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Thank you for visiting nature. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. 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. 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. 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. 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 1. As stated in several reports, the prevalence of drug addiction is high in Saudi Arabia, as are associated rates of hepatitis, HIV, crime, and socioeconomic decline for review see 2. Illicit Pregabalin Lyrica use has recently become more common among young Saudis and worldwide 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , likely secondary to lack of appropriate regulation. Pregabalin has a therapeutic value in the management of fibromyalgia, generalized anxiety disorder, diabetic neuropathy, partial epilepsy, and postherpetic neuralgia 12 , 13 , There remains controversy regarding the abuse potential of pregabalin in preclinical studies. However, these doses were small compared to higher doses used in previous case reports of pregabalin abuse 4 , 5 , 6 , 7 , 8 , 9. Interestingly, pregabalin has been reported to cause euphoric effects as a side effect in participants of controlled clinical studies 17 , 18 , 19 , Importantly, glutamate is the major excitatory neurotransmitter in the brain. The nucleus accumbens NAc is involved in the reinforcing and rewarding effects of several drugs of abuse 21 , 22 , 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 , The release of glutamate from prefrontal cortex PFC projections into the NAc has been shown to mediate drug seeking behavior in previous studies 29 , Blocking glutamatergic activation of mGlu1 31 , mGlu5 32 , 33 , AMPA receptors along with blocking the release of glutamate in the NAc was found to reduce reinstatement of self-administration for different drugs of abuse 30 , 34 , 35 , It is noteworthy that glutamate homeostasis is controlled by a number of glutamate receptors and transporters. One of these transporters is glutamate transporter type-1 GLT-1 which can clear the majority of the synaptic glutamate 37 , 38 , 39 , Moreover, treatment with ceftriaxone CEF , a well-known upregulator of GLT-1 expression, has been shown to oppose drug-seeking behavior induced, in part, by downregulation of GLT-1 following exposure to several drugs of abuse 26 , 41 , 42 , 43 , 44 , Therefore, 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. Animals had ad libitum intake of water and food. Mice were allowed to habituate for seven days before conducting any experiments. Ceftriaxone was gifted by King Abdulaziz Hospital at Taif. All the drugs used in this study were reconstituted in sterile saline solution 0. The overall experimental design is presented in Fig. Experimental design of the CPP experiment 1 and 2 A. Diagram of the CPP apparatus B. Time spent in chamber 1 and 2 in the control group C. No significant changes in time spent were found in chamber 1 and chamber 2 during the tested phases. Mice were then examined for place preference following completing the conditioning training. The dose of Pregabalin which induced CPP in the previous experiment was used in this study. A custom made acrylic CPP apparatus Fig. The two conditioning chambers are distinguished by both tactile and visual cues. The interior walls of the first chamber are white in color with horizontal black stripes and textured walls chamber 1. The interior walls of the other chamber chamber 2 are black in color with vertical white stripes and smooth walls. The floor of chamber 1 is perforated with round holes. The floor of the other chamber is perforated with rectangle holes. Habituation phase: The preconditioning day is considered as day one. On day three, the animal exploration in both conditioning chambers was recorded by a digital camera fixed on the top of the apparatus. Conditioning phase: An un-biased CPP design has been used. Therefore, in each treatment group, half of the animals were randomly assigned to receive pregabalin and were placed in chamber 1, while the other half received this drug and were placed in chamber 2 during the conditioning phase days four to eleven. The process was repeated until the completion of the eight conditioning sessions. The time spent by the mice in both chambers was documented using digital camera post-conditioning test and counted by ANY-maze video tracking system. This analysis was selected based on previous published work 46 , 47 , 