Effects of benztropine: A Synthesis of Findings from 24 Studies

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Original Abstract of the Article

Major Research Findings

Benztropine is a potent dopamine reuptake inhibitor that has been shown to increase dopamine levels in the brain. 18 demonstrated that benztropine increases dopamine levels in the rat striatum by blocking the reuptake of dopamine. This study also showed that the reuptake mechanism is dependent on the presence of sodium in the external medium, highlighting the role of the sodium pump in dopamine reuptake. 4 compared the effects of benztropine, cocaine, and nomifensine on dopamine overflow and reuptake in rat brain slices, suggesting that benztropine is more potent in blocking dopamine reuptake in the caudate putamen than in the nucleus accumbens. Additionally, 5 explored the effects of methoxylation on the two-carbon bridge region of benztropine, leading to the discovery of novel chiral ligands for the dopamine transporter.

Research has also focused on the behavioral effects of benztropine. 8 investigated N-substituted analogs of benztropine and found that these analogs, while possessing high affinity for the dopamine transporter, had reduced cocaine-like behavioral effects. This study suggests that modifying the structure of benztropine can reduce its addictive potential. 10 further examined N-substituted benztropine analogs and concluded that a fast onset of action is not a necessary condition for reduced cocaine-like effects, proposing multiple mechanisms for these effects.

Interestingly, benztropine has shown potential as a therapeutic agent for cocaine addiction. 9 found that benztropine analogs can block cocaine self-administration in rats, suggesting that they could be used to reduce the rewarding effects of cocaine. 22 investigated the behavioral and toxic effects of benztropine in combination with cocaine, noting that while benztropine shares some effects with cocaine, it lacks its addictive properties, suggesting a potential role in treating cocaine dependence.

Benefits and Risks

Benefits Summary

Benztropine is a dopamine reuptake inhibitor used to treat Parkinson’s disease and other movement disorders. It also shows promise in treating cocaine addiction by potentially reducing the reinforcing effects of cocaine. These therapeutic benefits are attributed to its ability to modulate dopamine neurotransmission.

Risks Summary

Benztropine can have side effects, including dry mouth, constipation, blurred vision, drowsiness, and dizziness. These side effects are more common in older adults and individuals with heart conditions. It is important to consult with a healthcare professional before taking benztropine, especially during pregnancy, breastfeeding, or if taking other medications.

Comparison Between Studies

Similarities

Many studies agree that benztropine is a dopamine reuptake inhibitor and that it can reduce the effects of cocaine. These consistent findings support the potential of benztropine as a treatment for Parkinson’s disease and cocaine addiction.

Differences

There are some differences in the specific effects of benztropine on dopamine neurotransmission reported across various studies. For example, while 18 found an increase in dopamine levels with benztropine, 4 observed a modulation of dopamine release and reuptake. These discrepancies may be due to differences in study methods, experimental conditions, or specific brain regions targeted. Further research is needed to fully understand the nuanced effects of benztropine on dopamine neurotransmission.

Consistency and Contradictions

Research on benztropine has yielded a mix of consistent findings and contradictions. Many studies support its effects on dopamine neurotransmission, but the exact mechanisms and extent of these effects remain open to further investigation. Additionally, while there is evidence that benztropine might be helpful in treating cocaine addiction, more clinical research is required to confirm its therapeutic effectiveness.

Real-World Applications and Precautions

Benztropine is used to treat Parkinson’s disease and may have therapeutic potential for cocaine addiction. However, due to its potential side effects, it is crucial to use benztropine under the guidance of a healthcare professional. Older adults, individuals with heart conditions, and pregnant or breastfeeding women should be particularly cautious when considering benztropine.

Limitations of Current Research

Despite the growing body of research on benztropine, more investigation is necessary to fully elucidate its effects on dopamine neurotransmission. Particularly, understanding the precise mechanisms and magnitude of these effects warrants further exploration. Additionally, large-scale clinical trials are needed to definitively confirm the effectiveness of benztropine in treating cocaine addiction.

Future Directions for Research

Further research is essential to gain a comprehensive understanding of the effects of benztropine on dopamine neurotransmission. This includes clarifying the specific mechanisms by which it alters dopamine levels and release. Additionally, more clinical trials are needed to determine the effectiveness of benztropine in treating cocaine addiction. Further research can lead to the development of new treatments and the refinement of existing therapies.

