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

Abstract

A promising approach in treating cocaine abuse is to metabolize cocaine in the blood using a mutated butyrylcholinesterase (BChE) that functions as a cocaine hydrolase (CocH). In rats, a helper-dependent adenoviral (hdAD) vector-mediated delivery of CocH abolished ongoing cocaine use and cocaine-primed reinstatement of drug-seeking for several months. This enzyme also metabolizes ghrelin, an effect that may be beneficial in maintaining healthy weights. The effect of a single hdAD-CocH vector injection was examined in rats on measures of anxiety, body weight, cocaine self-administration, and cocaine-induced locomotor activity. To examine anxiety, periadolescent rats were tested in an elevated-plus maze. Weight gain was then examined under four rodent diets. Ten months after CocH-injection, adult rats were trained to self-administer cocaine intravenously and, subsequently, cocaine-induced locomotion was tested. Viral gene transfer produced sustained plasma levels of CocH for over 13 months of testing. CocH-treated rats did not differ from controls in measures of anxiety, and only showed a transient reduction in weight gain during the first 3 weeks postinjection. However, CocH-treated rats were insensitive to cocaine. At 10 months postinjection, none of the CocH-treated rats initiated cocaine self-administration, unlike 90% of the control rats. At 13 months postinjection, CocH-treated rats showed no cocaineinduced locomotion, whereas control rats showed a dosedependent enhancement of locomotion. CocH vector produced a long-term blockade of the rewarding and behavioral effects of cocaine in rats, emphasizing its role as a promising therapeutic intervention in cocaine abuse.

Accuracy and reliability of a videogrammetry system in the analysis of displacement of Wistar rats

“…Methodologies based on videogrammetry allow to investigate and to better understand various phenomena in laboratory animals related to the displacement, such as: the effect of psychostimulant drugs on locomotion 13 , quantify the influence of the environment on physical activity levels 21 , improve animal study protocols 21 , to study memory information and spatial orientation 10 . The present study was designed to investigate the accuracy and reliability of measurement of displacement of Wistar rats by videogrammetry using manual tracking mode of the Dvideo.…”

“…The videogrammetry system allows the displacement analysis considering the animal's interaction with other animals and the environment, which can be manipulated by the researcher. Inside the videogrammetry analysis, the automatic method has been used in studies on the behavior in the light/dark cycle 21,22 , distance and speed 13,10 . On the other hand, to our knowledge, the videogrammetry with manual tracking mode had not yet been tested in animal experiments.…”

“…Classified as spontaneous physical activity, locomotor behavior is a key element in the daily lives of animals, required for survival and homeostasis 8 . In recent decades, the development of analytical methods to analyze displacement by videogrammetry has been used in studies with different objectives: to understand the effects of psychostimulants 9 , different environments 10 , food restriction 11 , different conditions of housing 12 , and drugs 13 .…”

Biologics to treat substance use disorders: Current status and new directions

“…For instance, viral-mediated transfer of BChE did not show signs of motor, cognitive, or cardiovascular toxicity in mice and rats. [172][173][174][175] Despite promising pre-clinical proof of efficacy and safety, it is not yet clear whether gene transfer approaches will be acceptable by the FDA, EMA, or other regulatory agencies. To date, the FDA's Center for Biologics Evaluation and Research (CBER) has not yet approved any human gene therapy product for market.…”

“…171 Additionally, helper-dependent adenoviral vector-mediated delivery of cocaine hydrolases showed longterm efficacy in blocking cocaine self-administration in rats. 172 To facilitate translation and regulatory approval, gene therapy approaches for treatment of SUD will need to be carefully evaluated for host immune responses to the viral vector components and other potential adverse effects in chronic toxicology studies. For instance, viral-mediated transfer of BChE did not show signs of motor, cognitive, or cardiovascular toxicity in mice and rats.…”