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At least 19 recordsLinked to original sources
PubMed1996

Effects of benztropine on behavioral and toxic effects of cocaine: comparison with atropine and the selective dopamine uptake inhibitor 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenyl-propyl)-piperazine.

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.

Animals↗
PubMed1984

Effects of benztropine mesylate on haloperidol-induced prolactin secretion and serum haloperidol levels in rats.

The effects of benztropine mesylate on haloperidol-induced prolactin secretion and serum haloperidol levels were investigated in 240 rats. Animals were pretreated with benztropine mesylate or saline 20 min prior to receiving haloperidol or saline. Serum prolactin and haloperidol levels were analyzed at six time periods over 150 min. There was no significant difference in prolactin levels of control animals, i.e., saline pretreated/saline treated rats compared to benztropine mesylate pretreated/saline treated rats. Haloperidol caused a significant rise (p less than 0.0001) in serum prolactin compared with controls. The prolactin concentration for the 30-150-min sampling period was significantly higher when the rats received benztropine mesylate prior to haloperidol (p less than 0.05). There was a significant correlation (r = 0.57, p less than 0.001) between serum haloperidol levels and serum prolactin levels in haloperidol-treated animals pretreated with either saline or benztropine mesylate. Additionally, serum haloperidol levels were not significantly different in animals pretreated with benztropine mesylate compared with those pretreated with saline. Thus, the enhancement of prolactin levels by benztropine mesylate was independent of any effect of haloperidol metabolism. This study appears to indicate that in the rat, cholinergic mechanisms exert a weak inhibitory effect on prolactin secretion under conditions of dopamine blockade.

Animals↗
PubMed1990

Mapping muscarinic receptors in human and baboon brain using [N-11C-methyl]-benztropine.

The muscarinic cholinergic system has been mapped in vivo in human and baboon brain using [N-11C-methyl]-benztropine and high resolution positron emission tomography (PET). [N-11C-methyl]-benztropine uptake was observed in frontal, parietal, occipital, and temporal cortices as well as in subcortical structures including the corpus striatum and thalamus. Uptake continued to increase in baboon and human brain in all areas over an 80 minute experimental period with the exception of the cerebellum where the accumulation of radioactivity began to decrease by 25 minutes postinjection. The ratio of incorporation of [N-11C-methyl]-benztropine between corpus striatum/cerebellum was 1.53 and 1.46 in humans and baboons, respectively, at 60 minutes. Blocking studies in baboons using the muscarinic cholinergic antagonists scopolamine and benztropine and the muscarinic cholinergic agonist pilocarpine combined with blocking studies in humans using benztropine indicate that the binding of this compound is specific for the muscarinic cholinergic system. Pretreatment with the potent dopamine reuptake blocker nomifensine produced no effect on the incorporation of radioactivity in any baboon brain region examined. Analysis of labelled plasma metabolites indicates that in humans, the rate of metabolism of [N-11C-methyl]-benztropine is slow (83.0% unchanged at 30 minutes postinjection) differing quite dramatically from the rate of metabolism observed in baboons (43.4% unchanged at 30 minutes postinjection). These data combined with postmortem studies in humans and primates demonstrate that [N-11C-methyl]-benztropine is a suitable muscarinic cholinergic ligand for use in humans and baboons with PET.

Adult↗
PubMed2006

Benztropine pretreatment does not affect responses to acute cocaine administration in human volunteers.

Benztropine (Cogentin ) was evaluated for its ability to block cocaine's physiological and subjective effects in humans. In healthy, recreational users of cocaine, placebo, or benztropine (1, 2, and 4 mg orally) was given 2 hr before subjects self-administered 0.9 mg/kg of cocaine intranasally. Measurements were made for 2 hr following cocaine administration, and plasma cocaine and cocaine metabolites were assayed. Cocaine produced typical increases in heart rate and alterations in self-reports measured by visual analog scales (VAS). Benztropine alone did not produce changes on any of these measures. Responses to cocaine with and without benztropine pretreatment were similar: benztropine did not change cocaine's effects. This study of one of the tropane-ring analogs that is approved for human use suggests this compound does not alter cocaine-induced effects, but just as importantly, does not produce any adverse behavioral or physiological effects. The exact therapeutic application of benztropine as a possible adjunct treatment for cocaine abuse in humans require further exploration.

Adult↗
PubMed1981

A stable isotope dilution assay for the antiparkinsonian drug benztropine in biological fluids.

A quantitative gas chromatographic-mass spectrometric (GC-MS) assay was developed for the determination of benztropine in human urine and plasma. The assay utilizes selected ion focusing to monitor in a GC effluent a specific fragment ion of benztropine generated by electron-impact ionization. Benztropine-d3 was the internal standard. The assay can measure 5 ng/ml of benztropine/ml with about 6% precision. The curve relating the amounts of benztropine added versus the amounts found over a large range of benztropine concentrations was a straight line with a nearly zero intercept and a slope of 0.98 +/- 0.02. The method was used for the analysis of benztropine in urine and plasma of patients on therapeutic dose of the drug.

