Evaluation of multitarget drugs on the expression of cocaine-induced locomotor sensitization in male rats: A comparative study.

Purpose: - Cocaine use disorder (CUD) is a complex disease. Several studies have shown the efficacy of multitarget drugs used to treat CUD. Here we compare the efficacy of mirtazapine (MIR), pindolol (PIN), fluoxetine (FLX), risperidone (RIS), trazodone (TRZ), ziprasidone (ZPR), ondansetron (OND), yohimbine (YOH), or prazosin (PRZ), to reduce long-term cocaine-induced locomotor activity and the expression of cocaine-induced locomotor sensitization in rats. Methods: - The study consists of four experiments, which were divided into four experimental phases. Induction (10 days), cocaine withdrawal (30 days), expression (10 days), and post-expression phase (10 days). Male Wistar rats were daily dosed with cocaine (10 mg/kg; i.p.) during the induction and post-expression phases. During drug withdrawal, the MIR, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ were administered 30 min before saline. In the expression, the multitarget drugs were administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min.During the agonism phase, in experiment four, 8-OH-DPAT, DOI, CP-809-101, SR-57227A, or clonidine (CLO) was administered 30 min before MIR and 60 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min. Results: -MIR, FLX, RIS, ZPR, OND, or PRZ attenuated the cocaine-induced locomotor activity and cocaine locomotor sensitization. PIN, TRZ, and YOH failed to decrease cocaine locomotor sensitization. At the optimal doses used, PIN, FLX, RIS, TRZ, ZPR, OND, YOH, or PRZ failed to attenuate long-term cocaine locomotor activation. MIR generated a decrease in cocaine-induced locomotor activity of greater magnitude and duration than the other multitarget drugs evaluated. Conclusion: - At the optimal doses of multitarget drugs evaluated, MIR was the multitarget drug that showed the greatest long-term cocaine-induced behavior effects compared to other multitarget drugs.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depression-like behaviors in rats during cocaine withdrawal.

Prenatal drug exposure is a public health problem, which results in profound behavioral problems during childhood and adolescence, mainly represented by an increase in the risk of cocaine abuse at an early age. In rodents, prenatal and postnatal cocaine exposure enhanced locomotor activity and cocaine- or nicotine-induced locomotor sensitization. Various authors consider that the adverse emotional states (anxiety and depression) that occur during cocaine withdrawal are the main factors that precipitate, relapse, and increase chronic cocaine abuse, which could increase the risk of relapse of cocaine abuse. Therefore, the objective of this study was to characterize anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal in rats born to females exposed prenatally and postnatally to cocaine. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine preexposure group), and another group of pregnant female rats was administered daily with saline (saline preexposure group). Of the litters resulting from the cocaine-pre-exposed and saline-pre-exposed pregnant female groups, only the male rats were used for the recording of the anxiety- and depression-like behaviors at different times (30, 60, 90, and 120 days) of cocaine withdrawal The study found that prenatal and postnatal cocaine exposure dose-dependent enhanced anxiety- and depression-like behaviors. This suggests that prenatal and postnatal cocaine exposure can result in enhanced vulnerability to cocaine abuse in young and adult humans.

COT-TT vaccine attenuates cocaine-seeking and cocaine-conditioned place preference in rats.

Vaccination active, promising alternative immunological strategy to treat of CUD. Various models of cocaine vaccines have been evaluated in animals and humans with relative success. In this sense, it is necessary to improve or optimize the cocaine vaccines already evaluated. Our laboratory previously reported the efficacy of the tetanus toxoid-conjugated morphine vaccine (M6-TT). The M6-TT vaccine can generate high titers of antibodies and reduce heroin-induced behavioral effects in rodents. So, it would be plausible to assume that if we modify the M6-TT vaccine by changing the hapten and maintaining the rest of the structural elements of the vaccine, we will maintain the properties of the M6-TT vaccine (high antibody titers). The objective of this study was to determine whether the antibodies generated by a tetanus toxoid-conjugated cocaine vaccine (COC-TT) can recognize and capture cocaine and decrease the cocaine-induced reinforcing effects. Male Wistar rats were immunized with the COC-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used cocaine self-administration and place-preference testing to evaluate the cocaine-reinforcing effects. The COC-TT vaccine could generate high levels of anti-cocaine antibodies. The antibodies reduced the cocaine self-administration and cocaine place preference. In addition, they decreased the cocaine-induced Fos protein expression. These findings suggest that the COC-TT vaccine generates a robust immunogenic response capable of reducing the reinforcing effects of cocaine, which supports its possible future use in clinical trials in patients with CUD.

