Alberto Salazar-Juárez

Endomorphin-1, effects on male sexual behavior

We examined the effect of endomorphin-1 (EM-1), an endogenous opioid peptide that binds selectively to the mu receptor, on male copulatory behavior in sexually vigorous Wistar rats. In the first experiment, four doses of EM-1 (1, 10, 50, and 100 muM) injected intracerebroventricularly produced a marked increase in ejaculation latency and interintromission interval and reduced the number of ejaculations during the test. In experiment 2 the effects of EM-1 were completely blocked by pretreatment with naloxone (5 mg/kg) 30 min prior to intracerebroventricular injection of EM-1 (100 microM). Collectively these results indicate that the activation of micro receptors by EM-1 modifies parameters associated with ejaculation (increases ejaculation latency and reduces the number of ejaculations) confirming that opioids are released during sexual behavior.

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.

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.

Chronic dosing with mirtazapine does not produce sedation in rats

Objective: Sedation/somnolence are major side effects of pharmacotherapies for depression, and negatively affect long-term treatment compliance in depressed patients. Use of mirtazapine (MIR), an atypical antidepressant approved for the treatment of moderate to severe depression with comorbid anxiety disorders, is associated with significant sedation/somnolence, especially in short-term therapy. Nonetheless, studies with human subjects suggest that MIR-induced sedation is transient, especially when high and repeated doses are used. The purpose of this study was to explore the effects of acute and chronic administration of different doses of MIR on sedation in the rat. Methods: Assessment of sedation was carried out behaviorally using the rotarod, spontaneous locomotor activity, and fixed-bar tests. Results: A 15-mg/kg dose of MIR induced sedative effects for up to 60 minutes, whereas 30 mg/kg or more produced sedation within minutes and only in the first few days of administration. Conclusion: These results suggest that 30 mg/kg is a safe, well-tolerated dose of MIR which generates only temporary sedative effects.

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

&NA; 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 &agr;2‐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 (30 mg/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.

Synergistic interactions between mirtazapine and prazosin prevent the induction and expression of behavioral sensitization to cocaine in rats

Cocaine abuse and dependence are a global public health problem. To date, no effective therapy has been established to treat cocaine dependence but mirtazapine-as well as prazosin used in preclinical and clinical trials-has been shown to decrease cocaine behavioral effects. Therefore, our hypothesis was that the effectiveness of mirtazapine might improve when used in combination with prazosin. This study investigated the combined effect of mirtazapine and prazosin on cocaine-induced locomotor activity impairment in rats subjected to locomotor sensitization testing. We found that chronic treatment with the mirtazapine-prazosin combination significantly improved the effect of single mirtazapine dosing on cocaine-induced locomotor activity and on the induction and expression of cocaine sensitization. These results suggest that the combined use of mirtazapine and prazosin may be a potentially effective treatment to attenuate induction and expression of locomotor sensitization to cocaine.

Nuevas vacunas contra la morfina/heroína

La adiccion a una droga de abuso representa uno de los problemas sanitarios mas importantes ya que esta patologia genera la muerte de cerca de 500 000 sujetos anualmente en el mundo. A pesar de este panorama, el desarrollo de terapias farmacologicas efectivas contra esta enfermedad es lento y poco exitoso. En los ultimos anos se han disenado y validado nuevas estrategias farmacologicas alternativas contra la adiccion a drogas de abuso, como las vacunas y su uso en procedimientos farmacologicos inmunoterapeuticos para el tratamiento de esas conductas tanto en modelos de animales como en el humano. Estas nuevas estrategias experimentales estan basadas en el diseno y sintesis de diversas formulaciones estructurales de vacunas terapeuticas contra las sustancias de abuso las cuales, al ser dosificadas en esquemas de inmunizacion activa, inducen la produccion de anticuerpos sericos especificos que reconocen y se unen a estas sustancias en el espacio intravascular sistemico e impiden que crucen la barrera hematoencefalica, con lo cual disminuyen sus efectos en el cerebro. En el ano 2006 nuestro grupo de trabajo en el Instituto Nacional de Psiquiatria Ramon de la Fuente Muniz (INPRFM) logro y consolido el diseno, sintesis, aplicacion y validacion de efectos terapeuticos inmunoprotectores contra recaidas al consumo adictivo de morfina-heroina, en un modelo animal con roedores y su escalamiento potencial para uso humano contra la adiccion a esas sustancias. Este modelo muestra capacidades inmunogenicas (titulos altos y sostenidos de anticuerpos altamente especificos) y de inmunoproteccion (atenua el efecto de hasta 15mg-Kg sc de morfina) que los modelos estructurales de vacuna desarrollados por otros grupos de investigadores no han podido igualar. Esto lo convierte en un modelo lider de vacuna contra los efectos adictivos de la heroina y morfina.