Conclusion

Benztropine, a dopamine reuptake inhibitor, is currently used for treating Parkinson’s disease and shows potential for treating cocaine addiction. Its therapeutic benefits stem from its ability to modulate dopamine neurotransmission. However, it’s important to use benztropine under medical supervision due to its potential side effects. Continued research is essential to fully understand benztropine’s effects and potential for treating various conditions.

Literature analysis of 24 papers
Positive Content
19
Neutral Content
1
Negative Content
4
Article Type
2
0
0
0
24
1.

Behavioral economic analysis of the effects of N-substituted benztropine analogs on cocaine self-administration in rats.

Author: ZanettiniClaudio, WilkinsonDerek S, KatzJonathan L

Cocaine self-administration reduction

This study investigated the effects of benztropine (BZT) analogs and other atypical dopamine uptake inhibitors on cocaine self-administration in rats. The results showed that these compounds selectively reduced cocaine intake at doses that did not affect responding maintained by other reinforcers.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., IntramuralFunding provided by the NIH for research projects within the NIH.

Language : English

5.

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

Author: SimoniD, RobertiM, RondaninR, BaruchelloR, RossiM, InvidiataF P, MerighiS, VaraniK, GessiS, BoreaP A, MarinoS, CavalliniS, BianchiC, SiniscalchiA

Potent DAT ligand

Methoxylation at the two-carbon bridge of benztropine produced a novel class of potent and selective DAT ligands.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

6.

Differential effects of benztropine and desipramine on the high affinity uptake of paratyramine in slices of the caudate nucleus and hypothalamus.

Author: PetraliE H

Benzotropine efficacy

Benzotropine and desipramine had different effects on dopamine and p-tyramine uptake in the caudate and hypothalamus.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

7.

A controlled comparison of the effects of propranolol, benztropine, and placebo on akathisia: an interim analysis.

Author: AdlerL A, PeselowE, RosenthalM, AngristB

Improved akathisia
Confusion
Forgetfulness

Propranolol and benztropine were effective in treating akathisia, showing significant improvement by day 3-5 of treatment. Placebo had no effect on akathisia. Benztropine caused confusion or forgetfulness in 3 patients, which resolved upon discontinuation.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, U.S. Gov't, Non-P.H.S.Research funding provided by US government agencies other than the Public Health Service.

Language : English

10.

N-substituted benztropine analogs: selective dopamine transporter ligands with a fast onset of action and minimal cocaine-like behavioral effects.

Author: LiSu-Min, KopajticTheresa A, O'CallaghanMatthew J, AgostonGregory E, CaoJianjing, NewmanAmy Hauck, KatzJonathan L

Treat cocaine addiction

Cocaine and benztropine analogs have different behavioral effects, possibly due to differences in their onset of action. This study investigated whether a faster onset of action would render the effects of benztropine analogs more similar to those of cocaine.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., IntramuralFunding provided by the NIH for research projects within the NIH.

Language : English

11.

Comparative side effects of imipramine, benztropine, or their combination in patients receiving fluphenazine decanoate.

Author: SirisS G, RifkinA, ReardonG T, NovemberM

Exacerbated extrapyramidal side effects

Patients taking fluphenazine decanoate experienced increased extrapyramidal side effects when switching from benztropine to imipramine. However, adding imipramine to fluphenazine decanoate and benztropine did not significantly increase anticholinergic side effects.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

12.

The stereotypy-inducing effects of N-substituted benztropine analogs alone and in combination with cocaine do not account for their blockade of cocaine self-administration.

Author: LiLibin, HiranitaTakato, HayashiShuichiro, NewmanAmy H, KatzJonathan L

Treat cocaine abuse

N-substituted 4', 4″-diF-benztropine (BZT) analogs decreased cocaine self-administration without affecting food-maintained behavior or increasing locomotor activity or stereotypies.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., IntramuralFunding provided by the NIH for research projects within the NIH.

Language : English

13.

Relationship between in vivo occupancy at the dopamine transporter and behavioral effects of cocaine, GBR 12909 [1-{2-[bis-(4-fluorophenyl)methoxy]ethyl}-4-(3-phenylpropyl)piperazine], and benztropine analogs.

