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RATIONALE: There are no FDA-approved treatments to facilitate recovery from cocaine use disorder. Contingency management offers non-drug reinforcers to encourage abstinence and is effective at reducing drug seeking during treatment, but once discontinued, relapse rates increase. OBJECTIVES: We sought to establish a choice-based rodent model of voluntary abstinence (VA) from cocaine to test the ability of ceftriaxone, an antibiotic consistently shown to prevent relapse to cocaine seeking in rodents, to attenuate relapse after discontinuation of VA, and to investigate relapse-induced neuronal activation via c-Fos expression. METHODS: Male Sprague–Dawley rats self-administered sucrose pellets for 5 days and intravenous cocaine for 12 days. Rats then underwent 14 days of voluntary or forced abstinence. VA sessions entailed the opportunity to choose between sucrose and cocaine delivery in discrete trials (20 trials/day). Ceftriaxone (or vehicle) was administered during the last 7 days of abstinence. During a relapse test, only the cocaine-paired lever was available and presses on the lever delivered cocaine-paired cues. RESULTS: There were more presses on the sucrose lever during VA, but cocaine intake did not decline to zero. Ceftriaxone had no effect on cocaine intake during VA. Neither ceftriaxone nor VA reduced cocaine seeking during the relapse test, and cocaine intake during VA positively correlated with cocaine seeking during the test in vehicle-treated animals. Relapse-induced c-Fos expression was found to be greater in the ventral orbitofrontal cortex following VA. CONCLUSIONS: Sucrose availability leads to a decrease in, but not cessation of, cocaine seeking and a differential engagement of the circuitry underlying relapse.

It is thought that goal-directed control of actions weakens or becomes masked by habits over time. We tested the opposing hypothesis that goal-directed control becomes stronger over time, and that this growth is modulated by the overall action–outcome contiguity. Despite group differences in action–outcome contiguity early in training, rats trained under random and fixed ratio schedules showed equivalent goal-directed control of lever pressing that appeared to grow over time. We confirmed that goal-directed control was maintained after extended training under another type of ratio schedule—continuous reinforcement—using specific satiety and taste aversion devaluation methods. These results add to the growing literature showing that extensive training does not reliably weaken goal-directed control and that it may strengthen it, or at least maintain it.

There are currently no FDA-approved medications to reduce cocaine relapse. The majority of preclinical studies aimed at identifying the neurobiology underlying relapse involve the self-administration of cocaine alone, whereas many, if not a majority, of cocaine users engage in polysubstance use. Here we developed a rat model of sequential cocaine and alcohol self-administration to test the hypothesis that this combination produces distinct neuroadaptations relative to those produced by cocaine alone. Male rats underwent intravenous cocaine self-administration (2 h/day) followed by 6 h access to unsweetened alcohol (20% v/v) for 12 days. After extinction training, we assessed surface expression of the glutamate transporter GLT-1 and glutamate efflux in the nucleus accumbens (NA) core during the reinstatement of cocaine-seeking. We also tested the ability of ceftriaxone to attenuate the reinstatement of cocaine-seeking and assessed reinstatement-induced Fos expression in several regions critical for reinstatement. Alcohol consumption did not alter cocaine intake, nor did access to cocaine alter alcohol consumption. However, we noted significant changes in glutamate homeostasis in the NA core of cocaine + alcohol rats relative to rats consuming cocaine alone, such as increased surface GLT-1 expression and a lack of increase in glutamate efflux during reinstatement of cocaine-seeking. A history of cocaine + alcohol also altered patterns of reinstatement-induced Fos expression. These changes likely account for the inability of ceftriaxone to attenuate cocaine relapse in cocaine + alcohol rats, while it does so in rats consuming only cocaine. As such glutamate neuroadaptations are targeted by medications to reduce cocaine relapse, preclinical models should consider polysubstance use.

Ceftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine-seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed relapse but NA core glutamate efflux still increases. Here we sought to determine if the same would occur when relapse is prompted by both context and discrete cues (context+cues) after cocaine abstinence. Male rats self-administered intravenous cocaine for 2 hr/day for 2 weeks. Cocaine delivery was accompanied by drug-associated cues (light+tone). Rats were then placed into abstinence with daily handling but no extinction training for two weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a context+cue relapse test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both context+cue-primed relapse and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when relapse is primed by drug-associated cues and context, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.

Ceftriaxone is an antibiotic that reliably attenuates the reinstatement of cocaine seeking after extinction while preventing the nucleus accumbens (NA) core glutamate efflux that drives reinstatement. However, when rats undergo abstinence without extinction, ceftriaxone attenuates context-primed cocaine seeking but NA core glutamate efflux still increases. Here, we sought to determine if the same would occur when cocaine seeking is prompted by both context and discrete cues (cue-induced seeking) after cocaine abstinence. Male rats self-administered intravenous cocaine accompanied by drug-associated cues (light + tone) for 2 h/day for 14 days. Rats then experienced abstinence with daily handling but no extinction training for 2 weeks. Ceftriaxone (200 mg/kg IP) or vehicle was administered during the last 6 days of abstinence. During a cue-induced cocaine seeking test, microdialysis procedures were conducted. Rats were perfused at the end of the test for later Fos analysis. A separate cohort of rats was infused with the retrograde tracer cholera toxin B in the NA core and underwent the same self-administration and relapse procedures. Ceftriaxone increased baseline glutamate and attenuated both cue-induced cocaine seeking and NA core glutamate efflux during this test. Ceftriaxone reduced Fos expression in regions sending projections to the NA core (prefrontal cortex, basolateral amygdala, ventral tegmental area) and specifically reduced Fos in prelimbic cortex and not infralimbic cortex neurons projecting to the NA core. Thus, when cocaine seeking is induced by drug-associated cues, ceftriaxone is able to attenuate relapse by preventing NA core glutamate efflux, likely through reducing activity in prelimbic NA core-projecting neurons.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are novel tools for the dissection of circuitry mediating behavior and neural function. Designer receptors based on the muscarinic M3 and M4 subtypes were designed to be activated by clozapine-N-oxide (CNO), a ligand previously shown to be an inert metabolite of clozapine. However, recent work in rats has shown that CNO is reverse metabolized to its parent compound. Furthermore, CNO administration (5 mg/kg IP) attenuates amphetamine-induced locomotion and the evoked dopamine response that accompanies it. As these systems are routinely used to probe the neurocircuitry underlying cocaine-seeking behavior, here we sought to determine whether CNO would have similar effects on cocaine-induced locomotion in rats with a history of cocaine self-administration. In order for muscarinic-based DREADDs to be utilized for the dissection of circuitry underlying behavioral responses to cocaine, the doses of CNO administered to induce DREADD signaling must themselves have no effect on cocaine-induced behavior. Male Sprague-Dawley rats self-administered cocaine (0.35 mg/infusion) for 12 days, followed by 14–21 days of instrumental extinction training. Rats then underwent locomotor testing. CNO (0, 3, or 5 mg/kg) was injected (utilizing a within-subjects design), followed 20 min later by cocaine (10 mg/kg IP). Locomotion was monitored for the following 120 min. We found that the 5, but not the 3 mg/kg, dose of CNO reduced cocaine-induced locomotion. Thus, studies utilizing DREAADs to probe cocaine-induced behavior should consider these findings when choosing a dose of CNO and include non-DREADD CNO controls.