Abstract
Preclinical models of cocaine use disorder are widely utilized to identify neuroadaptations underlying cocaine seeking and to screen medications to reduce seeking. However, while the majority of cocaine users engage in poly-substance use (PSU), a minority of preclinical studies employ PSU models. We previously reported that when rats consume alcohol after daily intravenous cocaine self-administration, nucleus accumbens (NA) core basal glutamate levels are reduced below those of rats that consumed only cocaine, and do not increase during cue + cocaine-primed reinstatement of cocaine-seeking. Here we used the same model of sequential cocaine and alcohol self-administration to test the hypothesis that a similar pattern of glutamate changes would be observed in the NA core prior to and during a cocaine-primed reinstatement test. Rats underwent intravenous cocaine self-administration followed by access to unsweetened alcohol in the home cage for 12 days. Rats underwent a minimum of 12 daily extinction sessions prior to a cocaine-primed reinstatement test conducted during microdialysis procedures. Contrary to our previous work using the same model, here we found that access to alcohol increased cocaine intake and increased responding during early extinction training. We found that as in our previous work, cocaine + alcohol-consuming rats displayed basal glutamate levels below those of rats that self-administered only cocaine. During the cocaine-primed reinstatement test, rats that consumed only cocaine displayed increased glutamate efflux in the NA core while those that consumed cocaine + alcohol did not. These results indicate that preclinical models of PSU should be utilized to develop experimental therapeutics for the reduction of cocaine seeking.
Highlights
Cocaine use disorder (CUD) remains a problem in the US today, with1 million Americans currently meeting DSM-V criteria for CUD (Center for Behavioral Health Statistics and Quality, 2015)
Because we previously found that ceftriaxone was unable to attenuate cocaine-primed reinstatement in rats with a history of both cocaine and alcohol consumption, we hypothesize that basal and reinstatement-associated glutamate levels in the nucleus accumbens (NA) core will differ between cocaine self-administering rats that do and do not consume alcohol
The amount of alcohol consumed by rats in the present study fell within the range in our previous study, and the increase in cocaine intake here did not stem from increased alcohol intake per se
Summary
Cocaine use disorder (CUD) remains a problem in the US today, with million Americans currently meeting DSM-V criteria for CUD (Center for Behavioral Health Statistics and Quality, 2015). A Rat Model of Cocaine-Alcohol Polysubstance Use between glutamate release and reuptake This dysregulation includes a decrease in the glutamate transporter GLT-1 expression and function in the NA core and increased synaptic glutamate during reinstatement of cocaine-seeking, regardless of the stimuli priming such reinstatement (e.g., cue, context, cocaine-prime) (McFarland et al, 2003; Knackstedt et al, 2010; Fischer et al, 2013; LaCrosse et al, 2016; Smith et al, 2017; Siemsen et al, 2020). Extra-synaptic glutamate levels are reduced in the NA core at the time of reinstatement testing, caused by reduction in function of the glutamate antiporter system xc- and protein expression of its catalytic subunit xCT (Baker et al, 2003; Knackstedt et al, 2010) Based on such adaptations, medications that restore glutamate homeostasis hold potential for the reduction of cocaine relapse. Subchronic treatment with the β-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine-seeking while increasing NA core GLT-1 and xCT protein expression and function, increasing basal extra-synaptic glutamate levels, and preventing the increase in glutamate efflux that accompanies reinstatement (Sari et al, 2009; Knackstedt et al, 2010; Sondheimer and Knackstedt, 2011; Trantham-Davidson et al, 2012; Fischer et al, 2013; Bechard et al, 2018)
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