The effect of chronic stress on the immunogenicity and immunoprotection of the M6-TT vaccine in female mice.

Active vaccination is an effective therapeutic option to reduce the reinforcing effects of opioids. Several studies showed that chronic stress affects the immune system decreasing the efficiency of some vaccines. Heroin withdrawal is a stressor and it is a stage in which the patient who abuses heroin is vulnerable to stress affects the immune response and consequently its immunoprotective capacity, then, the objective was to determine the effect of heroin-withdrawal and heroin-withdrawal plus immobilization, on the immune (immunogenicity) and protective response (behavioral response) of morphine-6-hemisuccinate-tetanus toxoid (M6-TT) vaccine in animals of two inbred mice strains with different sensitivity to drug-opioid and stress. Female BALB/c and C57Bl/6 inbred mice were immunized with the M6-TT. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. During the vaccination period, the animals were subjected to two different stress conditions: drug-withdrawal (DW) and immobilization (IMM). The study used tail-flick testing to evaluate the heroin-induced antinociceptive effects. Additionally, heroin-induced locomotor activity was evaluated. Stress decreased the heroin-specific antibody titer generated by the M6-TT vaccine in the two inbred mouse strains evaluated. In the two stress conditions, the antibody titer was not able to decrease the heroin-induced antinociceptive effects and locomotor activity. These findings suggest that stress decreases the production of antibodies and the immunoprotective capacity of the M6-TT vaccine. This observation is important to determine the efficacy of active vaccination as a potential therapy for patients with opioid drug use disorder, since these patients during drug-withdrawal present stress disorders, which could affect the efficacy of therapy such as active vaccination.

Estradiol enhances the mirtazapine effects on the expression of cocaine-induced locomotor sensitization in female rats.

Epidemiological studies have mentioned that cocaine use disorder (CUD) has increased in the last decade among women; these show endocrine and reproductive disorders and a high propensity to stress and depression disorders. Mirtazapine-a tetracyclic antidepressant-decreases cocaine-induced locomotor activity and locomotor sensitization in male rats. The objective of this study was to evaluate if estradiol alters the efficacy of mirtazapine to decrease cocaine-induced locomotor activity in sham and ovariectomized female rats. Three hundred and twenty adult female Wistar rats were assigned to three experimental protocols. For experiments, 1-3, female rats were daily dosed with 10 mg/kg of cocaine during the 10 days of induction and expression of locomotor sensitization. During drug withdrawal (30 days), cocaine was withdrawn and the groups received daily mirtazapine, estradiol, or saline. In addition, the females underwent sham or ovariectomy surgery. Tamoxifen was administered during the antagonism phase. After each administration, locomotor activity for each animal was recorded for 30 min in activity chambers. The dosage of mirtazapine reduces estradiol-induced enhancement in cocaine-dependent locomotor activity during the expression of locomotor sensitization in sham and ovariectomized female rats. As well as they showed that estradiol co-dosed with mirtazapine enhances the efficacy of mirtazapine to decrease cocaine-induced locomotor activity. Finally, tamoxifen enhanced the estradiol and mirtazapine-induced decrease in the cocaine motor effect in female rats. Mirtazapine may be considered an effective therapeutic option for the treatment of CUD in women, even in those who are on hormonal treatment or antidepressant therapy with estradiol.

Mirtazapine attenuates the cocaine-induced locomotor sensitization in male and female C57BL/6J and BALBA/cJ mouse.

