Mirtazapine attenuates the expression of nicotine-induced locomotor sensitization in rats.

Nicotine is the primary psychoactive component of tobacco. Many addictive nicotinic actions are mediated by an increase in the activity of the serotonin (5-HT) system. Some studies show that the 5-HT2A, 5-HT2C, and 5-HT3 receptors have a central role in the induction and expression of nicotine-induced locomotor sensitization. Mirtazapine, an antagonist of the α2-adrenergic receptors, the 5-HT2A/C, and the 5-HT3 receptors, has proven effective in reducing behavioral effects induced by drugs like cocaine and methamphetamines in human and animal. In this study, we evaluated the effect of mirtazapine on the locomotor activity and on the expression of nicotine-induced locomotor sensitization. We used the nicotine locomotor sensitization paradigm to assess the effects of mirtazapine on nicotine-induced locomotor activity and locomotor sensitization. Mirtazapine (30mg/kg, i.p.) was administered during extinction. Our study found that mirtazapine attenuated the expression of locomotor sensitization induced by different nicotine doses, decreased the duration of locomotor effects and locomotor activity induced by binge administration of nicotine. In addition, our study revealed that treatment with mirtazapine for 60 days produced an enhanced attenuation of nicotine-induced locomotor activity during the expression phase of behavioral sensitization, compared to that obtained when mirtazapine was administered for 30 days. This suggests that use of mirtazapine in controlled clinical trials may be a useful therapy to maintain abstinence for long periods.

Dose- and time-dependent effects of mirtazapine on the expression of cocaine-induced behavioral sensitization in rats.

Relapse to cocaine use is a major problem in the clinical treatment of cocaine dependence. Antidepressant medications have been studied as potential therapeutic drugs to relieve a cocaine dependence disorder. Mirtazapine is an antidepressant implicated in reducing behavioral alterations induced by drugs of abuse. We have reported elsewhere that 30mg/kg mirtazapine administered for 30 days during cocaine extinction significantly attenuated the induction and expression of cocaine-induced locomotor sensitization and decreased the duration of the cocaine-induced locomotor effect. This study focused on exploring whether different mirtazapine dosing regimens could optimize and/or improve the effect of 30mg/kg mirtazapine administered for 30 days on cocaine-induced locomotor activity during the expression phase of behavioral sensitization. Our study revealed that the daily dosing regimen with a fixed dose of mirtazapine (30mg/kg ip) over 60 days improved the decrease in cocaine-induced locomotor activity and behavioral sensitization obtained by dosing of 30mg mirtazapine for 30 days. In addition, it showed that a dosing regimen of 30mg/Kg mirtazapine for 30 days managed to reduce cocaine toxicity. These results suggested that dosage of mirtazapine for 30 consecutive days may be an effective therapy.

Las enzimas involucradas en el metabolismo de la cocaína: Una nueva aproximación farmacológica para el tratamiento de la intoxicación por sobredosis de cocaína / The enzymes involved in the metabolism of cocaine: A new pharmacological approach for the treatment of cocaine overdose toxicity

Resumen: Introducción: Se han desarrollado nuevas estrategias terapéuticas contra la toxicidad por sobredosis de cocaína basadas en el aumento en la actividad catalítica de enzimas que participan en la destrucción de su molécula, antes de que tenga la oportunidad de penetrar el tejido nervioso. Objetivo: Describir los avances en el efecto del aumento en la actividad catalítica de las enzimas BChE y las hCE, producidas para el tratamiento de pacientes en condiciones de toxicidad por sobredosis de cocaína, así como mencionar sus ventajas y desventajas y su potencial uso futuro en pacientes internados por una sobredosis de cocaína. Método: Se realizó una búsqueda bibliográfica por medio del PubMed, usando como descriptores las palabras "Cocaine", "hydrolase", "esterase" y "butyrylcholinesterase". Se obtuvieron 220 artículos de los cuales se usaron 126 para esta revisión. Resultados: Las enzimas BChE, COCH y CoCe bacteriana disminuyeron significativamente los niveles de cocaína en la sangre y el cerebro y con ello atenuaron los efectos de una sobredosis de cocaína. Discusión y conclusión: Los resultados obtenidos en modelos animales sugieren el potencial terapéutico del uso de estas enzimas en humanos, para inactivar rápidamente a la cocaína y desarrollar tratamientos para evitar las muertes asociadas con la intoxicación por sobredosis. Estas metodologías enzimáticas ofrecen una aplicación terapéutica novedosa para el tratamiento de la sobredosis.

Abstract: Introduction: New therapeutic strategies against cocaine overdose toxicity have been developed. These new approaches are based on the design and synthesis of proteins involved in the destruction of cocaine before it has a chance to penetrate nerve tissue. Objective: To review the progress in the effect of the increase in the catalytic activity of BChE and hCE enzymes produced for the treatment of patients in cocaine overdose toxicity conditions in order to determine the advantages and disadvantages of its use. Its potential future use in patients channeled by a cocaine overdose is also explored. Method: A bibliographic search was conducted using PubMed; descriptors were "cocaine", "hydrolase", "esterase" and "butyrylcholinesterase". 220 papers were obtained and 126 papers were used for these review. Results: The BChE, COCH and Coce bacterial enzymes significantly decrease the levels of cocaine in blood and brain and thereby attenuate the effects of a cocaine overdose. Discussion and conclusion: The results obtained in animal models suggest the potential therapeutic use of these enzymes in humans to rapidly inactivate cocaine and develop treatments to stop deaths associated with cocaine overdose intoxication. These enzymatic approaches offer a novel therapeutic application to treat cocaine overdose.

