Abstract
Drug addiction remains a prevalent and fatal disease worldwide that carries significant social and economic impacts. Recent reports suggest illicit pregabalin (Lyrica) use may be increasing among youth, however the addictive potential of pregabalin has not been well established. Drug seeking behavior and chronic drug use are associated with deficits in glutamate clearance and activation of postsynaptic glutamatergic receptors. In the current study, we investigated the abuse potential of pregabalin using conditioned place preference (CPP) paradigm. Different doses of pregabalin (30, 60, 90, and 120 mg/kg) were used to assess the seeking behavior in mice. Glutamate homeostasis is maintained by glutamate transporter type-1 (GLT-1), which plays a vital role in clearing the released glutamate from synapses and drug seeking behavior. Therefore, we investigated the role of glutamate in pregabalin-seeking behavior with ceftriaxone (CEF), a potent GLT-1 upregulator. Mice treated with pregabalin 60 and 90 mg/kg doses demonstrated drug seeking-like behavior, which was significantly blocked by CEF pretreatment. These results suggest that pregabalin-induced CPP was successfully modulated by CEF which could serve as a lead compound for developing treatment for pregabalin abuse.
Highlights
Addiction to several drugs and substances remains a critical health issue worldwide
No significant effect was observed between mice when treated with 60 mg/kg pregabalin throughout the conditioning training over phase [F (1, 9) = 2.215, p = 0.1709], we observed a significant effect between treatments [F (1,9) = 6.929, p = 0.0273], and an association between phase and treatments [F (1, 9) = 38.02, p = 0.0002]
Post-hoc analysis demonstrated that time spent was significantly elevated in in pregabalin-paired chamber in comparison with saline-paired chamber in the post-test (p < 0.0001; Fig. 2B), and time spent was significantly increased in pregabalin-paired chamber in the post-test compared to the pre-test (p < 0.01; Fig. 2B)
Summary
Addiction to several drugs and substances remains a critical health issue worldwide. According to the world drug report, Saudi Arabia had one of the highest reported drug seizure rates in 20111. In conditioned place preference (CPP) studies conducted in rats, pregabalin (up to 30 mg/kg) did not cause rewarding effects and did not change place preference[15,16]. These doses were small compared to higher doses used in previous case reports of pregabalin abuse[4,5,6,7,8,9]. Disturbances in glutamate homeostasis in the NAc have been shown to be associated with drug seeking behavior and chronic drug use[24,25,26,27,28]. In the present study we explored the abuse potential of different doses of pregabalin using CPP and assessed the potential mechanistic role of GLT-1 in pregabalin associated drug-seeking behavior by pretreatment with CEF
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