BACKGROUND: Clinical studies have described the efficacy of various therapeutic approaches. Results are inconsistent and clinical application is limited. Clinical trials have suggested that individual variability in the response to pharmacological therapies and sex affects the efficacy of some antidepressant drugs. Mouse strain-dependent variability influenced the response to antidepressant drugs. Some mouse strains respond faster and better to antidepressants than other mouse strains. We recently reported a series of preclinical studies that showed that dosing of mirtazapine, a noradrenergic and serotonergic antidepressant, in male and female Wistar rats decreased cocaine-induced locomotor activity and attenuated the induction and expression of cocaine-induced locomotor sensitization. Therefore, the aim of this study was to evaluate the mirtazapine effects, on cocaine-induced locomotor activity and cocaine-induced locomotor sensitization in male and female mice of the C57BL/6J and BALB/cJ strains, which differ in sensitivity to the cocaine motor effects and response to antidepressant drugs. METHODS: Male and female BALB/cJ and C57BL/6J inbred mice (20-25 g) were daily dosed with 10 mg/kg of cocaine during the induction and expression of locomotor sensitization. During drug withdrawal, cocaine was withdrawn, and the groups received daily mirtazapine (30 mg/kg, i.p.) or saline. Mirtazapine was administered 30 min before cocaine. After each administration, locomotor activity for each animal was recorded for 30 min in transparent Plexiglass activity chambers. RESULTS: Cocaine-induced locomotor activity were greater in C57BL/6J strain mice than BALB/cJ strain mice during the induction and expression phase of locomotor sensitization. The female mice of both strains showed a higher cocaine locomotor response than males and mirtazapine significantly decreased cocaine-induced locomotor activity, as well as the induction and expression of locomotor sensitization, regardless of mouse strain or sex. CONCLUSION: The results suggest mirtazapine may be considered an effective therapeutic option to treat cocaine use disorder in men and women with very diverse genetic backgrounds.

Agomelatine decreases cocaine-induced locomotor sensitisation and dopamine release in rats.

BACKGROUND: Agomelatine is a melatoninergic antidepressant approved to treat the major depressive disorder. Agomelatine exerts its behavioural, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors and the blockade of 5-HT2B and 5-HT2C serotonin receptors. Some studies have reported that the activation of the MT1 and MT2 melatonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. These findings from another study showed that agomelatine decreased alcohol consumption. This study aimed to evaluate the effects of agomelatine administration on cocaine-induced behavioural (cocaine-induced locomotor activity and cocaine-induced locomotor sensitisation) and neurochemical (dopamine levels) effects. METHODS: Male Wistar rats (250-280 g) received cocaine (10 mg/kg) during the induction and expression of locomotor sensitisation. Agomelatine (10 mg/kg) was administered 30 minutes before cocaine. After each treatment, locomotor activity was recorded for 30 minutes. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with agomelatine and cocaine. Luzindole (30 mg/kg) was administered to block the agomelatine effect. RESULTS: In this study, we found that agomelatine decreased cocaine-induced locomotor activity and the induction and expression of locomotor sensitisation. In addition, agomelatine decreased cocaine-induced dopamine levels. Luzindole blocked the agomelatine-induced decrease in the expression of locomotor sensitisation in rats. CONCLUSION: Our results suggest (1) that agomelatine showed efficacy in decreasing cocaine psychostimulant effects and (2) that agomelatine can be a useful therapeutic agent to reduce cocaine abuse.

Vortioxetine treatment decreases cocaine-induced locomotor sensitization in rats.