Benztropine↗
PubMed1995

Phase I and II metabolites of benztropine in rat urine and bile.

Following oral administration of benztropine (IO mg/kg, body weight), the phase I metabolites, benztropine N-oxide, N-desmethylbenztropine, tropine, 4'-hydroxybenz- tropine, N-desmethyl-4'-hydroxybenztropine, 4'-hydroxvbenztropine N-oxide and methoxy-4'-hydroxybenztropine, together with unmetabolized benztropine, were isolated and identified in rat urine and bile by GC-electron impact mass spectrometry (EI GC/MS), microcolumn LC-electrospray mass spectrometry (ES LC/MS) and hplc followed by MS analysis. The mass spectra and chromatographic properties of isolated N-desmethylbenztropine, benztropine N-oxide and tropine were confirmed by comparison with authentic reference standards. Sufficient quantities of 4'-hydroxybenztropine and N-desmethyl-4'-hydroxybenztropine were isolated from the urine by tlc and examined by 1H-nmr, ES/MS and EI/MS. The structure of the methoxy-4'-hydroxybenztropine metabolite was determined by EI/MS. 4'-Hydroxybenztropine N-oxide was identified by reacting it with a reducing agent, titanous chloride, to form 4'-hydroxybenztropine, which was then confirmed by comparing its EI/MS and ES/MS behaviour with a previously isolated and 1H-nmr-authenticated sample. In addition, four intact glucuronide conjugates of benztropine were also characterized in bile and urine as phase II metabolites, including 4'-O-glucuronylbenzotropine, N-desmethyl-4'-O-glucuronylbenztropine, methoxy-4'-O-glucuronylbenztropine and 4'- O-glucuronylbenztropine N-oxide by hplc followed by ES/MS analysis. These results provide the first direct evidence of the presence of these metabolites of benztropine in rat.

Animals↗
PubMed1993

Development of a sensitive and specific radioimmunoassay for benztropine.

A benztropine RIA based on polyclonal antisera raised in New Zealand white rabbits has been developed. The drug-protein conjugates employed had a variety of moles of benztropine hemisuccinate coupled per mole of protein (bovine serum albumin or bovine thyroglobulin). Six antisera were developed and the one with the highest titer was further evaluated for its cross reactivity to N-desmethylbenztropine (4%) and the antipsychotic agents fluphenazine, flupenthixol, chlorpromazine, and haloperidol (all < 1%). The selected antiserum demonstrated sufficient sensitivity to measure benztropine from 0.156 to 100 ng/mL plasma in a 200-microL plasma sample, with a mean CV of < 6%. The RIA was applied to the analysis of steady-state plasma samples obtained from patients undergoing treatment with benztropine and plasma samples obtained from human volunteers and dogs orally dosed with the drug. Both the human and dog plasma samples, when analyzed after hydrolysis with beta-glucuronidase/sulfatase, demonstrated increments in benztropine concentrations, suggesting the drug may be undergoing biotransformation to phase II metabolite(s). In addition, when benztropine was selectively extracted from the unhydrolyzed plasma samples, there was a significant decrease in drug level, which further suggested that the antiserum cross reacted with phase II metabolite(s). The shape of the plasma concentration versus time profile obtained from the dog studies suggested that the drug might also undergo enterohepatic recycling.

Animals↗
PubMed1999

Interaction of benztropine and haloperidol actions on rat substantia nigra dopamine cell electrophysiological activity in vivo.

Despite the known efficacy of antimuscarinic agents in treating dopamine-related movement disorders, their effects on dopamine cell activity have not been well studied. We investigated the effects of systemically administered benztropine, an antimuscarinic agent that also inhibits the dopamine transporter, on substantia nigra dopamine neuron electrophysiological activity. Benztropine caused a dose-dependent inhibition of the firing rate of dopamine neurons in control rats but exerted baseline-dependent changes in burst firing. In rats pre-treated with haloperidol, which prevents the effects of dopamine transporter inhibitors on dopamine cell activity, benztropine either increased or decreased firing rate; however, it consistently increased burst firing. Thus, the antimuscarinic and psychostimulant properties of benztropine have differential effects on dopamine neuron firing rate and burst firing. The increase in burst firing seen in the presence of haloperidol may mediate some of the therapeutic effects of benztropine in the treatment of antipsychotic drug-induced movement disorders.

Animals↗
PubMed1983

The withdrawal of benztropine mesylate in chronic schizophrenic patients.

