Lack of correlation between the activity of the mesolimbic dopaminergic system and the rewarding properties of pregabalin in mouse
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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 are 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.
KeywordsRewarding properties Pregabalin Dopamine VTA Nucleus accumbens
The authors greatly acknowledge “the Mouse Behavioural Phenotyping Core” (Center of Integrative Biology, Toulouse, France) for its expertise and assistance in setting up behavioral apparatus and procedures.
This independent study did not receive resources from pharmaceutical companies and was funded by the academic collaborating laboratories.
Compliance with ethical standards
All experiments were carried out in accordance with the European guidelines for the care of laboratory animals (European Communities Council Directive 86/609/ECC) and approved by the local Ethics Committee and the French Ministry of Education and Research (APAFIS#6659-2016090512114815 v3).
Conflict of interest
The authors declare that they have no conflict of interest.
- Barik J, Parnaudeau S, Saint Amaux AL, Guiard BP, Golib Dzib JF, Bocquet O, Bailly A, Benecke A, Tronche F (2010) Glucocorticoid receptors in dopaminoreceptive neurons, key for cocaine, are dispensable for molecular and behavioral morphine responses. Biol Psychiatry 68:231–239CrossRefPubMedGoogle Scholar
- Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP, Walker LC (2006) Calcium channel alpha2-delta type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice. Brain Res 1075:68–80CrossRefPubMedGoogle Scholar
- Daneshdoust D, Khalili-Fomeshi M, Ghasemi-Kasman M, Ghorbanian D, Hashemian M, Gholami M, Moghadamnia A, Shojaei A (2017) Pregabalin enhances myelin repair and attenuate glial activation in lysolecithin-induced demyelination model of rat optic chiasm. Neuroscience 344:148–156CrossRefPubMedGoogle Scholar
- Di Ciano P, Coury A, Depoortere RY, Egilmez Y, Lane JD, Emmett-Oglesby MW, Lepiane FG, Phillips AG, Blaha CD (1995) Comparison of changes in extracellular dopamine concentrations in the nucleus accumbens during intravenous self-administration of cocaine or d-amphetamine. Behav Pharmacol 6:311–322CrossRefPubMedGoogle Scholar
- Driot D, Jouanjus E, Oustric S, Dupouy J, Lapeyre-Mestre M (2016b) Pattern of gabapentin and pregabalin use and misuse: results of a population-based cohort study. Br J Clin Pharmacol (manuscript ID: MP-00410-18.R2)Google Scholar
- Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, Evrard A, Cazala P, Cormier A, Mameli-Engvall M, Dufour N, Cloëz-Tayarani I, Bemelmans AP, Mallet J, Gardier AM, David V, Fabre P, Granon S, Changeux JP (2005) Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436:103–107CrossRefPubMedGoogle Scholar
- Paxinos G, Franklin KBJ (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, San DiegoGoogle Scholar
- Schifano F, D'Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, Di Melchiorre G, Di Furia L, Farre M, Flesland L, Mannonen M, Majava A, Pagani S, Peltoniemi T, Siemann H, Skutle A, Torrens M, Pezzolesi C, van der Kreeft P, Scherbaum N (2011) Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom 80:118–122CrossRefPubMedGoogle Scholar
- Tsukada H, Harada N, Nishiyama S, Ohba H, Kakiuchi T (2000) Dose-response and duration effects of acute administrations of cocaine and GBR12909 on dopamine synthesis and transporter in the conscious monkey brain: PET studies combined with microdialysis. Brain Res 860:141–148CrossRefPubMedGoogle Scholar
- Yargic I, Ozdemiroglu FA (2011) Pregabalin abuse: a case report/pregabalin kötüye kullanımı: Bir olgu sunumu. Klinik Psikofarmakoloji Bülteni / Bulletin of Clinical Psychopharmacology:64–66Google Scholar