Vortioxetine is a serotoninergic multi-target antidepressant, approved to treat major depressive disorder, and carries out its behavioral, pharmacological, and physiological effects through the blocking of serotonin 5-HT1D, 5-HT3, and 5-HT7 receptors and by activating 5-HT1A receptors. Some studies report that the simultaneous activation of the 5-HT1A serotonin receptors or blockade of 5-HT3 serotonin receptors decreased cocaine-induced locomotor activity and cocaine self-administration. Recent studies showed that vortioxetine decreased alcohol consumption. This studio aimed to evaluate the effects of vortioxetine dosing on cocaine-induced behavioral (cocaine-induced locomotor activity and cocaine-induced locomotor sensitization) and neurochemical (dopamine levels) effects. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Vortioxetine was administered 30 min before cocaine. After each treatment, the locomotor activity was recorded for 30 min. Dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFC), and the ventral tegmental area (VTA) by high-performance liquid chromatographic (HPLC) in animals treated with vortioxetine and cocaine. In this study, we found that vortioxetine decreased cocaine-induced locomotor activity, as well as the induction and expression of locomotor sensitization. As well as the amount of cocaine-induced dopamine decreased. Vortioxetine can be a useful therapeutic agent to reduce cocaine abuse.

Prenatal and Postnatal Cocaine Enhances the Induction and Expression of Locomotor Sensitization to Nicotine in Male Rats.

INTRODUCTION: Several studies mention that early consumption of cannabis, alcohol, or even cocaine is related to an increase in the prevalence of daily consumption of tobacco in adulthood. However, other factors, such as genetic comorbidity, social influences, and even molecular, neurochemical, and behavioral alterations induced by prenatal and postnatal cocaine exposure, could also explain these observations, since these factors together increase the vulnerability of the offspring to the reinforcing effects of nicotine. The objective of this study was to determine the effect of prenatal and postnatal exposure to cocaine on nicotine-induced locomotor sensitization in young and adult rats. AIMS AND METHODS: The study was divided into two stages: prenatal and postnatal. In the prenatal stage, a group of pregnant female Wistar rats was administered cocaine daily from day GD0 to GD21 (cocaine preexposure group), and another group of pregnant female rats was administered saline daily (saline preexposure group). Of the litters resulting from the cocaine preexposed and saline preexposed pregnant female groups, in the postnatal stage, only the male rats were used for the recording of the locomotor activity induced by different doses of nicotine (0.2, 0.4, and 0.6 mg/kg) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90, and 120 days). RESULTS: Prenatal and postnatal cocaine exposure enhanced nicotine-induced locomotor activity and locomotor sensitization. CONCLUSIONS: This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to other drugs of abuse, such as nicotine, in humans. IMPLICATIONS: Several studies have shown that the abuse of a drug, such as cannabis, alcohol, or even cocaine, at an early age can progress to more severe levels of use of other drugs, such as nicotine, to adulthood. Our data are consistent with this hypothesis, since prenatal and postnatal cocaine exposure enhanced the nicotine-induced increase in locomotor activity and locomotor sensitization. This suggests that prenatal and postnatal exposure to cocaine enhances the drug's salience.

Mirtazapine-induced decrease in cocaine sensitization is enhanced by environmental enrichment in rats.

Several studies have reported that mirtazapine attenuated the induction and expression of cocaine-induced locomotor sensitization. Animals placed in enriched housing environments have shown a decrease in cocaine-induced locomotor activity and sensitization. In addition, it has been suggested that a pharmacological treatment combined with a behavioral intervention increases the efficacy of the former. Thus, the objective of this study was to determine if dosing of mirtazapine in an enriched housing environment enhanced the mirtazapine-induced decrease on the induction and expression of cocaine-induced locomotor sensitization. Wistar male rats were dosed with cocaine (10 mg/kg, i.p.). During the drug-withdrawal phase, mirtazapine (30 mg/kg, i.p.) was administered under standard and enriched housing environmental conditions. The environmental enrichment consisted of housing the animals in enclosures with plastic toys, tunnels, and running wheels. After each administration, locomotor activity for each animal was recorded for 30 min. The study found that treatment with mirtazapine in an enriched housing environment produced an enhanced and persistent attenuation of the induction and expression of cocaine-induced locomotor sensitization. Additionally, it reduced the duration of cocaine-induced locomotor activity in the expression phase of locomotor sensitization. Dosing of mirtazapine in an enriched housing environment enhanced the effectiveness of mirtazapine to decrease cocaine-induced locomotor sensitization. This suggests the potential use of enriched environments to enhance the effect of mirtazapine.

The morphine/heroin vaccine decreased the heroin-induced antinociceptive and reinforcing effects in three inbred strains mouse.