48 , When significant main interactions or effects were found, Newman-Keuls multiple comparisons were performed. All data were statistically analyzed by GraphPad Prism, using a 0. In this experiment, the abuse potential of different doses of pregabalin was assessed. Time spent in pregabalin-paired chamber as compared to saline-paired chamber in Preg group A. No significant changes in time spent were found in the tested chambers. Time spent in pregabalin-paired chamber as compared to saline-paired chamber in Preg group B. A significant increase in time spent was found in pregabalin-paired chamber as compared to saline-paired chamber during post-test. A significant increase in time spent was found in pregabalin-paired chamber during post-test as compared to pre-test. Time spent in chamber 1 and 2 in the C-C group A. Time spent in pregabalin-paired chamber as compared to saline-paired chamber in C-Preg group A. In the present study, we demonstrate for the first time, using a mice model of drug addiction, that pregabalin can induce CPP. Consistent with the previous findings from Andrews, et al. Interestingly, this effect is supported by previous controlled clinical studies 17 , 18 , 19 , 20 showing that pregabalin can cause euphoric effects as a side effect in participants of these studies. The drug seeking effects found in several drugs of abuse have been consistently reported to be mediated by glutamatergic mechanism. GLT-1, an astrocyte-specific excitatory amino acid transporter, which is responsible for glutamate homeostasis in the brain It had been previously demonstrated that downregulation of GLT-1 expression in the NAc was associated with continuous exposure to addicting drugs 50 , 51 , Interestingly, GLT-1 expression was found to be downregulated instantly in cocaine self-administration model Of note, the glutamatergic transmission is amplified as a result of increase in glutamate concentrations and decrease in glutamate uptake in the synapses Additionally, it has been observed that glutamate receptors such as mGlu-5 and N-Methyl-D-aspartate could be potentiated and activated by the spillover of glutamate which enhances drug seeking behavior Treatment with CEF has been reported to prevent drug seeking behavior caused by, in part, decreased GLT-1 expression in methamphetamine, cocaine, ethanol, nicotine, and heroin dependence 26 , 41 , 42 , 43 , 44 , 45 with the drug seeking associated with glutamate spillover secondary to GLT-1 downregulation 25 , 55 , 56 , Additionally, the normalization of GLT-1 expression, by CEF treatment, was associated with a decrease in drug-seeking behavior 58 , CEF has been demonstrated to have neuroprotective efficacy in many neurological disorders 60 , 61 and can offer neuroprotective effects in drug addiction associated with glutamate excitotoxicity 60 , 62 , CEF can freely pass the blood brain barrier and enter the central nervous system to up-regulate GLT-1 making it an attractive potential therapeutic for future clinical use in antagonizing pregabalin-induced drug-seeking behavior 60 , 62 , 63 , One limitation of the present study is that we did not demonstrate a mechanisms of action for CEF in antagonism of pregabalin-induced drug-seeking behavior. GLT-1 plays a central role in inflammatory mechanisms in the brain, which has previously been demonstrated to be associated with drug addition 65 , 66 , It has been previously reported that central administration of some neurotoxicants causes significant impairement in motor functions, increased neuroinflammation and increased drug addiction 68 , 69 , Taken together, CEF-mediated antagonism of pregabalin-induced drug seeking like effects could promote restoration of glutamate homeostasis, and in this way modulate drug-seeking behavior. CEF could serve as a lead compound for developing treatment for pregabalin abuse as other pharmacological effects of this antibiotic could not be excluded. Future studies are needed to investigate a mechanistic role for neuroinflamation in pregabalin abuse, as well as sex- and age-related mechanisms in pregabalin-induced neurochemical changes. Bassiony, M. Substance use disorders in Saudi Arabia. Journal of Substance use 18 , — Article Google Scholar. Halaby, A. Pregabalin dependence: a case report. Current drug safety 10 , — Article PubMed Google Scholar. Aldemir, E. Turk Psikiyatri Derg 26 , — PubMed Google Scholar. Pregabalin Dependence: A Case Report Grosshans, M. Pregabalin abuse, dependence, and withdrawal: a case report. American