Riluzole Impairs Cocaine Reinstatement and Restores Adaptations in Intrinsic Excitability and GLT-1 Expression

Abstract

Adaptations in glutamate signaling within the brain's reward circuitry are observed following withdrawal from several abused drugs, including cocaine. These include changes in intrinsic cellular excitability, glutamate release, and glutamate uptake. Pharmacological or optogenetic reversal of these adaptations have been shown to reduce measures of cocaine craving and seeking, raising the hypothesis that regulation of glutamatergic signaling represents a viable target for the treatment of substance use disorders. Here, we tested the hypothesis that administration of the compound riluzole, which regulates glutamate dynamics in several ways, would reduce cocaine seeking in the rat self-administration and reinstatement model of addiction. Riluzole dose-dependently inhibited cue- and cocaine-primed reinstatement to cocaine, but did not affect locomotor activity or reinstatement to sucrose seeking. Moreover, riluzole reversed bidirectional cocaine-induced adaptations in intrinsic excitability of prelimbic (PL) and infralimbic (IL) pyramidal neurons; a cocaine-induced increase in PL excitability was decreased by riluzole, and a cocaine-induced decrease in IL excitability was increased to normal levels. Riluzole also reversed the cocaine-induced suppression of the high-affinity glutamate transporter 1 (EAAT2/GLT-1) in the nucleus accumbens (NAc). GLT-1 is responsible for the majority of glutamate uptake in the brain, and has been previously reported to be downregulated by cocaine. These results demonstrate that riluzole impairs cocaine reinstatement while rectifying several cellular adaptations in glutamatergic signaling within the brain's reward circuitry, and support the hypothesis that regulators of glutamate homeostasis represent viable candidates for pharmacotherapeutic treatment of psychostimulant relapse.

Biphasic effect of abstinence duration following cocaine self-administration on spine morphology and plasticity-related proteins in prelimbic cortical neurons projecting to the nucleus accumbens core

“…This interpretation is supported by findings showing that overexpression of CREB in a subset of amygdala neurons increases the likelihood that these neurons are involved in a neuronal ensemble encoding a fear memory context (Han et al 2007), perhaps through CREB-mediated increases in intrinsic excitability (Yiu et al 2014; Han et al 2007) or stabilization of individual excitatory synapses (Lisman et al 2018). The increase in nuclear pCREB and the potential for subsequent increased excitability following abstinence from cocaine SA are supported by recent data indicating that extinction from cocaine SA increases the intrinsic excitability of layer V PrL neurons, an effect required for cue-induced reinstatement (Sepulveda-Orengo et al 2017; Parrilla-Carrero et al 2018). Similarly, cocaine conditioned place preference (CPP) training increases evoked AMPA receptor-mediated excitatory transmission in layer V PrL cortical neurons and normalization of this adaptation prevents subsequent CPP memory retrieval (Otis and Mueller 2017).…”

“…Given that PrL glutamatergic transmission switches from a putatively hypoactive to a hyperactive state as a function of the duration of abstinence from cocaine SA (Dennis et al 2018; Sepulveda-Orengo et al 2017), we hypothesized that nuclear (Fos, pCREB) and dendritic (GluA1, GluA2) PRPs and dendritic spine morphometric features would follow a similar trajectory in PrL-NA core neurons since pathological adaptations that promote cocaine seeking occur within this pathway (Kalivas et al 2005; Kalivas 2009; Chen et al 2013). …”

Targeting Protein Kinase CK1δ with Riluzole: Could It Be One of the Possible Missing Bricks to Interpret Its Effect in the Treatment of ALS from a Molecular Point of View?

“…CK1δ inhibitors are able to restore the correct nuclear localization of TDP‐43, and thus riluzole itself modulating CK1δ activity could ensure the physiological processing and maturation of specific mRNA transcripts, mediated by TDP‐43 . This hypothesis found an experimental confirmation in two independent studies: in the first, riluzole showed the ability to reverse cocaine‐induced suppression of the glutamate transporter EAAT2 in the nucleus accumbens (NAc), and coherently, in the second study, long‐term riluzole administration rescued EAAT2 mRNA levels and protein expression in the hippocampus . Moreover, in a murine model, depletion of EAAT2 promoted the progressive impairment of glutamate reuptake, with consequent death of motor neurons, muscular weakness, and paralysis conditions similar to those of ALS …”

“…[25] This hypothesis found an experimentalc onfirmation in two independents tudies:i nt he first, riluzole showed the ability to reversec ocaineinduced suppression of the glutamatet ransporter EAAT2 in the nucleusa ccumbens (NAc), and coherently,i nt he second study,l ong-term riluzole administration rescued EAAT2 mRNA levels andp rotein expression in the hippocampus. [26,27] Moreover,i namurine model,d epletion of EAAT2 promoted the progressive impairmento fg lutamate reuptake, with consequent death of motor neurons,muscular weakness, and paralysis conditions similar to those of ALS. [28] All this evidenceallows us to speculate that riluzole, through the inhibition of CK1d,e nsures the physiological nuclearc ompartmentalization of TDP-43, which guaranteest he correct maturation of EAAT2 mRNA transcripts.…”

Divergent behavioral consequences of manipulations enhancing pyramidal neuron excitability in the prelimbic cortex

“…Pyramidal neurons, particularly those from layers 5 and 6, are the primary projection neurons, while GABA neurons regulate pyramidal neuron excitability (3,4). Repeated cocaine exposure triggers an array of adaptations that increase PL pyramidal neuron excitability (35)(36)(37)(38)(39)(40)(41)(42). Repeated cocaine also reduces GABAergic neurotransmission in PL pyramidal neurons via suppression of presynaptic GABA release (43), and blunting of postsynaptic GABAAR-and GABABR-mediated signaling (40,43,44).…”