In this double-blind, four-week study, 28 chronic schizophrenic patients receiving neuroleptic medication plus the antiparkinsonian drug, benztropine mesylate, were either switched to placebo or maintained on benztropine. Patients withdrawn from benztropine reliably increased their overall scores on the Wechsler Memory Scale in comparison with the drug group. Sub-test scores suggest that deficits in attention and concentration were induced by treatment with benztropine. Psychotic decompensation appeared to develop simultaneously with extrapyramidal symptoms (EPS) in some patients, but only 14.2 per cent of the placebo group experienced extrapyramidal symptoms severe enough to require resumption of benztropine therapy. It is suggested that antiparkinsonian agents should be prescribed only if and when EPS occur.

Adolescent↗
PubMed1991

The effect of benztropine on haloperidol-induced dystonia, clinical efficacy and pharmacokinetics: a prospective, double-blind trial.

Twenty-nine inpatients with major psychotic disorders were treated for 14 days with a clinician-determined dose of haloperidol and with either benztropine or placebo given by double-blind random assignment on days 1 through 7. No differences were noted in haloperidol mean dose, haloperidol blood levels, or BPRS scores during the first seven days between benztropine (N = 14) and placebo (N = 15) groups. Benztropine-treated patients demonstrated increased dry mouth and diminished sweat and a non-significantly lower rate of dystonia compared to placebo (14% vs. 33%). Dystonic patients were significantly younger than nondystonic patients, but did not differ in haloperidol mean dose or plasma concentration. The effect of benztropine on the incidence of dystonia was consistent with other studies, which, when analyzed together, demonstrate the efficacy of anticholinergic prophylaxis. The relatively low incidence of anticholinergic side effects, coupled with the lack of effect on haloperidol blood levels or antipsychotic efficacy, suggest that moderate doses of benztropine in conjunction with haloperidol are a rational approach for the treatment of acute psychosis in young patients.

Adult↗
PubMed1989

Anticholinergic effects on memory: benztropine versus amantadine.

To evaluate anticholinergic effects on cognition and other functions, we studied 60 healthy volunteers in a double-blind crossover trial of two antiparkinsonian agents, benztropine and amantadine. Benztropine 4 mg/day, but not amantadine 200 mg/day, impaired free recall and perception of time, and subjects' perception of their own memory impairment was significantly greater with benztropine. Side effects in general were worse with benztropine, particularly such anticholinergic effects as dry mouth and blurred vision, and benztropine decreased measured salivary flow to a significantly greater degree than amantadine. Our findings support the hypothesis that drugs that decrease cholinergic transmission impair storage of new information into long-term memory, but have little effect on retrieval from memory or on tasks involving only immediate memory. Clinically, anticholinergic agents can levy a considerable burden on memory and time perception.

Adolescent↗
PubMed1982

A comparison of atropine, benztropine and diphenhydramine on the reversal of haloperidol induced suppression of self-stimulation.

Acute haloperidol administration (0.25, 0.5 mg/kg) produced a severe reduction in locomotor activity and operant responding for intracranial self-stimulation in rats. If the rats were also given 10 mg/kg of either diphenhydramine or benztropine, this behavioral inhibition was substantially reversed. Atropine (10 mg/kg), however, did not significantly alter the haloperidol inhibition. In a second study, the rats were tested 30 and 120 minutes after the haloperidol treatment (0.25 mg/kg). Again, diphenhydramine and benztropine but not atropine substantially reversed the haloperidol suppression after 30 minutes. When retested after 120 minutes, however, atropine and benztropine but not diphenhydramine partially reversed the haloperidol suppression. Thus, the present study provides support that diphenhydramine can be effective in reversing haloperidol induced suppression of self-stimulation but for a shorter duration than benztropine.

Animals↗
PubMed1989

Serial serum drug concentrations and prolonged anticholinergic toxicity after benztropine (Cogentin) overdose.

A 38-year-old man overdosed on benztropine mesylate (Cogentin; Merck Sharpe & Dohme, West Point, PA) and developed anticholinergic poisoning syndrome, which lasted nine days. Serial serum benztropine concentrations were obtained during his hospitalization. Fluctuating benztropine levels suggested that his lengthy intoxication may have been secondary to prolonged, intermittent absorption rather than from slow plasma clearance. This is believed to be the first report of serial serum benztropine concentrations after overdose.

Adult↗
PubMed2001

Effects of two-carbon bridge region methoxylation of benztropine: discovery of novel chiral ligands for the dopamine transporter.

6-Methoxylated and 8-oxygenated benztropines were prepared and evaluated for their DAT and SERT activity (binding and uptake inhibition). Methoxylation at the two-carbon bridge of benztropine produced a novel class of potent and selective DAT ligands. An interesting enantioselectivity was also observed for this new class of chiral benztropines. The inactivity of the 8-oxygenated analogues seems to point out that, unlike cocaine and its analogues, interactions of benztropine ligands with DAT may be strongly governed by the nitrogen atom.