Journal of Psychiatry , — Gahr, M. Concerns about pregabalin: further experience with its potential of causing addictive behaviors. Journal of addiction medicine 7 , — Filipetto, F. Potential for pregabalin abuse or diversion after past drug-seeking behavior. The Journal of the American Osteopathic Association , — Chiappini, S. CNS drugs 30 , — Li, Z. European journal of pharmacology , 80—90 Pexton, T. Targeting voltage-gated calcium channels for the treatment of neuropathic pain: a review of drug development. Expert opinion on investigational drugs 20 , — Boschen, M. A meta-analysis of the efficacy of pregabalin in the treatment of generalized anxiety disorder. The Canadian Journal of Psychiatry 56 , — Feltner, D. Efficacy of pregabalin in generalized social anxiety disorder: results of a double-blind, placebo-controlled, fixed-dose study. International clinical psychopharmacology 26 , — Andrews, N. Effect of gabapentin-like compounds on development and maintenance of morphine-induced conditioned place preference. Psychopharmacology , — Ruttenl, K. Dissociation of rewarding, anti-aversive and anti-nociceptive effects of different classes of anti-nociceptives in the rat. European Journal of Pain 15 , — Drug Enforcement Administration, D. Schedules of controlled substances: placement of pregabalin into schedule V. Final rule. Federal register 70 , Lang, N. Epilepsia 47 , — Chua, Y. Randomised clinical trial: pregabalin attenuates the development of acid-induced oesophageal hypersensitivity in healthy volunteers—a placebo-controlled study. Chew, M. Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies. Clinical drug investigation 34 , — Koob, G. Cellular and molecular mechanisms of drug dependence. Science , — Bardo, M. Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens. Wise, R. Brain dopamine and reward. Annual review of psychology 40 , — Fujio, M. Gene transfer of GLT-1, a glutamate transporter, into the nucleus accumbens shell attenuates methamphetamine-and morphine-induced conditioned place preference in rats. European Journal of Neuroscience 22 , — Melendez, R. Ethanol exposure decreases glutamate uptake in the nucleus accumbens. Alcoholism: Clinical and Experimental Research 29 , — Knackstedt, L. Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking. Biological psychiatry 67 , 81—84 Das, S. Ceftriaxone attenuates ethanol drinking and restores extracellular glutamate concentration through normalization of GLT-1 in nucleus accumbens of male alcohol-preferring rats. Neuropharmacology Althobaiti, Y. Effects of ceftriaxone on glial glutamate transporters in Wistar rats administered sequential ethanol and methamphetamine. Frontiers in Neuroscience 10 McFarland, K. Prefrontal glutamate release into the core of the nucleus accumbens mediates cocaine-induced reinstatement of drug-seeking behavior. The Journal of neuroscience 23 , — Limbic and motor circuitry underlying footshock-induced reinstatement of cocaine-seeking behavior. The Journal of neuroscience 24 , — Dravolina, O. Neuropharmacology 52 , — Tessari, M. Antagonism at metabotropic glutamate 5 receptors inhibits nicotine-and cocaine-taking behaviours and prevents nicotine-triggered relapse to nicotine-seeking. European journal of pharmacology , — Lee, B. Attenuation of behavioral effects of cocaine by the metabotropic glutamate receptor 5 antagonist 2-methyl phenylethynyl -pyridine in squirrel monkeys: comparison with dizocilpine. Journal of Pharmacology and Experimental Therapeutics , — Cornish, J. Glutamate transmission in the nucleus accumbens mediates relapse in cocaine addiction. J Neurosci 20 , RC89 Park, W. Cocaine administered into the medial prefrontal cortex reinstates cocaine-seeking behavior by increasing AMPA receptor-mediated glutamate transmission in the nucleus accumbens. The Journal of neuroscience 22 , — Danbolt, N. Glutamate uptake. Progress in neurobiology 65 , 1— Mitani, A. Functional changes of glial glutamate transporter GLT-1 during ischemia: an in vivo study in the hippocampal CA1 of normal mice and mutant mice lacking GLT Ginsberg, S. Journal of neurochemistry 65 , — Rothstein, J. