Paradoxical tolerance to cocaine after initial supersensitivity in drug‐use‐prone animals

Abstract

There is great interest in outlining biological factors and behavioral characteristics that either predispose or predict vulnerability to substance use disorders. Response to an inescapable novel environment has been shown to predict a “drug-use prone” phenotype that is defined by rapid acquisition of cocaine self-administration. Here, we show that response to novelty can also predict neurochemical and behavioral effects of acute and repeated cocaine. We used cocaine self-administration under a fixed-ratio one schedule followed by fast scan cyclic voltammetry in brain slices to measure sub-second dopamine release and uptake parameters in drug-use prone and resistant phenotypes. Despite no significant differences in stimulated release and uptake, animals with high responses to a novel environment had dopamine transporters that were more sensitive to cocaine-induced uptake inhibition, which corresponded to greater locomotor activating effects of cocaine. These animals also acquired cocaine self-administration more rapidly, and after five days of extended access cocaine self-administration, high responding animals showed robust tolerance to DA uptake inhibition by cocaine. The effects of cocaine remained unchanged in animals with low novelty responses. Similarly, the rate of acquisition was negatively correlated with DA uptake inhibition by cocaine after self-administration. Thus, we show that tolerance to cocaine-induced inhibition of DA uptake coexists with a behavioral phenotype that is defined by increased preoccupation with cocaine as measured by rapid acquisition and early high intake.

α6β2 subunit containing nicotinic acetylcholine receptors exert opposing actions on rapid dopamine signaling in the nucleus accumbens of rats with high-versus low-response to novelty

“…To examine the frequency dependence of dopamine signaling, dopamine was elicited by 5 pulse stimulations across the physiological range of dopamine neuron firing. Consistent with previous results (Ferris et al,2013a) response to novelty did not predict dopamine release magnitude in response to single pulse stimulations (Figure 1B) (r = −0.10, p = 0.68). Further, response to novelty did not predict dopamine release magnitude for any of the frequencies tested (Figure 1B; 5 Hz: r = −0.23, p = 0.35; 10 Hz: r = −0.08, p = 0.74; 20 Hz: r = −0.05, p = 0.85; 100 Hz: r = − 0.10, p = 0.69).…”

“…In preclinical rodent models, drug abuse vulnerability can be predicted by an animal’s locomotor responsiveness to an inescapable novel environment. Indeed, animals with higher response to the novel environment (high-responder; HR) acquire drug self-administration more rapidly and at lower doses than their low-responder (LR) counterparts for many drugs of abuse, including psychostimulants such as cocaine and nicotine (Suto et al,2001; Ferris et al,2013a; Piazza et al,1989). Thus, the HR/LR model is a powerful tool for determining antecedent neurochemical characteristics that contribute to drug abuse vulnerability.…”

Intermittent Cocaine Self-Administration Produces Sensitization of Stimulant Effects at the Dopamine Transporter

“…Previous work has demonstrated that LgA cocaine selfadministration results in decreased cocaine potency; however, here we show no change in MPH or amphetamine potency, indicating that LgA-induced DAT changes do not affect the function of amphetamine-like compounds. This is consistent with work using a limited-intake, extended-access self-administration paradigm (5 days; 40 injections; 1.5 mg/kg per injection), which showed reduced potency of cocaine and other blockers (nomifensine, bupropion) at the DAT but no change in the potency of any releasers (amphetamine, phentermine, methamphetamine, benzypiperidine; methylenedioxymethamphetamine) or MPH (Ferris et al, 2011(Ferris et al, , 2013aCalipari et al, 2012Calipari et al, , 2014a. In addition, we show that IntA causes a sensitization of amphetamine and MPH, which is consistent with previous studies examining cocaine potency following IntA (Calipari et al, 2013c).…”

Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine

“…Despite finding no difference across groups in novel environment-induced locomotion, we did observe an increase in basal DA tone using in vivo microdialysis. While there are reports of a relationship between basal DA tone in the NAc and novel environment-induced locomotor activity (Hooks et al, 1992), others have failed to observe this relationship (Antoniou et al, 2008; Chefer et al, 2003; Ferris et al, 2013a), and thus our current finding is not without precedent. In subsequent in vitro FSCV experiments we found a reduction in evoked DA release and slower DA uptake.…”