Enhancement of haloperidol-induced catalepsy by nicotine: an investigation of possible mechanisms

2000 ◽  
Vol 78 (11) ◽  
pp. 882-891 ◽  
Author(s):  
Sandra M Boye ◽  
Paul BS Clarke
Keyword(s):  
Receptor Antagonist ◽  
Nicotinic Receptors ◽  
Dopamine Release ◽  
Combined Treatment ◽  
Active Metabolites ◽  
Dopamine Receptor Antagonist ◽  
Nigrostriatal Dopamine ◽  
Brain Nicotinic Receptors ◽  
Pharmacologically Active ◽  
Depolarization Inactivation

Nicotine has been reported to potentiate the cataleptic effect of the dopamine receptor antagonist haloperidol in rats. This effect is paradoxical, since nicotine alone tends to increase nigrostriatal dopamine release. In the present experiments, a pro-cataleptic effect of nicotine was confirmed statistically but was small and variable. Three potential mechanisms underlying this effect were investigated. (i) Desensitization of brain nicotinic receptors appears to make little if any contribution to the pro-cataleptic effect of nicotine, insofar as the latter was not mimicked by two centrally active nicotinic antagonists (mecamylamine and chlorisondamine). (ii) Depolarization inactivation resulting from combined treatment with haloperidol and nicotine does not appear to be critical, since the pro-cataleptic effect of nicotine was not enhanced by chronic haloperidol administration, a treatment designed to enhance depolarization inactivation. (iii) The slow emergence and persistence of the acute pro-cataleptic effect of nicotine suggested possible mediation by a nicotine metabolite. However, neither cotinine nor nornicotine, the principal pharmacologically-active metabolites of nicotine, exerted a significant pro-cataleptic effect. In conclusion, the pro-cataleptic effect of nicotine was weak and variable in the present study, and its mechanism remains obscure.Key words: catalepsy, nicotine, haloperidol, Tourette's Syndrome, dopamine, nornicotine.

scholarly journals Combined Treatment with Dopamine Receptor Antagonists and Radiation Creates a Metabolic Vulnerability in Mouse Models of Glioblastoma

2020 ◽  
Author(s):  
Mohammad Saki ◽  
Kruttika Bhat ◽  
Fei Cheng ◽  
Ling He ◽  
Le Zhang ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Dopamine Receptor ◽  
Mouse Models ◽  
Cholesterol Biosynthesis ◽  
Combined Treatment ◽  
Unmet Need ◽  
Survival Times ◽  
Self Renewal ◽  
Dopamine Receptor Antagonist

AbstractBackgroundGlioblastoma is the deadliest brain tumor in adults and the standard-of-care consists of surgery followed by radiation and treatment with temozolomide. Overall survival times for patients suffering from glioblastoma are unacceptably low indicating an unmet need for novel treatment options.MethodsUsing patient-derived glioblastoma lines and mouse models of glioblastoma we test the effect of radiation and the dopamine receptor antagonist on glioblastoma self-renewal in vitro and survival in vivo. A possible resistance mechanism is investigated using RNA-Sequencing.ResultsTreatment of glioma cells with the dopamine receptor antagonist quetiapine reduced glioma cell self-renewal in vitro and combined treatment of mice with quetiapine and radiation prolonged the survival of glioma-bearing animals. The combined treatment induced the expression of genes involved in cholesterol biosynthesis. This rendered the tumors vulnerable to simultaneous treatment with atorvastatin and further significantly prolonged the survival of the animals.ConclusionsOur results indicate high efficacy of a triple combination of quetiapine, atorvastatin and radiation against glioblastoma without increasing the toxicity of radiation. With both drugs readily available for clinical use our study could be rapidly translated into a clinical trial.

scholarly journals Peganum harmala and its Alkaloids as Dopamine Receptor Antagonists: in Silico Study

2020 ◽  
Vol 11 (3) ◽  
pp. 10301-10316
Keyword(s):  
Receptor Antagonist ◽  
Dopamine Receptor ◽  
Neurological Diseases ◽  
Peganum Harmala ◽  
Active Metabolites ◽  
Receptor Antagonists ◽  
Dopamine Receptor Antagonist ◽  
Dopamine Receptor Antagonists ◽  
Reference Ligand ◽  
The Central Nervous System

Peganum harmala is known to have active metabolites such as alkaloids, which can affect the central nervous system. One of the various alkaloids is thought to be related to their activity as dopamine receptor antagonists, which can be developed in the therapy of various neurological diseases. This study aims to determine the alkaloid from P. harmala, which has the highest potential as the dopamine receptor antagonist. The method used was molecular docking against dopamine receptors with risperidone as the reference ligand. The results showed that among the known alkaloids from P. harmala, dipegine, harmalanine, and harmalacinine showed the highest potency in terms of both free energy of binding and similarity of ligand-receptor interactions. The results of this investigation anticipate that some alkaloids from P. harmala have the potential as the dopamine receptor antagonist.