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Annals of neurology 38 , 73—84 Sari, Y. Upregulation of GLT1 attenuates cue-induced reinstatement of cocaine-seeking behavior in rats. The Journal of Neuroscience 29 , — Qrunfleh, A. Ceftriaxone, a beta-lactam antibiotic, attenuates relapse-like ethanol-drinking behavior in alcohol-preferring rats. Journal of psychopharmacology , Alajaji, M. Effects of the beta-lactam antibiotic ceftriaxone on nicotine withdrawal and nicotine-induced reinstatement of preference in mice. He, Z. Inhibition of vesicular glutamate transporters contributes to attenuate methamphetamine-induced conditioned place preference in rats. Behavioural brain research , 1—5 Abulseoud, O. Ceftriaxone upregulates the glutamate transporter in medial prefrontal cortex and blocks reinstatement of methamphetamine seeking in a condition place preference paradigm. Brain research , 14—21 Role of venlafaxine in relapse to methamphetamine seeking. Potential treatment option for drug dependence. Saudi Medical Journal 40 Journal of Molecular Neuroscience , 1—15 Alshehri, F. Effects of ceftriaxone on hydrocodone seeking behavior and glial glutamate transporters in P rats. Behavioural brain research , — Hammad, A. Gipson, C. Reinstatement of nicotine seeking is mediated by glutamatergic plasticity. Kalivas, P. Glutamate transmission and addiction to cocaine. Annals of the New York Academy of Sciences , — Fischer-Smith, K. Differential effects of cocaine access and withdrawal on glutamate type 1 transporter expression in rat nucleus accumbens core and shell. The glutamate homeostasis hypothesis of addiction. Nature reviews. Trantham-Davidson, H. Ceftriaxone normalizes nucleus accumbens synaptic transmission, glutamate transport, and export following cocaine self-administration and extinction training. Shen, H. Synaptic glutamate spillover due to impaired glutamate uptake mediates heroin relapse. Reissner, K. Glutamate transporter GLT-1 mediates N-acetylcysteine inhibition of cocaine reinstatement. Nature , 73—77 Verma, R. European journal of pharmacology , 65—71 Cui, C. Neuroprotective effect of ceftriaxone in a rat model of traumatic brain injury. Neurological Sciences 35 , — Inui, T. Neuroprotective effect of ceftriaxone on the penumbra in a rat venous ischemia model. Neuroscience , 1—10 Leung, T. Ceftriaxone ameliorates motor deficits and protects dopaminergic neurons in 6-hydroxydopamine-lesioned rats. ACS chemical neuroscience 3 , 22—30 Chen, S. Low-dose memantine attenuated morphine addictive behavior through its anti-inflammation and neurotrophic effects in rats. Journal of Neuroimmune Pharmacology 7 , — Ward, R. Journal of neurochemistry , — Eidson, L. Toll-like receptor 4 mediates morphine-induced neuroinflammation and tolerance via soluble tumor necrosis factor signaling. Neuropsychopharmacology 42 , Langston, J. Mechanism of MPTP toxicity: more answers, more questions. Trends in Pharmacological Sciences 6 , — Jones, D. The effects of environmental neurotoxicants on the dopaminergic system: a possible role in drug addiction. Biochemical pharmacology 76 , — Itzhak, Y. Effect of the dopaminergic neurotoxin MPTP on cocaine-induced locomotor sensitization. Pharmacology Biochemistry and Behavior 63 , — Chu, K. Pharmacological induction of ischemic tolerance by glutamate transporter-1 EAAT2 upregulation. Stroke 38 , — Bisht, R. Neurotoxicology 44 , 71—79 Download references. The authors would like to thank Hussam Almalki for his help in the experiments and the graphic designer Marwah Alkhateeb for her help in the figures. Yusuf S. You can also search for this author in PubMed Google Scholar. All authors approved the final version of the manuscript. Correspondence to Yusuf S. Reprints and permissions. Sci Rep 9 , Download citation. Received : 06 June Accepted : 30 September Published : 22 October Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Naunyn-Schmiedeberg's Archives of Pharmacology Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. Download PDF. Subjects Medical research Neuroscience. Abstract Drug addiction remains a prevalent and fatal disease worldwide that carries significant social and economic impacts. Involvement of the dopaminergic system in the reward-related behavior of pregabalin Article Open access 19 May Gabapentin-induced drug-seeking-like behavior: a potential role for the dopaminergic system Article Open access 26 June Introduction Addiction to several drugs and substances remains a critical health issue worldwide. Experimental design The overall experimental design is presented in Fig. Figure 1. Full size image. Results Experiment 1 In this experiment, the abuse potential of different doses of pregabalin was assessed. Figure 2. Figure 3. Figure 4. Figure 5. Discussion In the present study, we demonstrate for the first time, using a mice model of drug addiction, that pregabalin can induce