Pharmacologic Treatment with GABAB Receptor Agonist of Methamphetamine-Induced Cognitive Impairment in Mice

Hiroyuki Mizoguchi,Kiyofumi Yamada

doi:10.2174/157015911795016976

Abstract

Methamphetamine (METH) is a highly addictive drug, and addiction to METH has increased to epidemic proportions worldwide. Chronic use of METH causes psychiatric symptoms, such as hallucinations and delusions, and long-term cognitive deficits, which are indistinguishable from paranoid schizophrenia. The GABA receptor system is known to play a significant role in modulating the dopaminergic neuronal system, which is related to behavioral changes induced by drug abuse. However, few studies have investigated the effects of GABA receptor agonists on cognitive deficits induced by METH. In the present review, we show that baclofen, a GABA receptor agonist, is effective in treating METH-induced impairment of object recognition memory and prepulse inhibition (PPI) of the startle reflex, a measure of sensorimotor gating in mice. Acute and repeated treatment with METH induced a significant impairment of PPI. Furthermore, repeated but not acute treatment of METH resulted in a long-lasting deficit of object recognition memory. Baclofen, a GABAB receptor agonist, dose-dependently ameliorated the METH-induced PPI deficits and object recognition memory impairment in mice. On the other hand, THIP, a GABAA receptor agonist, had no effect on METH-induced cognitive deficits. These results suggest that GABAB receptors may constitute a putative new target in treating cognitive deficits in chronic METH users.

Highlights

Methamphetamine (METH) increases the amount of dopamine released in synapses by reversing the function of the dopamine transporter, which is associated with the rewarding effects of the drug [1,2,3,4]
Because clinical evidence has shown that clozapine is superior to typical therapeutics such as haloperidol in improving cognitive deficits in schizophrenic patients [13, 14], the METH-induced cognitive impairment in rodents may be useful as an animal model for cognitive deficits in METH abusers as well as schizophrenic patients, in which cognitive deficits are regarded as a core feature
We have proposed that impairment of the dopamine D1 receptor-ERK1/2 signaling pathway in the prefrontal cortex (PFC) is involved in METH-induced

Summary

GABA RECEPTOR

The GABA receptor system is known to play a significant role in modulating the dopamine system [22]. Baclofen has been shown to attenuate amphetamine-induced increase in dopamine levels in the nucleus accumbens [24], and GABAA receptors on dopamine neurons in the ventral tegmental area play a significant role in attenuating the effects of drug abuse in a similar manner to that of GABAB receptors [25]. To develop novel pharmacotherapy for cognitive deficits in METH abusers, we Mizoguchi and Yamada examined the effects of GABAA and GABAB receptor agonists in this animal model. Gaboxadol (1-3 mg/kg), a GABAA receptor agonist, had no effect on METH-induced cognitive deficits These results suggest that GABAB receptor agonists may be useful for the treatment of cognitive deficit in METH abusers (Table 1) [34]. A previous study demonstrated that activation of GABAB receptors led to an increase in ERK1/2 phosphorylation in the CA1 area of mouse hippocampal slices and promoted CREB2-mediated transcription through an ERK-dependent mechanism, suggesting that GABAB receptors may play a crucial role in regulating synaptic facilitation and memory through regulating protein synthesis and gene expression [35]

Recongnition Memory Sensorimotor Gating*

Pharmacologic Treatment with GABAB Receptor

CONCLUSION