Lack of correlation between the activity of the mesolimbic dopaminergic system and the rewarding properties of pregabalin in mouse

Abstract

Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans. Although some preclinical data support this possibility, the rewarding properties of gabapentinoid is still a matter for debate. The aim of this work was to evaluate the rewarding properties of pregabalin and to determine its putative mechanism of action in healthy mice. Pregabalin alone (60 mg/kg; s.c.) produced a rewarding effect in the conditioned place preference (CPP) test albeit to a lower extent than cocaine (30 mg/kg; s.c.). Interestingly, when assessing locomotor activity in the CPP, the PGB60 group, similarly to the cocaine group, showed an increased locomotor activity. In vivo single unit extracellular recording showed that pregabalin had mixed effects on dopamine (DA) neuronal activity in the ventral tegmental area since it decreased the activity of 50% of neurons and increased 28.5% of them. In contrast, cocaine decreased 75% of VTA DA neuronal activity whereas none of the neurons were activated. Intracerebal microdialysis was then conducted in awake freely mice to determine to what extent such electrophysiological parameters influence the extracellular DA concentrations ([DA]ext) in the Nucleus Accumbens. Although pregabalin failed to modify this parameter, cocaine produced a robust increase (800%) in [DA]ext. Collectively these electrophysiological and neurochemical experiments suggest that the rewarding properties of pregabalin result from a different mode of action than that observed with cocaine. Further experiments are warranted to determine whether such undesirable effects can be potentiated under pathological conditions such as neuropathic pain, mood disorders or addiction and to identify the key neurotransmitter system involved.

Gabapentinoid Benefit and Risk Stratification: Mechanisms Over Myth

“…Disproportionate and phasic dopaminergic signal elicitation within the nucleus accumbens (NAc, the terminus of the mesolimbic system) is currently held to comprise the sine qua non of rewarding and addictive drugs or pursuits [47] and forms the cornerstone of modern neurobiology's mechanistic explanation of how dependence and addiction develops/is maintained. Multiple investigations have corroborated a lack of dopaminergic signal alterations in the NAc with the administration of gabapentin and pregabalin [48][49][50][51][52], or elevation only in experimental groups subjected to chronic painful stimulus via surgical ligation of a spinal nerve. Both drugs have also been shown to decrease or even block opioid-induced NAc dopaminergism [53].…”

Current Evidence on Abuse and Misuse of Gabapentinoids

“…A later study also in rats [7] challenged these results and found that pregabalin produced the same rewarding effects under painful conditions as under pain-free conditions when given in supratherapeutic doses. In a recent study on mice [8], pregabalin produced a rewarding effect in a conditioned place preference test. In another animal study [9], mice were exposed to a partial sciatic nerve ligation or were in a control group.…”

Non-medical Use of Prescription Gabapentinoids (Gabapentin and Pregabalin) in Five European Countries

“…The neurobiological mechanism involved in the abuse liability of gabapentinoids has not been yet clearly investigated. The usual increase in the dopamine levels at the mesolimbic brain circuits has not been proved in preclinical studies ( 14 , 15 ). Gabapentinoids have been reported to produce alcohol/gamma hydroxybutyrate (GHB)/benzodiazepine-type effects mixed with euphoria.…”