Effects of Clavulanic Acid Treatment on Reinstatement to Methamphetamine, Glial Glutamate Transporters, and mGluR 2/3 Expression in P Rats Exposed to Ethanol

Abstract

Evidence demonstrated that glutamatergic system is implicated in mediating relapse to several drugs of abuse, including methamphetamine (METH). Glutamate homeostasis is maintained by a number of glutamate transporters, such as glutamate transporter type 1 (GLT-1), cystine/glutamate transporter (xCT), and glutamate aspartate transporter (GLAST). In addition, group II metabotropic glutamate receptors (mGluR2/3) were found to be implicated in relapse-seeking behavior. Ample evidence showed that β-lactam antibiotics are effective in upregulating GLT-1 and xCT expression, thus improving glutamate homeostasis and attenuating relapse to drugs of abuse. In this study, we investigated the reinstatement of METH using conditioned place preference (CPP) in male alcohol-preferring (P) rats exposed to home-cage free choice ethanol drinking. Here, we tested the effect of clavulanic acid (CA), a β-lactam, on the reinstatement of METH-seeking and ethanol drinking. In addition, we examined the expression of GLT-1, xCT and GLAST as well as metabotropic glutamate receptor (mGluR2/3) in the nucleus accumbens (NAc) shell, NAc core and dorsomedial prefrontal cortex (dmPFC). A priming i.p. injection of METH reinstated preference in METH-paired chamber following extinction. Chronic exposure to ethanol decreased the expression of GLT-1 and xCT in the NAc shell, but not in the NAc core or dmPFC. CA treatment blocked the reinstatement of METH-seeking, decreased ethanol intake and restored the expression of GLT-1 and xCT in the NAc shell. In addition, the expression of mGluR2/3 was increased by CA treatment in the NAc shell and dmPFC. These findings suggest that these glutamate transporters and mGluR2/3 might be potential therapeutic targets for the attenuation of reinstatement to METH-seeking.

Effects of Methamphetamine Self-Administration and Extinction on Astrocyte Structure and Function in the Nucleus Accumbens Core

“…Apart from its action in the NAcore, systemic NAC administration likely produces effects in other relevant brain regions, such as the prelimbic cortex; indirectly altering plasticity in the NAcore. In keeping with this hypothesis, meth conditioned place preference (CPP) followed by extinction decreases GLT-1 protein expression in the NAshell, but not the NAcore (Althobaiti et al, 2019) and overexpressing GLT-1 in the NAshell attenuates the induction of meth CPP (Fujio et al, 2005). Given that NAC produces its anti-relapse effects, at least in part, by elevating GLT-1 expression (Reissner et al, 2015), it remains possible that NAC also engages a more canonical GLT-1 based restoration of homeostatic glutamate systems in the NAshell, which parallels what has been reported with ceftriaxone (Althobaiti et al, 2019).…”

Ampicillin/Sulbactam Treatment Modulates NMDA Receptor NR2B Subunit and Attenuates Neuroinflammation and Alcohol Intake in Male High Alcohol Drinking Rats

“…This is in agreement with previous studies from our laboratory demonstrating that ethanol drinking for five weeks resulted in downregulation of GLT-1 expression in the Acb [ 3 , 69 ]. We have previously reported that chronic ethanol drinking for approximately 7–8 weeks decreased GLT-1 expression in the AcbSh, but not in the AcbCo of P rats [ 70 ]. The present study and previous studies from our laboratory revealed that the increase in water intake might be a compensatory response for the attenuation of ethanol intake during treatments with β-lactam antibiotics [ 13 , 14 ].…”

Gabapentin-induced drug-seeking-like behavior: a potential role for the dopaminergic system

“…The CPP procedure is widely accepted for studying and evaluating motivational properties, including the rewarding effects of drugs of abuse in experimental animals [43][44][45][46][47] . Under the CPP paradigm, we used a range of GBP doses (100, 200, 300 mg/kg) higher than those used by previous studies that used doses of GBP such as 10, 30, and 100 mg/kg and did not elicit any increase in place preference in rats 30,48 .…”

“…The time spent in each chamber was recorded by automated processing using a digital camera and the ANY-maze video tracking software system. To ensure that there was no chamber preference bias, prior to conditioning test, we excluded any mouse who showed an initial preference to either chamber by spending > 67% of their time exploring that chamber 46,61,62 . The four conditioning sessions using GBP were performed over an eight-day span with one session of GBP occurring every other day.…”