CPP. Naciones Unidas Nueva York, Article Google Scholar Saudigazette. Article Google Scholar Gahr, M. Article Google Scholar Melendez, R. Shah Authors Yusuf S. Althobaiti View author publications. View author publications. Ethics declarations Competing interests The authors declare no competing interests. About this article. Cite this article Althobaiti, Y. Copy to clipboard. Elsukary Ahmed M. Helaly Mohammad A. El-Kattan Neurotoxicity Research Involvement of the dopaminergic system in the reward-related behavior of pregabalin Yusuf S. Althobaiti Farooq M. Almutairi Zahoor A. Shah Scientific Reports Gabapentin-induced drug-seeking-like behavior: a potential role for the dopaminergic system Yusuf S. Althobaiti Amal Alghorabi Zahoor A. Shah Scientific Reports The neurotoxic effect of long-term use of high-dose Pregabalin and the role of alpha tocopherol in amelioration: implication of MAPK signaling with oxidative stress and apoptosis Sarah Hamed N. Publish with us For authors Language editing services Submit manuscript. Search Search articles by subject, keyword or author. Show results from All journals This journal. Advanced search. Close banner Close. Email address Sign up. Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing.
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Official websites use. Share sensitive information only on official, secure websites. Drugs of abuse represent a growing public health crisis. Accumulating evidence indicates that gabapentin GBP , a prescription drug, is prone to misuse, abuse, withdrawal, and dependence. Commonly, drugs of abuse modulate the dopaminergic system to induce addiction. In this study, we used the conditioned place preference CPP model to investigate the involvement of the dopamine 1 D1 receptor on the reward and reinforcement behavior of GBP. In the pre-conditioning phase, mice were conditioned for 3 days, and baseline data were collected. In the conditioning phase, mice were given once-daily alternating injections of either GBP or saline for 8 days and subsequently assessed in a post-conditioning test. The abuse and misuse of prescription drugs is a rapidly growing problem worldwide. The non-medical use of prescription drugs is universally considered one of the highest risk factors for poor health 1. The abuse of gabapentinoids i. Clinically, GBP is used as an adjunctive drug for treating partial epilepsy 4 and for treating neuropathic pain associated with post-herpetic neuralgia 5. Historically, GBP was assumed to have little or no potential for abuse, and this has contributed to dramatic growth in GBP prescriptions 2 , 6. Also, GBP was proposed to aid in the management of cocaine dependence, benzodiazepine, and alcohol detoxification as it can protect from seizures induced by withdrawal symptoms 7. Initial research proposed that GBP may be useful for treating drug and alcohol withdrawal symptoms, thus increasing the likelihood of gabapentinoid abuse among vulnerable patients 8. The mechanism underpinning gabapentinoid abuse has not yet been thoroughly investigated. This binding is believed to result in blocking of calcium influx by voltage-gated channels Several studies have suggested that gabapentinoids can modulate the release of various neurotransmitters for review see Of note, studies have found that most drugs that can modulate GABA possess abuse potential, such as alcohol and benzodiazepines Furthermore, it has been suggested that the dopaminergic system could be involved in the gabapentinoid abuse mechanism as gabapentinoids produce euphoria and withdrawal symptoms upon discontinuation The administration of mind-altering drugs can impact the concentration and availability of numerous neurotransmitters in the central nervous system Dopamine, in particular, is a neurotransmitter that acts through the mesocorticolimbic dopamine system to facilitate reinforcing behaviors, and its regulation by drugs of abuse is strongly linked to addiction Indeed, studies in animal models have found that the reinforcing effects of different drugs of abuse such as methamphetamine, cocaine, and heroin are associated with high levels of dopamine in the mesocorticolimbic system Moreover, the release of dopamine in the mesocorticolimbic system is thought to be related to the activity of drugs of abuse in the ventral tegmental area, which projects into the nucleus accumbens and the medial prefrontal cortex, among other brain regions Repeated exposure to these drugs produces a behavioral sensitization state that