Effects of cocaine hydrolase on cocaine self-administration under a PR schedule and during extended access (escalation) in rats

Abstract

Rationale and objectives Previously, Albu-CocH, a cocaine hydrolase derived from human butyrylcholinesterase, blocked cocaine-induced reinstatement of drug seeking in rats. In the present study, rats were treated with Albu-CocH while self-administering cocaine under a progressive ratio (PR) schedule during 2-h sessions and under a fixed-ratio 1 (FR 1) schedule during 6-h sessions. Methods In experiment 1, rats were treated with saline or Albu-CocH (2 or 4 mg/kg) before a single 2-h cocaine (0.2 mg/kg) self-administration (PR) session. In experiment 2, rats were treated with Albu-CocH or saline for the first seven of the 21-day 6-h sessions prior to cocaine (0.2 or 0.4 mg/kg) self-administration sessions (FR 1). Results In experiment 1, Albu-CocH (vs saline) reduced cocaine infusions immediately following treatment compared with sessions pretreatment and posttreatment. In experiment 2, the Albu-CocH-treated groups (vs saline) showed an initial twofold to threefold increase in 0.2 and 0.4 mg/kg cocaine infusions over the 7 days of treatment, but they decreased to the infusion levels of saline controls by day 7. Cocaine (0.4 mg/kg) intake in the saline-treated group was elevated during the last 3 days of 6-h access compared with the first 3 days, indicating an escalation effect. Responding for 0.4 mg/kg (but not 0.2 mg/kg) cocaine during 2-h sessions after the 21 days of 6-h access was elevated in the saline groups (compared with 2-h sessions before long access) but not in the Albu-CocH-treated groups. Conclusions Albu-CocH decreased cocaine infusions under the PR schedule, indicating a reduced reward value of cocaine (experiment 1). However, Albu-CocH, compared with saline, temporarily increased cocaine infusions during long access. The post-long access 2-h cocaine intake was not increased in the Albu-CocH-treated groups as it was in the saline-treated groups. Albu-CocH is an effective agent for reducing cocaine reward under conditions of low cocaine exposure and chronic treatment.

Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase

“…The findings confirm work showing that exogenously administered CocH reduces the physiologic and reinforcing effects of cocaine (e.g., Brimijoin et al, 2008;Carroll et al, 2011). These behavioral effects are achieved by the drastic reduction in the amount of cocaine reaching the brain as a result of CocH activity (Sun et al, 2002a).…”

“…A near-optimal enzyme rescued rats from a lethal 100 mg/kg injection of cocaine and blocked cocaine-primed reinstatement, a model of relapse into cocaine-seeking behavior (Brimijoin et al, 2008). Later CocH significantly reduced progressive-ratio responding (i.e., motivation) for intravenous cocaine self-administration (Carroll et al, 2011), suggesting that CocH substantially dampened its reinforcing effects.…”

Long-Lasting Effects of a PEGylated Mutant Cocaine Esterase (CocE) on the Reinforcing and Discriminative Stimulus Effects of Cocaine in Rats

“…Previous studies with mutant bacterial CocEs (Brim et al, 2010;Collins et al, 2009) or mutant human BChEs (Carroll et al, 2011) have demonstrated the capacity of highly efficient cocaine-specific hydrolase to inhibit the reinforcing effects of cocaine; however, in each of these studies the inhibitory effects of the enzymes were short-lived, lasting from minutes to hours. The results of the current studies with PEG-CCRQ CocE not only confirm this effect of cocaine-specific esterases, but they also provide convergent evidence that PEG-CCRQ CocE represents a significant improvement over previously described mutant bacterial and human cocaine hydrolases with respect to both the magnitude and duration of its antagonism of the reinforcing effects of cocaine.…”

“…These mutant BChEs have shown promising results when evaluated in rodents, effectively reducing the cardiovascular, lethal, and response-reinstating effects of cocaine (Brimijoin et al, 2008;Xue et al, 2010;Zheng et al, 2008). In addition, an albumin-fused mutant BChE (Albu-CocH) has been shown to decrease progressive ratio responding for cocaine (Carroll et al, 2011), suggesting that it is also capable of reducing the reinforcing effectiveness of cocaine.…”

Avances en el desarrollo de productos biológicos para el tratamiento de la adicción a las drogas y las sobredosis

“…Therefore, an antibody can be injected and rapidly block the effect of the drug before it reaches the brain. These effects make antibodies more suitable to treat drug overdose than to extinguish addictive behavior s (Gentry et al, 2010;Zheng & Zhan, 2009;Carroll, Gao, Brimijoin, & Zhan, 2009;Carroll, Gao, Brimijoin, & & Anker, 2011).…”