Mirtazapine prevents induction and expression of cocaine-induced behavioral sensitization in rats.

Cocaine abuse is a major health problem worldwide. Treatment based on both 5-HT2A/C and 5-HT3 receptor antagonists attenuate not only the effects of cocaine abuse but also the incentive/motivational effect related to cocaine-paired cues. Mirtazapine, an antagonist of postsynaptic α2-adrenergic, 5-HT2A/C and 5HT3 receptors and inverse agonist of the 5-HT2C receptor, has been shown to effectively modify, at the preclinical and clinical levels, various behavioral alterations induced by drugs abuse. Therefore, it is important to assess whether chronic dosing of mirtazapine alters locomotor effects of cocaine as well as induction and expression of cocaine sensitization. Our results reveal that a daily mirtazapine regimen administered for 30days effectively induces a significant attenuation of cocaine-dependent locomotor activity and as well as the induction and expression of behavioral sensitization. These results suggest that mirtazapine may be used as a potentially effective therapy to attenuate induction and expression of cocaine-induced locomotor sensitization.

Inmunoprotección activa contra cocaína / Active immunoprotection to cocaine

INTRODUCCIÓN: La farmacopea clásica, empleada para atenuar la dependencia a ciertas drogas de abuso ilegal, como la cocaína, ha demostrado una pobre eficacia terapéutica. Basado en este desalentador panorama clínico-terapéutico, desde hace más de una década diversos investigadores han desarrollado nuevas estrategias terapéuticas contra la adicción a la cocaína. Estas nuevas estrategias experimentales están basadas en el diseño y la síntesis de formulaciones estructurales de vacunas terapéuticas contra la adicción a la cocaína. OBJETIVO: Realizar una descripción del desarrollo y la validación terapéutica de la inmunización activa contra la cocaína. MÉTODO: Se realizó una búsqueda bibliográfica con el uso del PubMed, usando como descriptores las palabras "Cocaine" y "Vaccine". Se obtuvieron 155 artículos, de los cuales se usaron 46 para esta revisión. RESULTADOS: A nivel preclínico, la vacunación activa genera altos niveles de anticuerpos capaces de reconocer con alta especificidad a la cocaína dentro del torrente sanguíneo, atenuando las alteraciones conductuales inducidas por diversas dosis de cocaína. DISCUSIÓN Y CONCLUSIÓN: Los resultados preclínicos y clínicos han reforzado "la prueba de concepto" terapéutica de la vacunación activa para el control farmacológico de la recaída al consumo adictivo de la cocaína en el humano, sin embargo, dieron pauta a la postulación y a la justificación de sintetizar nuevos modelos de uso humano de vacunas anticocaína. Esta estrategia farmacológica experimental, de naturaleza "inmunoprotectora", ha demostrado ser un tratamiento eficaz al atenuar significativamente las conductas de búsqueda y consumo adictivo a la cocaína, tanto a nivel pre-clínico, en el modelo del roedor, como en el humano.

INTRODUCTION: The classic pharmacopoeia used to attenuate cocaine dependence has proved a poor therapeutic efficacy. Based on this discouraging clinical and therapeutic panorama, since more than a decade, various researchers have developed new therapeutic strategies against cocaine addiction. These new experimental strategies are based on the structural design and synthesis of therapeutic vaccine formulations against cocaine addiction. OBJECTIVE: To describe the development and therapeutic evaluation of active immunization against cocaine. METHOD: A bibliographical search was made using PubMed, using as descriptors the words "Cocaine" and "Vaccine." 155 articles were obtained which were used for these review 46 items. RESULTS: At preclinical level, active vaccination generates high levels of antibodies capable of recognizing with high specificity the cocaine present in the bloodstream, which attenuates the behavioral changes induced by different doses of cocaine. DISCUSSION AND CONCLUSION: Preclinical and clinical results have reinforced "proof of concept" active therapeutic vaccination to pharmacological control to cocaine use relapse in humans, but gave guidelines to the postulation and justification of synthesizing new models of anti-cocaine vaccines for human use. This experimental pharmacological strategy of "immunoprotective" nature has proven an effective treatment that significantly reduces drug-seeking behaviors, both at pre-clinical levels in the rodent model as well as in humans.

Methodologic pitfalls in measurement of 5-hydroxytriptamine uptake transporters in human platelets by [3H]-paroxetine binding assay.

BACKGROUND: Studies in platelet of 5-HT uptake transporters have been performed using binding assay methodology designed for ligand-receptor interactions; however, uptake transporters present requirements that may question the validity of these particular binding assays. METHODS: To explore methodologic aspects that may be crucial to the validity of these assays, we studied the binding of [3H]-paroxetine to platelet membranes of healthy subjects under different conditions of time, temperature, and protein concentrations. RESULTS: A correlation between protein concentration in incubation media and percentage of specific binding of [3H]-paroxetine was found: the lower the protein concentrations (10 and 20 microg/mL) in incubation media, the lower the percentage of specific [3H]-paroxetine binding. Moreover, low specificity in [3H]-paroxetine binding affected Bmax values obtained in saturation binding experiments. CONCLUSIONS: The use of low protein concentrations could affect Bmax values in binding assays of 5-HT uptake transporters. This may induce confusing interpretation of data in clinical experiments that use human platelets to explore the participation of serotonin in depressed patients.