Methamphetamine self-administration modulates glutamate neurophysiology

Abstract

World-wide methamphetamine (meth) use is increasing at a rapid rate; therefore, it has become increasingly important to understand the synaptic changes and neural mechanisms affected by drug exposure. In rodents, 6-hr access to contingent meth results in an escalation of drug intake and impaired cognitive sequelae typically associated with changes within the corticostriatal circuitry. There is a dearth of knowledge regarding the underlying physiological changes within this circuit following meth self-administration. We assessed pre- and postsynaptic changes in glutamate transmission in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) following daily 6-hr meth self-administration. In the mPFC, meth caused postsynaptic adaptations in ionotropic glutamate receptor distribution and function, expressed as a decrease in AMPA/NMDA ratio. This change was driven by an increase in NMDA receptor currents and an increase in GluN2B surface expression. In the NAc, meth decreased the paired-pulse ratio and increased the frequency of spontaneous excitatory postsynaptic currents with no indication of postsynaptic changes. These changes in mPFC synapses and NAc activity begin to characterize the impact of meth on the corticostriatal circuitry.

Transgenic Analyses of Homer2 Function Within Nucleus Accumbens Subregions in the Regulation of Methamphetamine Reward and Reinforcement in Mice

“…In addition, such exposure is sufficient to increase the expression/ function of mGlu1/5 glutamate receptors and their associated scaffolding protein Homer2 within this region (8). Indeed, a survey of the extant literature on animal models of MA abuse supports a correlative link between potentiated indices of glutamate signaling and addiction-related behavior, including self-administration, MA-induced reinstatement of drug-seeking after abstinence or extinction, incubation of MA-craving, and conditioned place-preference (CPP) (8)(9)(10)(11)(12)(13)(14)(15)(16)(17).…”

Methamphetamine Self-Administration Elicits Sex-Related Changes in Postsynaptic Glutamate Transmission in the Prefrontal Cortex

“…Additionally, we have shown that long-access METH self-administration (SA; 6 h/d) increases the proportion of burst firing pyramidal cells compared to tonic firing cells in mPFC (Parsegian et al, 2011); however, it was unknown whether this increased burst firing results from presynaptic and/or postsynaptic changes. In a recent study, we found that long-access METH SA decreases AMPA/NMDA ratio in pyramidal neurons of the mPFC, accompanied by an increase in NMDA currents and surface expression of the GluN2B subunit of the NMDA receptor (NMDAR; Mishra et al, 2017). Together, these results show that METH elicits multiple forms of long-term synaptic changes in the PFC, suggesting that altered synaptic function is one of the fundamental mechanisms affected by this drug.…”

MeBib Suppressed Methamphetamine Self-Administration Response via Inhibition of BDNF/ERK/CREB Signal Pathway in the Hippocampus

“…These data are consistent with previous reports suggesting that the expression of NMDA receptor was regulated after MA exposure and modulated the excitotoxic effect ( Bowyer and Ali, 2006 ; Kalivas and Volkow, 2011 ). Another study also reported that MA self-administration increased the NMDA receptor currents and surface expression of the GluN2B subunit ( Mishra et al ., 2017 ). In addition, the expression of GluN2B by MA is considered one of the fundamental mechanisms affected by addictive drugs ( Galinato et al ., 2015 ; Mishra et al ., 2017 ).…”

“…Another study also reported that MA self-administration increased the NMDA receptor currents and surface expression of the GluN2B subunit ( Mishra et al ., 2017 ). In addition, the expression of GluN2B by MA is considered one of the fundamental mechanisms affected by addictive drugs ( Galinato et al ., 2015 ; Mishra et al ., 2017 ). These studies suggest that the overexpression of GluN2B is an important factor in MA intoxication.…”