ultimately promotes addiction Interestingly, blocking dopamine receptor activity prevented reinforcement behavior and behavioral sensitization associated with the repeated administration of most drugs of abuse, including methamphetamine, cocaine, and heroin 19 — Likewise, blocking the dopamine receptor attenuated heroin- and nicotine-seeking behavior in animal models of relapse 21 , Of note, D1 receptors, rather than D2, have been consistently shown to play a crucial role in mediating reward and its translation into action 23 — However, D2 receptors have been suggested to be involved more in mediating motor functions 28 , However, to date, no pre-clinical studies have investigated the addictive potential of higher doses of GBP or the involvement of the dopaminergic system in GBP-induced reward. A two-way RM-ANOVA analysis was used to identify changes based on the phase, the preference for a chamber, or an interaction between the two. The saline only group Fig. No significant changes in time spent were found in chambers during all tested phases in the control, GBP and GBP groups. Moreover, Newman-Keuls multiple comparisons test did not show any significant difference in time spent between the GBP- and saline-paired chambers in pre- or post-test. We did not find any significant changes in time spent in the GBP-paired chamber during pre-test compared to post-test. Similarly, no significant changes were found in time spent in the saline-paired chamber during pre-test compared to post-test. Similarly, mice pre-treated with SKF, a D1 antagonist, 30 min before saline post-treatment Fig. No significant changes in time spent were found in chambers during all tested phases in the Saline-Saline and SKF-S groups. In this study, for the first time, we demonstrated that GBP can induce drug-seeking behavior in an animal model of drug addiction. Our results are in accordance with those of several reports on the potential misuse, abuse, and withdrawal associated with GBP 12 , 31 — The number of gabapentinoid misuse, abuse, dependence, and overdose incidences reported by the Food And Drug Administration Adverse Events Reporting System FAERS between and is alarming and requires immediate attention from the regulatory authorities 2. Similarly, according to the results of the ADRs reporting system in Sweden, pregabalin has been concluded to have a potential for abuse Recent reports indicate that GBP abuse commonly occurred when it was used recreationally, combined with other addictive drugs, synergized with existing prescriptions, used to control mood or anxiety, used as a substitution for other drugs, or used in drug abuse treatment 31 , In addition, several cases have reported that high doses of GBP can cause dependency and drug intoxication, which in turn is associated with delirium 12 , 38 , These cases raise an alarming concern about the off-label prescription of GBP to patients with psychiatric conditions. The most common symptoms associated with GBP use include relaxation, delirium, euphoria, talkativeness, increased energy and dissociation, sedation and cognitive difficulties, and other side effects while taking the medication 6 , 40 — Many of these side effects commonly occur with other addictive substances. The CPP procedure is widely accepted for studying and evaluating motivational properties, including the rewarding effects of drugs of abuse in experimental animals 43 — This is consistent with our previous findings that the newer class member, pregabalin, can induce CPP, suggesting its possible abuse potential Although the mechanism of GBP abuse is not completely understood, given that alcohol, nicotine, and opiates have high abuse potential and modulate dopamine, it is thought that the GBP mechanism is also dopamine-mediated The release of dopamine in the nucleus accumbens and subsequent activation of D1 receptors have been consistently shown to cause rewarding effects 51 , In line with our findings, commonly reported motivations for GBP use among abusers include recreation i. In many of the previous case reports, most individuals used GBP at doses higher than the prescribed dose. Descriptive reports indicate that GBP induces subjective effects, including euphoria, talkativeness, increased energy, and sedation. These effects are not specific to a particular dose and might occur within the therapeutic dose Moreover, the dose taken did not correlate with any effect or with the motivation for its use. This might be due to non-linear bioavailability of GBP and its