Mirtazapine attenuates nicotine-seeking behavior in rats

Background: Nicotine is the major psychoactive component of tobacco. A number of pharmacological therapies have been evaluated, with poor results. Given the lack of success of these therapies, several authors have proposed alternative therapeutic strategies. One of these is the use of antidepressant drugs that may have a specific effect on the neural pathways or receptors underlying nicotine addiction. Mirtazapine is an antagonist of α2 NE receptors (noradrenergic receptor), 5-HT2A/C and 5-HT3 receptors and has demonstrated efficacy in reducing behavioral effects induced by drugs of abuse in human and animal models. Aims: In this study, we evaluated the effect of chronic dosing of mirtazapine during extinction on the re-acquisition of nicotine-seeking in rodents. Methods: We used the nicotine self-administration paradigm to assess the effects of mirtazapine on rats trained to self-administer nicotine under a pharmacological fixed-ratio schedule. Mirtazapine (30 mg/kg, i.p.) was administered during extinction. Results: In this work, we found that mirtazapine attenuates the re-acquisition of nicotine-seeking responses. Conclusions: These results support the use of mirtazapine in clinical controlled trials as a useful therapy that prolongs and increases rates of preventing relapse into nicotine intake in humans.

Cocaine + nicotine mixture enhances induction and expression of behavioral sensitization in rats

BACKGROUND Psychoactive substance abuse is a health problem worldwide. Has been reported a high prevalence of use of tobacco and cocaine, either separately or in combination. Clinical and animal studies have suggested that the concurrent use of cocaine and nicotine reinforces the potency of one or both drugs and that nicotine may enhance the reinforcing effects of cocaine. Our study evaluated the combined effects of cocaine and nicotine on locomotor activity during the induction and expression phases of locomotor sensitization-a physiological mechanism that plays an important role in establishing some of the defining characteristics of drug abuse. METHODS We used Wistar rats which were dosed with cocaine, nicotine or cocaine and nicotine combination and recorded their locomotor activity in different phases of the experiment. RESULTS We found that a daily dose of cocaine combined with nicotine enhanced cocaine- and nicotine-induced locomotor activity, as well as induction and expression of locomotor sensitization. Moreover, we found that pretreatment with nicotine enhanced the locomotor sensitization expression. CONCLUSION These results suggest that concurrent use of cocaine and nicotine may result in co-abuse of these drugs.

Mirtazapine impairs acquisition and reinstatement of cocaine-induced place preference in rats

ABSTRACT Exposure to cues previously associated with drug use and the environment can trigger intense craving and drug‐seeking, often leading to relapse in individuals with substance use disorders. Several studies suggest that the decrease in the effects of the cues and the environment could help maintain abstinence from drug use in individuals abusing drugs. Mirtazapine, an antagonist of the noradrenergic (NE) &agr;2 receptor and the 5‐HT2A/C and 5‐HT3 receptors has demonstrated efficacy in reducing the rewarding effect of different drugs. The purpose of the present study was to investigate whether the mirtazapine, blocks the acquisition and reinstatement of cocaine‐induced conditioned place preference (CPP). In this study, 120 Wistar male rats were utilized and we use the CPP as a behavioral tool to measure the context‐rewarding effect of an unconditioned stimulus such as cocaine. Mirtazapine was dosed for 30 or 60 consecutive days prior to treatment with cocaine or during the extinction phase. We found that dosing with mirtazapine for 30 consecutive days caused a time‐related reduction in acquisition or reinstatement of preference for the cocaine‐paired chamber. When the duration of treatment is increased (60 days), reductions in preference for the cocaine‐paired chamber were potentiated. These observations support its potential clinical anti‐addictive properties against drugs.