Author: DesaiRajeev I, KopajticTheresa A, FrenchDawn, NewmanAmy H, KatzJonathan L

Inhibition of DA uptake
Behavioral effects

This study examined the effects of cocaine and benztropine analogs on dopamine uptake and locomotor activity. It found that benztropine analogs are less effective than cocaine at stimulating locomotor activity.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

14.

Effects of benztropine on ketamine-induced behaviors in Cebus monkeys.

Author: ShiigiY, CaseyD E

schizophrenic-like psychosis

This double-blind randomized study evaluated the effects of benztropine, an anticholinergic agent, on ketamine-induced behaviors in Cebus monkeys. Benztropine was found to significantly reduce ketamine-induced hypersalivation and partially ameliorate dystonia, but it did not affect ketamine-induced decreased reactivity to external stimuli.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, U.S. Gov't, Non-P.H.S.Research funding provided by US government agencies other than the Public Health Service.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

15.

Anticholinergic effects on memory: benztropine versus amantadine.

Author: GelenbergA J, Van PuttenT, LavoriP W, WojcikJ D, FalkW E, MarderS, Galvin-NadeauM, SpringB, MohsR C, BrotmanA W

Blurred vision
Dry mouth
Memory impairment
Time perception impairment

Benztropine, an anticholinergic agent, can impair cognition and other functions. In a double-blind crossover trial of 60 healthy volunteers, benztropine, but not amantadine, impaired free recall and perception of time. Subjects' perception of their own memory impairment was also significantly greater with benztropine. Benztropine decreased salivary flow to a greater degree than amantadine, and side effects were more common with benztropine.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Controlled Clinical TrialA clinical trial that evaluates the effectiveness of a treatment by comparing a group that receives the intervention with a group that receives a placebo or standard treatment.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

16.

Assessment of reinforcing effects of benztropine analogs and their effects on cocaine self-administration in rats: comparisons with monoamine uptake inhibitors.

Author: HiranitaTakato, SotoPaul L, NewmanAmy H, KatzJonathan L

Cocaine abuse treatment

Benztropine (BZT) analogs inhibit dopamine uptake but are less effective than cocaine in producing behavioral effects that predict abuse liability. This study compared the reinforcing effects of intravenous BZT analogs with standard monoamine uptake inhibitors and the effects of oral pretreatment with these analogs on cocaine self-administration. Rats were trained to self-administer cocaine (0.032-1.0 mg/kg/injection) or food under fixed-ratio five-response schedules. The highest rates of responding were maintained by 0.32 mg/kg/injection cocaine or substituted methylphenidate, with lower rates maintained at lower and higher doses. The N-methyl BZT analog, AHN 1-055, also maintained responding (0.1 mg/kg/injection), but at lower rates than cocaine. Responding was not maintained above vehicle levels by the N-allyl (AHN 2-005) and N-butyl (JHW 007) BZT analogs, or by nisoxetine or citalopram. Presession treatment with methylphenidate (3.2-32 mg/kg) dose-dependently shifted the cocaine self-administration dose-effect curve leftward, while nisoxetine and citalopram effects were not significant. An intermediate dose of AHN 1-055 (32 mg/kg) increased responding maintained by low cocaine doses and decreased responding maintained by higher doses. A higher dose of AHN 1-055 completely suppressed cocaine-maintained responding. Both AHN 2-005 and JHW 007 dose-dependently (10-32 mg/kg) decreased cocaine self-administration, shifting the dose-effect curve downward. Decreases in cocaine-maintained responding occurred at doses of methylphenidate and BZT analogs that did not affect food-maintained responding. During a component in which injections were not available, methylphenidate and AHN 1-055, but not AHN 2-005 or JHW 007, increased response rates. These findings further support the low abuse liability of BZT analogs and their potential development as medications for cocaine abuse.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., IntramuralFunding provided by the NIH for research projects within the NIH.

Language : English

19.

A comparative study of haloperidol and chlorpromazine in terms of clinical effects and therapeutic reversal with benztropine in schizophrenia. Theoretical implications for potency differences among neuroleptics.

