the role of the glutamate aspartate transporter (GLAST) in cocaine's actions to test the hypothesis that the locomotor-stimulant effects, reinforcing efficacy, and drug-seeking properties of cocaine are dependent on GLAST.