unpredictable pharmacokinetics. Further experimental research is needed to characterize and evaluate GBP psychopharmacology and to uncover the risks associated with GBP use, especially among those who use it for recreational purposes To the best of our knowledge, this is the first pre-clinical study that has explored the ability of GBP to cause rewarding effects. Furthermore, we showed that the suppression of D1-receptor activation can suppress GBP-induced place preference, indicating a critical role for dopamine in facilitating the addictive tendencies of GBP. Therefore, there is a need to impose further regulations to restrict the prescription of GBP. Moreover, additional research is needed to re-evaluate the potential for GBP to be abused and misused, especially in patients with a history of drug addiction. Mice were housed in groups of 5 per cage with ad libitum feeding. Isolated housing was avoided because it has been shown to affect the reinforcing behavior of different drugs of abuse 53 — Both drugs were dissolved in 0. In experiment 2, mice received a pretreatment of 0. It has been previously shown that 0. Mice were handled gently to limit the potential for confounding effects on the behavioral testing of the mice. The chambers had different visual and tactile cues. One chamber had rough white walls with horizontal black stripes and round holes on the floor. The other chamber had smooth black walls with vertical white stripes walls and rectangular holes on the floor. The CPP procedure was performed as described in our previous studies 46 , The experiments and drug dosages are illustrated in Fig. Baseline preference was determined by placing each mouse in the start chamber of the CPP apparatus and allowing free access to the chambers for 30 min. This was done for the first three days Day 1, 2 and 3. Each mouse underwent these three days of habituation to eliminate stress. On day three, the pre-test was conducted by placing the mice in the start chamber and allowing free access to both conditioning chambers for 30 min. The time spent in each chamber was recorded by automated processing using a digital camera and the ANY-maze video tracking software system. The four conditioning sessions using GBP were performed over an eight-day span with one session of GBP occurring every other day. Each mouse received only one injection per day of either GBP or saline. After completing the conditioning sessions, mice were tested for their chamber preference post-test on day The post-test was identical to the pre-test procedure. The CPP design was un-biased and counterbalanced whereby half of the mice were randomly assigned to receive GBP in chamber 1 and the other half received this drug in chamber 2. Moreover, half of the mice were randomly divided to be administered GBP in the first conditioning day, while the other half received saline in the first conditioning day. The baseline preference was assessed according to experiment 1. After completing the pre-test, mice were divided into four groups, with each group given two injections of a combination of either saline, SKF, or GBF. Mice were then tested for place preference post-test on day 12 after the completion of the conditioning sessions. Time spent in each chamber for pre-conditioning and post-conditioning was analyzed using a two-way repeated measures analysis of variance test RM-ANOVA Phase x Chamber. Further post-hoc testing was performed using the Newman-Keuls multiple comparisons test. All analysis was conducted using GraphPad Prism version 5. A designed and conceptualized the experiments, analyzed the data and helped in writing and editing the manuscript. A, and B. A and S. All authors approved the final version of the manuscript. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. As a library, NLM provides access to scientific literature. Sci Rep. Find articles by Yusuf S Althobaiti. Find articles by Amal Alghorabi. Find articles by Fahad S Alshehri. Find articles by Bandar Baothman. Find articles by Atiah H Almalki. Find articles by Hashem O Alsaab. Find articles by Walaa Alsanie. Find articles by Ahmed Gaber. Find articles by Hussam Almalki. Find articles by Abdulrahman S Alghamdi. Find articles by Ahmad Basfer. Find articles by Sultan Althobaiti. Find articles by Ana Maria Gregio Hardy. Find articles by Zahoor A Shah. Received Feb 9; Accepted Jun 5; Collection date Open in a new tab. Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.
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