Author: SinghM M, KayS R

Schizophrenia treatment
Diminished therapeutic response

Haloperidol was generally more effective than chlorpromazine in treating schizophrenic patients. Haloperidol was faster-acting and showed greater improvement in social, emotional, and cognitive areas. Chlorpromazine resulted in less dysphoria compared to haloperidol. Benztropine was found to diminish therapeutic response to both neuroleptics, with haloperidol being less susceptible to this effect.

Clinical TrialA clinical trial is a planned study conducted on humans to evaluate the efficacy and safety of pharmaceuticals, medical devices, and treatment methods. It aims to explore the possibilities of new treatments and improve the health of patients.
Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Controlled Clinical TrialA clinical trial that evaluates the effectiveness of a treatment by comparing a group that receives the intervention with a group that receives a placebo or standard treatment.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

20.

Dopamine Transporter Dynamics of <i>N</i>-Substituted Benztropine Analogs with Atypical Behavioral Effects.

Author: HongWeimin C, WaskoMichael J, WilkinsonDerek S, HiranitaTakato, LiLibin, HayashiShuichiro, SnellDavid B, MaduraJeffry D, SurrattChristopher K, KatzJonathan L

Potential treatments for psychomotor-stimulant abuse

This study examines the effects of atypical dopamine transporter (DAT) inhibitors on DAT conformation. Several 3α-(4',4''-difluoro-diphenylmethoxy)tropanes were examined, and their DAT conformational bias was assessed using substituted-cysteine accessibility and molecular dynamics simulations. These analogs exhibited bias for a cytoplasmic-facing DAT conformation, except GA2-99. The study suggests that DAT conformation can influence the actions of DAT inhibitors and may be useful for designing treatments for psychomotor-stimulant abuse.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., IntramuralFunding provided by the NIH for research projects within the NIH.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

21.

Extrapyramidal side effects in chlorpromazine recipients: emergence according to benztropine prophylaxis.

Author: SwettC, ColeJ O, ShapiroS, SloneD

Extrapyramidal symptoms

The frequency of extrapyramidal symptoms (EPS) attributed to chlorpromazine was compared in 86 patients receiving benztropine for EPS prevention and 568 patients receiving chlorpromazine alone. The study found no significant difference in the rate of EPS between the two groups, suggesting that prophylactic use of benztropine does not reduce the rate of EPS.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, U.S. Gov't, Non-P.H.S.Research funding provided by US government agencies other than the Public Health Service.

Language : English

22.

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.

Author: AcriJ B, SiedleckB K, WitkinJ M

Cocaine dependence treatment

Benztropine, an antiparkinson agent, showed a unique behavioral and toxicity profile compared to classic dopamine uptake blockers. It stimulated locomotor activity but did not enhance the stimulant effects of cocaine, unlike GBR 12935. Benztropine did not reproduce the discriminative stimulus effects of cocaine, but GBR 12935 did, suggesting potential for benztropine in cocaine dependence treatment.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

23.

Effects of the histamine H₁ receptor antagonist and benztropine analog diphenylpyraline on dopamine uptake, locomotion and reward.

Author: OlesonErik B, FerrisMark J, EspañaRodrigo A, HarpJill, JonesSara R

Cocaine addiction treatment

Diphenylpyraline hydrochloride (DPP), an antihistamine, was found to inhibit dopamine uptake in the nucleus accumbens (NAc) in a manner similar to cocaine. While DPP induced locomotor activation, it did not produce significant conditioned place preference, suggesting that it may have potential as a pharmacotherapy for cocaine addiction without producing rewarding effects.

Comparative StudyResearch that compares multiple groups/interventions to determine differences/similarities in outcomes/characteristics.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

24.

Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents.

Author: KatzJ L, AgostonG E, AllingK L, KlineR H, ForsterM J, WoolvertonW L, KopajticT A, NewmanA H

Dopamine transporter affinity

Previous studies showed that halogen substitutions on the diphenylether system of benztropine (BZT) retained high affinity at the cocaine binding site on the dopamine transporter, but with different behavioral effects. This study suggests that meta-Cl substitutions on BZT may have effects more similar to cocaine.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, U.S. Gov't, P.H.S.Research funding provided by the Public Health Service (PHS).

Language : English

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