83 research outputs found
Modification of pharmacokinetic and abuse-related effects of cocaine by human-derived cocaine hydrolase in monkeys
Although substantial research effort has focused on developing pharmacological treatments for
cocaine abuse, no effective medications have been developed. Recent studies show that enzymes
that metabolize cocaine in the periphery, forestalling its entry into the brain, can prevent cocaine
toxicity and its behavioral effects in rodents. Here we report on effects of one such enzyme (Albu-
CocH) on the pharmacokinetic and behavioral effects of cocaine in squirrel monkeys. Albu-CocH
was developed from successive mutations of human butyrylcholinesterase (BChE) and has 1000-
fold greater catalytic activity against cocaine than naturally occurring BChE. Pharmacokinetic
studies showed that Albu-CocH (5 mg/kg) had a half-life of 56.6 hours in squirrel monkeys. In
these studies, plasma levels of cocaine following i.v. 1 mg/kg cocaine were reduced two hours
after administration of Albu-CocH, whereas plasma levels of the cocaine metabolite ecgonine
methyl ester were increased. These effects were still evident 72 hrs following Albu-CocH
administration. In behavioral experiments in monkeys, pretreatment with 5 mg/kg Albu-CocH
dramatically decreased self-administration of a reinforcing dose of i.v. cocaine (30 μg/kg/
injection) for over 24 hours. Pretreatment with 5 mg/kg Albu-CocH also attenuated the
reinstatement of extinguished cocaine self-administration by an i.v. priming injection of cocaine
(0.1 or 0.3 mg/kg) and, in separate studies, attenuated the discriminative stimulus effects of
cocaine. The ability of Albu-CocH to attenuate the abuse-related effects of cocaine in squirrel monkeys indicates that further investigation of BChE mutants as potential treatment for cocaine
abuse and toxicity is warranted.This research was supported in part by the Intramural Research Program of the NIH, National Institute on Drug
Abuse
BMP-2 and cAMP elevation confer locus coeruleus neurons responsiveness to multiple neurotrophic factors
Chronic morphine induces visible changes in the morphology of mesolimbic dopamine neurons.
Morphological Deficits in Noradrenergic Neurons in GEPR-9s Stem from Abnormalities in both the Locus Coeruleus and Its Target Tissues
Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Is a Neurotrophic Factor for Cultured Rat Cortical Neurons
Chronic morphine induces up-regulation of the pro-apoptotic Fas receptor and down-regulation of the anti-apoptotic Bcl-2 oncoprotein in rat brain
1. This study was designed to assess the influence of activation and blockade of the endogenous opioid system in the brain on two key proteins involved in the regulation of programmed cell death: the pro-apoptotic Fas receptor and the anti-apoptotic Bcl-2 oncoprotein. 2. The acute treatment of rats with the μ-opioid receptor agonist morphine (3 – 30 mg kg(−1), i.p., 2 h) did not modify the immunodensity of Fas or Bcl-2 proteins in the cerebral cortex. Similarly, the acute treatment with low and high doses of the antagonist naloxone (1 and 100 mg kg(−1), i.p., 2 h) did not alter Fas or Bcl-2 protein expression in brain cortex. These results discounted a tonic regulation through opioid receptors on Fas and Bcl-2 proteins in rat brain. 3. Chronic morphine (10 – 100 mg kg(−1), 5 days, and 10 mg kg(−1), 13 days) induced marked increases (47 – 123%) in the immunodensity of Fas receptor in the cerebral cortex. In contrast, chronic morphine (5 and 13 days) decreased the immunodensity of Bcl-2 protein (15 – 30%) in brain cortex. Chronic naloxone (10 mg kg(−1), 13 days) did not alter the immunodensities of Fas and Bcl-2 proteins in the cerebral cortex. 4. The concurrent chronic treatment (13 days) of naloxone (10 mg kg(−1)) and morphine (10 mg kg(−1)) completely prevented the morphine-induced increase in Fas receptor and decrease in Bcl-2 protein immunoreactivities in the cerebral cortex. 5. The results indicate that morphine, through the sustained activation of opioid receptors, can promote abnormal programmed cell death by enhancing the expression of pro-apoptotic Fas receptor protein and damping the expression of anti-apoptotic Bcl-2 oncoprotein
Cerebral CT findings in male opioid-dependent patients: Stereological, planimetric and linear measurements
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