benztropine and Seizures

Topics: Agranulocytosis; Barbiturates; Basal Ganglia Diseases; Benztropine; Biperiden; Delayed-Action Preparations; Depression; Diazepam; Drug Interactions; Eye Manifestations; Fatty Acids; Female; Fluphenazine; Humans; Jaundice; Male; Mental Disorders; Movement Disorders; Parkinson Disease, Secondary; Schizophrenia; Seizures; Skin Manifestations

Behavioral effects of cocaine that are relevant to its abuse have been associated with pharmacological actions at the dopamine uptake carrier. Benztropine (Cogentin) is an antiparkinson agent that has limited abuse despite its ability to block dopamine uptake, and has been suggested as a candidate for the treatment of cocaine dependence. Preclinical studies were conducted to assess the behavioral and toxic effects of benztropine alone and in conjunction with cocaine. Because of the mixed pharmacology of benztropine which includes antimuscarinic as well as dopaminergic actions, results obtained from parallel experiments with atropine and the selective dopamine uptake inhibitor, GBR 12935 (1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-propyl)-piperazine), were performed. All of the drugs stimulated locomotor activity of mice, but atropine and benztropine had much lower efficacy. Nonstimulatory doses of GBR 12935 enhanced the locomotor stimulant effects of cocaine, whereas benztropine and atropine did not share this effect. GBR 12935, benztropine and cocaine increased fixed-interval responding, whereas atropine decreased fixed-interval response rates in rats. Only GBR 12935 and cocaine increased responding during timeout periods. GBR 12935, but not benztropine or atropine, fully reproduced the discriminative stimulus effects of cocaine (10 mg/kg). GBR 12935 and atropine augmented the discriminative stimulus effects of lower cocaine doses in rats. Only GBR 12935 and cocaine had convulsant effects and only GBR 12935 significantly enhanced the convulsant effects of cocaine in mice. These results document a behavioral and toxicity profile for benztropine distinct from that of classical dopamine uptake blockers. The data underscore further the potential of benztropine as a candidate for clinical evaluation in the treatment of cocaine dependence.

Topics: Animals; Atropine; Behavior, Animal; Benztropine; Cocaine; Discrimination Learning; Dopamine Uptake Inhibitors; Male; Mice; Motor Activity; Piperazines; Rats; Rats, Sprague-Dawley; Seizures

The ability of various treatments to prevent peripheral parasympathetic actions, central effects and lethality of the muscarinic agonist oxotremorine was studied in rats. The percentage of animals exhibiting effects of oxotremorine was dose and time dependent. The ED50 for producing lacrimation, salivation, tremor, convulsions and death was 2.5, 1.3, 1.6, 3.2 and 8.3 mg/kg i.p., respectively. Pretreatment with 5 mg/kg of atropine completely prevented all observable effects of oxotremorine at doses of 5 mg/kg and below. Doses of oxotremorine in excess of 5 mg/kg produced tremor, generalized clonic convulsions and death that could not be prevented by atropine when given at up to 160 mg/kg; lacrimation and salivation were not present in atropine-treated rats. In the presence of 40 mg/kg of atropine, ED50 values for oxotremorine were shifted more than 12-fold for lacrimation, salivation and tremor, whereas convulsions and death were maximally altered by a factor of 2. Scopolamine, benactyzine and benztropine were also incapable of completely preventing tremor, convulsions and death induced by 10 or 15 mg/kg of oxotremorine. Atropine methyl nitrate had effects comparable to atropine sulfate on lacrimation, salivation and lethality induced by oxotremorine (10 or 15 mg/kg) but had no effect on tremor or convulsions. A similar profile of atropine-insensitive effects was produced by pilocarpine and arecoline. Doses of diazepam 4 times higher (4 mg/kg) than necessary to prevent tonic-clonic convulsions induced by pentylenetetrazol were ineffective against tremor, convulsions or death produced by oxotremorine (10 or 15 mg/kg) unless given in conjunction with atropine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arecoline; Atropine; Atropine Derivatives; Benactyzine; Benztropine; Crying; Diazepam; Dose-Response Relationship, Drug; Drug Interactions; Male; Mecamylamine; Nervous System; Nicotine; Oxotremorine; Pilocarpine; Rats; Rats, Inbred Strains; Salivation; Scopolamine; Seizures; Time Factors

Topics: Animals; Benztropine; Biperiden; Cholinesterase Inhibitors; Diazepam; Dose-Response Relationship, Drug; Male; Mice; Parasympatholytics; Physostigmine; Plant Extracts; Plants, Toxic; Seizures

Topics: Alkaloids; Animals; Antiparkinson Agents; Atropine; Benztropine; Body Temperature; Central Nervous System; Dibenzazepines; Drug Antagonism; Indoles; Male; Methylamines; Mice; Nicotine; Oxotremorine; Parasympatholytics; Procyclidine; Pupil; Pyridines; Seizures; Tremor; Trihexyphenidyl