Elevation of Extracellular Glutamate by Blockade of Astrocyte Glutamate Transporters Inhibits Cocaine Reinforcement in Rats via a NMDA-GluN2B Receptor Mechanism

Abstract

It is well established that glutamate plays an important role in drug-induced and cue-induced reinstatement of drug seeking. However, the role of glutamate in drug reward is unclear. In this study, we systemically evaluated the effects of multiple glutamate transporter (GLT) inhibitors on extracellular glutamate and dopamine (DA) in the nucleus accumbens (NAc), intravenous cocaine self-administration, intracranial brain-stimulation reward (BSR), and reinstatement of cocaine seeking in male and female rats. Among the five GLT inhibitors we tested, TFB-TBOA was the most potent. Microinjections of TFB-TBOA into the NAc, but not the ventral tegmental area (VTA), or dorsal striatum (DS), dose-dependently inhibited cocaine selfadministration under fixed-ratio and progressive-ratio (PR) reinforcement schedules, shifted the cocaine dose-response curve downward, and inhibited intracranial BSR. Selective downregulation of astrocytic GLT-1 expression in the NAc by GLT-1 antisense oligonucleotides also inhibited cocaine self-administration. The reduction in cocaine self-administration following TFB-TBOA administration was NMDA GluN2B receptor dependent, and rats self-administering cocaine showed upregulation of GluN2B expression in NAc DA-and cAMP-regulated phosphoprotein 32 (DARPP-32)-positive medium-spiny neurons (MSNs). In contrast, TFB-TBOA, when locally administered into the NAc, VTA, or ventral pallidum (VP), dose-dependently reinstated cocaine-seeking behavior. Intra-NAc TFB-TBOA-evoked drug-seeking was long-lasting and NMDA/AMPA receptor dependent. These findings, for the first time, indicate that glutamate in the NAc negatively regulates cocaine's rewarding effects, while an excess of glutamate in multiple brain regions can trigger reinstatement of drug-seeking behavior.

Ventral pallidal regulation of motivated behaviors and reinforcement

“…Ionotropic glutamatergic neurotransmission in the VP regulates exploratory locomotor behavior and is necessary for cued rewardseeking (Churchill and Kalivas, 1999;Richard et al, 2018), the formation of context-drug reward associations (Dallimore et al, 2006), and the development of sensitized locomotor responses to repeated administration of drugs of abuse (Dallimore et al, 2006). In line with these findings, increasing VP glutamate by blocking astroglial glutamate uptake potentiates relapse to heroin seeking (Yang et al, 2022). However, VP glutamate is also capable of reducing cocaine self-administration and cocaine-primed reinstatement through the activation of type III metabotropic receptors in the VP (Li et al, 2009(Li et al, , 2010.…”

“…In addition to these sources of glutamate, VP neurons receive intrinsic synaptic glutamate inputs from local VP Glu neurons (Levi et al, 2020 ; Stephenson-Jones et al, 2020 ; McKenna et al, 2021 ). Furthermore, glutamatergic tone in the VP is regulated by glial glutamate transporters (Wydra et al, 2013 ; Yang et al, 2022 ).…”

Development of a Highly Efficient Long-Acting Cocaine Hydrolase Entity to Accelerate Cocaine Metabolism

“…Cocaine is known as a widely abused drug. There is no pharmacotherapy approved by the Food and Drug Administration (FDA) for cocaine use disorder (CUD) treatment. − Traditional pharmacological approaches to the development of a treatment for CUD aim to block the action of cocaine on various neuronal receptors , and monoamine transporters, particularly dopamine transporter (DAT) as the primary target responsible for the stimulant effects of cocaine in the brain . Due to the fact that the brain transporters/receptors have their own intrinsic pharmacological functions, it would be very difficult to directly antagonize cocaine’s physiological effects without affecting brain’s normal functions using a traditional pharmacological approach. − Aspiration to meet the unmet medical need led to exploring biologics, such as monoclonal antibodies, vaccines, and enzymes, as alternative pharmacotherapeutic strategies.…”

Kinetic characterization of an efficient cocaine hydrolase against toxic metabolites of cocaine

“…3 Most of the previously reported efforts have been focused on blocking the interactions of cocaine with its neuronal receptors or transporters responsible for cocaine's stimulant effects. 4,5 Unfortunately, cocaine interacts with many human proteins, including multiple receptors and transporters in the brain. 3,[6][7][8][9][10][11] It would be extremely challenging to directly antagonize the physiological effects of cocaine without impairing the brain's normal functions because all the neuronal receptors and transporters have their own normal physiological functions.…”