Chronic Administration of the Methylxanthine Propentofylline Impairs Reinstatement to Cocaine by a GLT-1-Dependent Mechanism

Abstract

In recent years, interactions between neurons and glia have been evaluated as mediators of neuropsychiatric diseases, including drug addiction. In particular, compounds that increase expression of the astroglial glutamate transporter GLT-1 (N-acetylcysteine and ceftriaxone) can decrease measures of drug seeking. However, it is unknown whether the compounds that influence broad measures of glial physiology can influence behavioral measures of drug relapse, nor is it clear whether the upregulated GLT-1 is functionally important for suppressing of drug seeking. To address these questions, we sought to determine whether the glial modulator and neuroprotective agent propentofylline (PPF) modifies drug seeking in rats using a reinstatement model of cocaine relapse. We found that 7 days of chronic (but not acute) administration of PPF significantly decreased both cue- and cocaine-induced reinstatement of cocaine seeking. We next determined whether the effect of systemic PPF on reinstatement depended upon its ability to restore expression of GLT-1 in the nucleus accumbens. PPF restored the cocaine-induced decrease in GLT-1 in the accumbens core; then, using an antisense strategy against glutamate transporter GLT-1, we found that restored transporter expression was necessary for PPF to inhibit cue-primed cocaine seeking. These findings indicate that modulating glial physiology with atypical xanthine derivatives like PPF is a potential avenue for developing new medications for cocaine abuse, and support the hypothesis that neuron-glial interactions contribute to mechanisms of psychostimulant addiction, particularly via expression and function of astroglial glutamate transporters.

The Nucleus Accumbens: Mechanisms of Addiction across Drug Classes Reflect the Importance of Glutamate Homeostasis

“…As expected, PPF inhibits both cued-induced and drug-primed reinstatement of cocaine seeking (Reissner et al, 2014), as well as morphine CPP (Narita et al, 2006). Interestingly, as is the case for NAC, the ability of PPF to prevent reinstatement required the reversal of cocaine-induced downregulation of GLT-1 expression (Reissner et al, 2014).…”

“…As such, PPF is an exciting drug that combines the therapeutic action of a glial modulator with the restoration of glutamate homeostasis (discussed in section III), is augmented by exposure to drugs of abuse, and contributes heavily to relapse vulnerability (Kalivas, 2009). As expected, PPF inhibits both cued-induced and drug-primed reinstatement of cocaine seeking (Reissner et al, 2014), as well as morphine CPP (Narita et al, 2006). Interestingly, as is the case for NAC, the ability of PPF to prevent reinstatement required the reversal of cocaine-induced downregulation of GLT-1 expression (Reissner et al, 2014).…”

Persistent reduction of cocaine seeking by pharmacological manipulation of adenosine A1 and A2A receptors during extinction training in rats

“…Cocaine self-administration reduces the expression of glial glutamate transporter (GLT-1) that contributes to low basal glutamate in the NAc (Knackstedt et al 2010a). Restoration of GLT-1 deficits during withdrawal corresponds with a persistent attenuation of cocaine- and cue-primed reinstatement (Knackstedt et al 2010a; Reissner et al 2013). Interestingly, increasing A1AR transmission in the accumbens results in increased expression of GLT-1 mRNA (Wu et al 2011).…”

Astrocytic Dysfunction and Addiction

“…Interestingly, PPF has also been shown to up-regulate GLT-1, making it a potential pharmacotherapy for addiction (Tawfik and others 2006). Indeed, preclinical studies support the ability of PPF to inhibit both cued- and drug-primed reinstatement to cocaine seeking in rodents (Reissner and others 2014a). Furthermore, as discussed above for NAC, the ability of PPF to inhibit cocaine seeking was dependent on its ability to enhance GLT-1 expression (Reissner and others 2014a).…”