N-methyl-d-aspartate receptor subunit expression in adult and adolescent brain following chronic ethanol exposure

Abstract

Substantial evidence suggests that glutamatergic neurotransmission is a critical mediator of the experience-dependent synaptic plasticity that may underlie alcohol dependence. Substance abuse typically begins in adolescence; therefore, the impact of alcohol on glutamatergic systems during this critical time in brain development is of particular importance. The N-methyl-D-aspartate receptor (NMDAR) is involved in developmental mechanisms underlying neuronal differentiation and synaptogenesis and as such may be a target system for alcohol effects during adolescence. In the present study quantitative biochemical determinations were made of the relative abundance of different protein expressions of NMDAR subunits in adolescents and adults after 2 wks of ethanol vapor exposure, and 24 hrs and 2 wks following withdrawal. After 2 wks of ethanol vapor exposure NR1, NR2A, and NR2B subunit expression was found to be increased in hippocampus of the adults. In contrast, 2 wks of ethanol exposure resulted in no significant changes in NR1 and NR2B subunits and a reduction NR2A subunit expression in hippocampus in adolescents. Twenty-four hours and 2 wks following withdrawal from ethanol vapor NR1 and NR2A subunit expression in hippocampus was decreased in adolescents, whereas in adults it had returned to control levels. In frontal cortex, 2 wks of chronic ethanol exposure produced decreases in NR1 subunit expression in both adults and adolescents but also produced decreases in NR2A and NR2B subunit expression in adults that returned or exceeded control levels by 2 wks following withdrawal from ethanol vapor. These results demonstrate that NMDAR subunit composition can be modulated differentially between adolescents and adults by chronic ethanol exposure and withdrawal. These developmental differences in NMDAR subunits composition may also be associated with the enhanced vulnerability of the adolescent brain to ethanol dependence.

Chronic Intermittent Ethanol Exposure Produces Persistent Anxiety in Adolescent and Adult Rats

“…However, animals in this study were administered 9–15 g/kg ethanol per day for six days via gavage, for a grand total of between 54–90 g/kg ethanol, with no clear withdrawal periods (Kalluri et al, 1998). In Pian et al (2010), researchers administered 14 hours of ethanol vapor exposure every day for two weeks, for a total of 196 hours of ethanol vapor exposure, and found age-dependent changes in NMDA receptor subunit expression in frontal cortex and hippocampus at both 24 hours and 2 weeks of ethanol withdrawal. Prior research with GABA A subunits found a 12–18% increase in different cortical layers, as well as a 26–46% increase in α4 mRNA in different subregions of the hippocampus at 48 hours withdrawal, using a 60-dose CIE procedure, where animals received 355 g/kg ethanol over the entire duration of the study (Mahmoudi et al, 1997).…”

“…Comparing these studies highlights the importance of the exposure paradigm, including total ethanol exposure, route of administration, the inclusion or absence of withdrawal periods, and the timing of neuropeptide assessments. Based on the current body of research, it appears as though most of the changes in NMDA and GABA A receptor subunit expression occur within 24 hours of the final chronic ethanol exposure (Devaud et al, 1997, Mahmoudi et al, 1997, Matthews et al, 1998, Pian et al, 2010). However, there is some indication that the expression of certain NMDA subunits can still be affected by chronic intermittent ethanol exposure after an abstinence period of up to two weeks (Pian et al, 2010), although the quantity of subunits that show persistent versus immediate changes are more limited.…”

“…Additionally dependence, tolerance, and withdrawal symptoms in the adult rat are marked by increased function of NMDA receptors (Grant et al, 1990; Krystal et al, 1998; Leite & Nobre, 2012; Sanna et al, 1993) and attenuated function of GABA A receptors (Grobin et al,. 1998; Kang et al, 1998; Kang et al, 1996; Morrow, 1995), which coincide with altered receptor subunit expression (Grobin et al, 1998; Kang et al, 1996; Morrow, 1995; Pian et al, 2010). However, the effects of CIE exposure on receptor subunit expression in adolescence are not yet completely known, and likely differ from the adult.…”

“…However, only one study has addressed the age-dependent changes in NMDA receptor subunit expression following CIE exposure (Pian et al, 2010). Additionally, much previous research conducted on GABA A receptor subunit changes in the adult has focused on rapidly inducing physical dependence by administering large quantities of ethanol (e.g.…”

Reduced ethanol drinking following selective cortical interneuron deletion of the GluN2B NMDA receptors subunit

“…NMDARs containing the GluN2B subunit are generally more sensitive to EtOH’s antagonist actions (Wills et al, 2012; Woodward, 2000). GluN2B-containing NMDARs are further implicated in the functional effects of chronic EtOH by increased expression of the subunit in cortical, limbic and striatal regions in rodents repeated exposed to EtOH (de Ferron et al, 2015; Follesa and Ticku, 1995; Hardy et al, 1999; Kalluri et al, 1998; Kash et al, 2009; Kroener et al, 2012; McGuier et al, 2015; Narita et al, 2000; Nelson et al, 2005; Nimitvilai et al, 2015; Pian et al, 2010; Rani and Ticku, 2006; Wang et al, 2010) and in the hippocampus of human alcoholics (Enoch et al, 2014). There is also evidence that pharmacologically blocking GluN2B (via systemic ifenprodil administration) can reduce EtOH drinking in rats (Vengeliene et al, 2005).…”