Activation of nicotinic receptors on GABAergic amacrine cells in the rabbit retina indirectly stimulates dopamine release

2001 ◽  
Vol 18 (1) ◽  
pp. 55-64 ◽  
Author(s):  
MICHAEL J. NEAL ◽  
JOANNA R. CUNNINGHAM ◽  
KIM L. MATTHEWS
Keyword(s):  
Receptor Antagonist ◽  
Nicotinic Receptors ◽  
Dopamine Release ◽  
Amacrine Cells ◽  
Gaba Release ◽  
Rabbit Retina ◽  
Glutamate Antagonists ◽  
Endogenous Gaba ◽  
Nicotinic Agonists ◽  
Inhibitory Transmitter

The retina possesses subpopulations of amacrine cells, which utilize different transmitters, including acetylcholine (ACh), GABA, and dopamine. We have examined interactions between these neurones by studying the effects of nicotinic agonists on GABA and dopamine release. Isolated rabbit retinas were incubated with [3H]dopamine and then superfused. Fractions of the superfusate (2 min) were collected and the [3H]dopamine in each sample was measured. Endogenous GABA release was examined by incubating retinas in a small chamber. At 5-min intervals, the medium was changed and the GABA measured by high-pressure liquid chromatography (HPLC). Exposure of the retina to nicotine, epibatidine, and other nicotinic agonists increased the release of both GABA and dopamine. The effects of nicotine and epibatidine were blocked by mecamylamine, confirming an action on nicotinic receptors. The action of epibatidine on dopamine release was unaffected by glutamate antagonists but was blocked by picrotoxin and gabazine. These results suggested that nicotine might increase dopamine release indirectly by stimulating the release of GABA, which in turn inhibited the release of an inhibitory transmitter acting tonically on the dopaminergic amacrines. Exposure of the retina to GABA caused a small increase in dopamine release. This hypothetical inhibitory transmitter was not GABA, an opioid, adenosine, glycine, nociceptin, a cannabinoid, or nitric oxide because appropriate antagonists did not affect the resting release of dopamine. However, metergoline, a 5HT1/5HT2 receptor antagonist, and ketanserin, a 5HT2A receptor antagonist, but not the 5HT1A antagonist WAY100635, increased the resting release of dopamine and blocked the effects of nicotine. The 5HT1A/5HT7 agonist 8-hydroxy DPAT inhibited both the nicotine and GABA-evoked release of dopamine. We conclude that nicotinic agonists directly stimulate the release of GABA, but the evoked release of dopamine is indirect, and arises from GABA inhibiting the input of an inhibitory transmitter, which we tentatively identify as serotonin.

scholarly journals Ketamine—50 years in use: from anesthesia to rapid antidepressant effects and neurobiological mechanisms

2021 ◽  
Vol 73 (2) ◽  
pp. 323-345
Author(s):  
Samuel Kohtala
Keyword(s):  
Traumatic Stress ◽  
Molecular Mechanisms ◽  
Post Traumatic Stress ◽  
Active Metabolites ◽  
The Past ◽  
Antidepressant Effects ◽  
Post Traumatic ◽  
Pharmacologically Active ◽  
Dose Dependent ◽  
Different Doses

AbstractOver the past 50 years, ketamine has solidified its position in both human and veterinary medicine as an important anesthetic with many uses. More recently, ketamine has been studied and used for several new indications, ranging from chronic pain to drug addiction and post-traumatic stress disorder. The discovery of the rapid-acting antidepressant effects of ketamine has resulted in a surge of interest towards understanding the precise mechanisms driving its effects. Indeed, ketamine may have had the largest impact for advancements in the research and treatment of psychiatric disorders in the past few decades. While intense research efforts have been aimed towards uncovering the molecular targets underlying ketamine’s effects in treating depression, the underlying neurobiological mechanisms remain elusive. These efforts are made more difficult by ketamine’s complex dose-dependent effects on molecular mechanisms, multiple pharmacologically active metabolites, and a mechanism of action associated with the facilitation of synaptic plasticity. This review aims to provide a brief overview of the different uses of ketamine, with an emphasis on examining ketamine’s rapid antidepressant effects spanning molecular, cellular, and network levels. Another focus of the review is to offer a perspective on studies related to the different doses of ketamine used in antidepressant research. Finally, the review discusses some of the latest hypotheses concerning ketamine’s action.

scholarly journals Inhibition of Nigrostriatal Dopamine Release by Striatal GABAA and GABAB Receptors

2018 ◽  
Vol 39 (6) ◽  
pp. 1058-1065 ◽  
Author(s):  
Emanuel F. Lopes ◽  
Bradley M. Roberts ◽  
Ruth E. Siddorn ◽  
Michael A. Clements ◽  
Stephanie J. Cragg
Keyword(s):  
Dopamine Release ◽  
Gabab Receptors ◽  
Nigrostriatal Dopamine ◽  
Gabaa And Gabab Receptors
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