Benztropine↗
PubMed2001

The uptake inhibitors cocaine and benztropine differentially alter the conformation of the human dopamine transporter.

The binding affinity of the cocaine analog [(3)H]2 beta-carbomethoxy-3beta-(4-fluorophenyl) tropane (WIN) for the dopamine transporter (DAT) is increased by the reaction of Cys-90, at the extracellular end of the first transmembrane segment, with methanethiosulfonate (MTS) reagents. Cocaine enhances the reaction of Cys-90 with the sulfhydryl reagents, thereby augmenting the increase in binding. In contrast, cocaine decreases the reaction of Cys-135 and Cys-342, endogenous cysteines in cytoplasmic loops, with MTS reagents. Because this reaction inhibits [(3)H]WIN binding, cocaine protects against the loss of binding caused by reaction of these cysteines. In the present work, we compare the abilities of DAT inhibitors and substrates to affect the reaction of Cys-90, Cys-135, and Cys-342 with MTS ethyltrimethylammonium (MTSET). The results indicate that the different abilities of compounds to protect against the MTSET-induced inhibition of binding are attributable to differences in their abilities to attenuate the inhibitory effects of modification of Cys-135 and Cys-342 as well as to enhance the reaction with Cys-90 and the resulting potentiation of binding. The inhibitor benztropine was unique in its inability to protect Cys-135. Moreover, whereas cocaine, WIN, mazindol, and dopamine enhanced the reaction of Cys-90 with MTSET, benztropine had no effect on this reaction. These two features combine to give benztropine its weak potency in protecting ligand binding to wild-type DAT from MTSET. These results indicate that different inhibitors of DAT, such as cocaine and benztropine, produce different conformational changes in the transporter. There are differences in the psychomotor stimulant-like effects of these compounds, and it is possible that the different behavioral effects of these DAT inhibitors stem from their different molecular actions on DAT.

Benztropine↗
PubMed1994

Benztropine identification and quantitation in a suicidal overdose.

For a human fatality involving suspected overdose with the anticholinergic agent benztropine, GC-MS analysis was utilized for identification, quantitation, and investigation of metabolism. Organic extracts of blood and urine were analyzed by a capillary-column gas chromatograph interfaced with an ion-trap mass spectrometer, which was programmed for wide-spectrum data acquisition. Electron impact and chemical ionization were used for benztropine detection. The chemical structures of the ion fragments are proposed. Benztropine-d3 was synthesized and used as an internal standard. Quantitative determinations of benztropine revealed 0.183 mg/L in blood and 7.12 mg/L in urine from the decedent. Drug concentrations were interpreted relative to the case findings, published data, and a limited evaluation of the therapeutic concentrations in psychiatric patients. In addition, the possible metabolic conversion to norbenztropine was investigated by the synthesis of the norbenztropine derivative. Chromatographic evaluation of samples from the case study did not reveal significant bioconversion via the N-desmethylation pathway.

Adult↗
PubMed2004

Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine.

The different psychomotor-stimulant effects of cocaine, GBR12909, and benztropine may partially stem from their different molecular actions on the dopamine transporter (DAT). To explore this possibility, we examined binding of these inhibitors to mutated DATs with altered Na(+) dependence of DAT activities and with enhanced binding of a cocaine analog, [(3)H]2 beta-carbomethoxy-3 beta-(4-fluorophenyl)tropane (CFT). In [(3)H]CFT competition assays with intact cells, the mutation-induced change in the ability of Na(+) to enhance the apparent affinity of CFT, cocaine, GBR12909, and benztropine was inhibitor-independent. Thus, for the four inhibitors, the curve of [Na(+)] versus apparent ligand affinity was steeper at W84L compared with wild type, shallower at D313N, and flat at W84LD313N. At each mutant, the apparent affinity of CFT and cocaine was enhanced regardless of whether Na(+) was present. However, the apparent affinity of GBR12909 and benztropine for W84L was reduced in the absence of Na(+) but near normal in the presence of 130 mm Na(+), and that for D313N and W84LD313N was barely changed. At the single mutants, the alterations in Na(+) dependence and apparent affinity of the four inhibitors were comparable between [(3)H]CFT competition assays and [(3)H]dopamine uptake inhibition assays. These results demonstrate that DAT inhibitors producing different behavioral profiles can respond in an opposite way when residues of the DAT protein are mutated. For GBR12909 and benztropine, their cocaine-like changes in Na(+) dependence suggest that they prefer a DAT state similar to that for cocaine. However, their cocaine-unlike changes in apparent affinity argue that they, likely via their diphenylmethoxy moiety, share DAT binding epitopes that are different from those for cocaine.

Amino Acid Substitution↗
PubMed2006

Gain of function mutants reveal sites important for the interaction of the atypical inhibitors benztropine and bupropion with monoamine transporters.

Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.

Alanine↗