Resumption Of Self-administration Research Articles

5-HT1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats.

The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21-60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

Prolonging the Reduction of Nicotine Self-Administration in Rats by Coadministering Chronic Nicotine With Amitifadine, a Triple Monoamine Reuptake Inhibitor With CYP2B6 Inhibitory Actions.

Existing treatments can aid tobacco smoking cessation, but they have low efficacy. Because there is a network of neural systems involved in tobacco addiction, combination treatments may provide greater efficacy. Chronic nicotine and amitifadine have each been shown to significantly reduce nicotine self-administration in rats. This study was conducted to determine if the combination of chronic nicotine with amitifadine, a triple monoamine reuptake inhibitor with CYP2B inhibitory effects, would reduce nicotine self-administration to a greater extent than either alone or placebo. This study tested the combination of nicotine plus amitifadine in young adult female Sprague-Dawley rats self-administering nicotine (0.03 mg/kg/infusion). This combination was compared with each treatment alone and the vehicle during continuing nicotine self-administration as well as during resumption of self-administration after a week of enforced abstinence, modeling a quit attempt. Finally, we studied the residual effects of these therapies after discontinuation of treatment. Treatment with either chronic nicotine or amitifadine alone significantly reduced nicotine self-administration relative to controls. The combination of the treatments significantly enhanced this effect. After treatment withdrawal, all of the groups showed increases in nicotine self-administration, but only the combined treatment group remained significantly below control rates of nicotine self-administration. This study showed the promise of amitifadine as a possible new treatment for smoking cessation and suggested that amitifadine is more effective when given with chronic nicotine. The improved efficacy of the amitifadine and nicotine combination may be potentiated by amitifadine's inhibitory effects on CYP2B, which slows nicotine metabolism. This study replicated the effects that chronic nicotine or chronic amitifadine, a triple reuptake inhibitor, significantly reduces nicotine self-administration in rats. It extends those findings by showing that the combination of chronic nicotine plus amitifadine causes significantly greater reduction in nicotine self-administration than either drug treatment alone. The combination of chronic amitifadine and chronic nicotine also causes a persistent significant reduction in nicotine self-administration after the end of treatment. The amitifadine and nicotine treatment should be assessed in humans to determine whether this combination provides greater efficacy in smoking cessation than transdermal nicotine treatment alone.

Cocaine-Associated Stimuli Increase Cocaine Seeking and Activate Accumbens Core Neurons after Abstinence

Electrophysiological recordings were completed in rats (n = 14) trained to self-administer cocaine to determine whether activation of nucleus accumbens (Acb) neurons (core vs shell) by cocaine-associated stimuli is enhanced after 1 month of cocaine abstinence. After self-administration training, 170 cells were recorded during a single test session conducted either the next day or 1 month later. The test session consisted of three phases during which (1) the cocaine cue was presented unexpectedly to rats, (2) rats responded for the same cue in the absence of the drug (extinction), and (3) the cocaine cue was presented randomly between cocaine-reinforced responding during resumption of self-administration. The cocaine stimulus significantly increased activation of Acb core (not shell) neurons after 1 month of cocaine abstinence (compared with 1 d); this finding occurred regardless of contingency of cue presentation or cocaine availability. Acb core activation was not observed in other rats (n = 7) presented with the same stimulus never paired with cocaine. The results reflect a cellular neuroadaptation in the Acb core related to cocaine-associated cues that is observed during initial cue exposure and sustained during extinction and resumption of self-administration after prolonged drug abstinence.

Changes in dopamine oxidation currents in the nucleus accumbens during unlimited-access self-administration of d-amphetamine by rats.

In-vivo chronoamperometry in conjunction with stearate-modified carbon paste electrodes was used to monitor changes in dopamine (DA) oxidation currents in the nucleus accumbens during extended 24h and 48h sessions of i.v. self-administration of d-amphetamine (0.1mg/infusion) by rats. Animals in two control groups received "yoked" administration of d-amphetamine or saline vehicle. In a separate experiment, microdialysis with probes adjacent to the electrochemical electrodes was employed to estimate the sensitivity of these electrodes to different extracellular concentrations of DA reverse dialyzed at the probe surface in the presence of pharmacological blockade of the DA transporter. During unlimited access to d-amphetamine self-administration, several distinct changes in basal DA oxidation currents were observed: 1) a significant elevation that peaked after asymptotically equal to 4h; 2) a steady decline to values that were not significantly different from the values in the "yoked" vehicle group at asymptotically equal to 9h; 3) a further decline below control levels, reaching a nadir at asymptotically equal to 24h; 4) in the 48h session, a second phase of increased DA oxidation currents accompanied the reinstatement of a second bout of d-amphetamine self-administration, which followed an abstinence period. Examination of chronoamperometric records for individual rats, before, during and after the abstinence periods revealed 1) a significant reduction in basal DA oxidation currents in the self-administration group, relative to both "yoked" groups; 2) resumption of self-administration when DA currents were still attenuated; 3) an increase in DA currents following reinitiation of d-amphetamine self-administration. Comparison of changes in DA oxidation currents between groups revealed 1) significantly greater increases with self-administration vs "yoked" d-amphetamine administration; 2) a significant decrease in the self-administration vs the "yoked" d-amphetamine group during abstinence and 3) a circadian variation in the "yoked" vehicle group that was out of phase with the groups receiving the drug.