Neuroimaging markers of glutamatergic and GABAergic systems in drug addiction: Relationships to resting-state functional connectivity

Abstract

Drug addiction is characterized by widespread abnormalities in brain function and neurochemistry, including drug-associated effects on concentrations of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. In healthy individuals, these neurotransmitters drive the resting state, a default condition of brain function also disrupted in addiction. Here, our primary goal was to review in vivo magnetic resonance spectroscopy and positron emission tomography studies that examined markers of glutamate and GABA abnormalities in human drug addiction. Addicted individuals tended to show decreases in these markers compared with healthy controls, but findings also varied by individual characteristics (e.g., abstinence length). Interestingly, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction. Thus, our secondary goals were to provide a brief review of this resting-state literature, and an initial rationale for the hypothesis that abnormalities in glutamatergic and/or GABAergic neurotransmission may underlie resting-state functional deficits in drug addiction. In doing so, we suggest future research directions and possible treatment implications.

Rat animal models for screening medications to treat alcohol use disorders

“…Particularly germane to the present topic, animal models have led to important findings on neural substrates mediating addiction to multiple substances of abuse (c.f., Bell and Rahman, 2016; De Biasi, 2015; Dwoskin, 2014; Ekhtiari and Paulus, 2016a, 2016b; Frascella et al, 2011; Heidbreder, 2008; Koob et al, 2014a; McArthur and Borsini, 2008c; Nader, 2016; Olmstead, 2011) and ethanol in particular (Bell et al, 2005, 2006b, 2012, 2013, 2014, 2016; Ciccocioppo, 2013; Crabbe et al, 2013; Knapp and Breese, 2012; Maldonado-Devincci et al, 2012; McBride and Li, 1998; McBride et al, 2014b; Ramsden, 2015; Ryabinin, 2012). As indicated above, advanced neuroimaging techniques including resting state functional connectivity are being used to develop endophenotypes for medications development targeting AUDs (e.g., Brown et al, 2015; Cui et al, 2015; Ernst et al, 2015; Fedota and Stein, 2015; Gowin et al, 2015; Gullo et al, 2011; Moeller et al, 2016; Muller-Oehring et al, 2015a, 2015b; Schuckit et al, 2016; Squeglia et al, 2014). In general, an animal model has the advantage of allowing the experimenter to control factors such as the animal's genetic background, environment, and drug exposure.…”

Dopamine homeostasis brain functional connectivity in reward deficiency syndrome

“…Studies have shown that addicted individuals tended to show decreases in the glutaminergic system compared with healthy controls. Moreover, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in resting-state functional connectivity deficits in drug addiction (186). There are many studies showing impairments of resting state functional connectivity with alcohol, opiates, cannabis, psychostimulants, nicotine, glucose and even some of the behavioral addictions, further suggesting the need to find compounds that will restore normal resting state functional connectivity (6,(187)(188)(189)(190)(191)(192)(193)(194)(195)(196)(197)(198)(199)(200).…”

Neurogenetics of acute and chronic opiate opioid abstinence treating symptoms and the cause

“…We are in agreement with the concept that resting state functional connectivity may have clinical relevance crucial to the development of and risk for all RDS behaviors. Studies have shown that addicted individuals tended to show decreases in the glutaminergic system compared to healthy controls (262). Moreover, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in restingstate functional connectivity deficits in drug addiction (262).…”

“…Studies have shown that addicted individuals tended to show decreases in the glutaminergic system compared to healthy controls (262). Moreover, select corticolimbic brain regions showing glutamatergic and/or GABAergic abnormalities have been similarly implicated in restingstate functional connectivity deficits in drug addiction (262). There are many studies showing impairments of resting state functional connectivity with alcohol, opiates, cannabis, psychostimulants, nicotine, glucose, and even some behavioral addictions, further suggesting the need to find compounds that will restore normal resting state functional connectivity (263)(264)(265)(266)(267)(268)(269)(270)(271)(272)(273)(274)(275)(276)(277).…”