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Rewarding memories induced by addictive drugs may contribute to persistent drug-seeking behaviors, which is an important contributing factor to drug addiction. However, the biological mechanisms underlying drug-associated rewarding memories have not yet been fully understood, especially the new synthetic drugs, such as amphetamine-type stimulants (ATS). In this study, using the rat-conditioned place preference (CPP) model, a classic animal model for the reward-associated effects of addictive drugs, we found that the expression level of GABAA α1 subunits was significantly decreased in the dorsal striatum (Dstr) after conditioned methamphetamine (METH) pairing, and no significant differences were observed in the other four rewarding memory-associated areas (medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala (Amy), and dorsal hippocampus (DH)). Intra-Dstr injection of either the GABAA receptor agonist muscimol or the specific α1GABAA receptor-preferring benzodiazepine (BDZ) agonist zolpidem significantly abolished METH CPP formation. Thus, this study extends previous findings by showing that GABAA receptors, particularly the α1-containing GABAA receptors, may be strongly implicated in METH-associated rewarding memories. This work provides us with a new perspective on the goal of treating ATS addiction.

Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABAAα1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr. The siRNA knockdown of SYVN1 significantly increased GABAAα1 protein levels in both primary cultured neurons and rodent Dstr. Inhibition of proteasomal activity by MG132 and Lactacystin significantly increased GABAAα1 protein levels. We further found that SYVN1 knockdown increased GABAAα1 in the intra-ER, but not in the extra-ER. Accordingly, endoplasmic reticulum stress (ERS)-associated Glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) increased. Thus, this study revealed that SYVN1, as the ERAD E3 ubiquitin ligase, was associated with Dstr GABAAα1 degradation induced by METH conditioned pairing.

The abuse of amphetamine-type stimulants (ATS) has become a global public health issue in recent years, these new-type drugs can cause addiction and serious cognitive impairment . However, there are no effective methods for the prevention and treatment of ATS addiction at present. Repetitive transcranial magnetic stimulation (rTMS) is a painless and non-invasive new therapeutic approach that has been used for the treatment of depression and other neuropsychiatric disorders , but whether it can be used to treat drug addiction is unclear. In the present study, we investigated the possible effects of rTMS on methamphetamine(METH)-induced conditioned place preference (CPP). High-frequency (10 Hz) and low-frequency stimulation patterns (1 Hz) were applied to test the effect of rTMS on METH-induced CPP. The results showed that low-frequency but not high-frequency rTMS could block METH-CPP, accompanied with a downregulation of gamma-aminobutyric acid type B receptor subunit 1 (GABA BR1) expression in rat dorsolateral striatum. These results suggested that low-frequency rTMS could effectively inhibit the development of METH addiction and shed light on the rTMS as a potential approach for the prevention of drug addiction.

Repeated exposure to methamphetamine (METH) can cause severe neurotoxicity to the cortical neurons. In the present study, we investigated the effect of METH on cognitive function deficits, and determined the neuroprotective effects of memantine (MEM) on memory impairment induced by METH. The protein levels of Bcl-2 and cleaved caspase-3 in prefrontal cortex (PFC) were further examined to exploring the underlying mechanism. We found that repeated METH administration impaired long term (24h) memory retention without affecting short term (5min) memory retention. Co-administration of MEM with METH before training session significantly improved METH-induced cognitive function. METH significantly decreased expression level of Bcl-2 and increased expression level of cleaved caspase-3 in the PFC. The changes can be prevented by MEM pretreatment. Thus, these results demonstrated that MEM pretreatment reversed METH-induced changes of protein levels of apoptotic-related gene, and produced protective effects against METH-induced cognitive deficits, suggesting the effectiveness of MEM may be due to its anti-apoptotic activity.