Clinical trials have indicated that a vaccine must be immunogenic in genetically diverse human populations and that immunogenicity and protective efficacy in animal models are two key indices required for the approval of a new vaccine. Additionally, the immune response (immunogenicity) and immunoprotection are dependent on the mouse strain. Therefore, the objective of the present study was to determine the immune response (immunogenicity) and the protective efficacy (behavioral response) in three inbred mouse strains immunized with the M6TT vaccine. Female BALB/c, C57Bl/6, and DBA/2 inbred mice were immunized with the M6-TT vaccine. A solid-phase antibody-capture ELISA was used to monitor antibody titer responses after each booster dose in vaccinated animals. The study used tail-flick testing to evaluate the antinociceptive effects induced by heroin. Additionally, heroin-induced locomotor activity and place preference were evaluated. The M6-TT vaccine was able to generate a specific antibody titer in the three inbred mouse strains evaluated. The antibodies reduced the antinociceptive effect of different doses of heroin. In addition, they decreased the heroin-induced locomotor activity and place preference. These findings suggest that the M6-TT vaccine generates a powerful immunogenic response capable of reducing the antinociceptive and reinforcing effects of heroin in different inbred mouse strains, which supports its possible future use in clinical trials in genetically diverse human populations.

Synergistic immune and antinociceptive effects induced from the combination of two different vaccines against morphine/heroin in mouse.

Animal studies have reported the use of different opioid-vaccine formulations with relative success These studies have suggested that new opioid-vaccine formulations are required, which are capable of triggering a robust humoral response. One strategy that has been used is the co-administration of two or more vaccines with different but complementary properties, which are capable of generating a robust immune response. We have developed two formulations of opioid-vaccine, the M6-TT, and M3-TT, which generate a robust immune response capable of recognizing heroin and morphine. In this work, we evaluate the combination of two vaccine formulations, which we call the M3/6-TT vaccine, to elicit a robust immune response and protection against heroin and morphine. Balb/c mice were immunized simultaneously with M6-TT vaccine and with M3-TT vaccine. A solid-phase antibody-capture ELISA was used for monitoring antibody titer responses after each booster dose in vaccinated animals. The study used tail-flick and hot-plate testing to evaluate the antinociceptive effects induced by heroin or morphine. Immunization with M3-TT and M6-TT vaccine elicits a robust immune response with an antibody titer of 1: 590 000 able to recognize heroin and morphine. These antibodies are capable of reducing the antinociceptive effects induced by doses of up to 40 mg/Kg. of morphine or 10 mg/kg of heroin. This suggests that the combination of two vaccine formulations that generate antibodies with different but complementary characteristics would be a new therapeutic strategy aimed at reducing drug relapses.

Melatonin decreases cocaine-induced locomotor sensitization and cocaine-conditioned place preference in rats.

Melatonin is a hormone that produces behavioral, pharmacological, and physiological effects through the activation of MT1 and MT2 melatonin receptors. Melatonin receptors participate in the modulation of the reinforcing effects of cocaine. Some studies report that dosing of melatonin decreases cocaine-induced locomotor activity and cocaine self-administration and that luzindole, an MT1, and MT2 melatonin receptor antagonist, blocks the melatonin-dependent decrease in cocaine-induced locomotor activity. The objective of this study was to evaluate the effect of acute or chronic dosing of melatonin on the induction and expression of cocaine-induced locomotor sensitization and cocaine-CPP in rats. Male Wistar rats received cocaine during the induction and expression of locomotor sensitization. Melatonin was administered 30 min before cocaine. After each treatment, locomotor activity was recorded for 30 min. Additionally, dopamine levels were determined in the ventral striatum, the prefrontal cortex (PFc), and the ventral tegmental area (VTA) by HPLC in animals treated with melatonin and cocaine. Melatonin decreased cocaine-induced locomotor sensitization and intracellular dopamine levels, as well as cocaine-CPP. Luzindole blocked the melatonin-induced decrease in the expression of locomotor sensitization in rats. These data suggest that melatonin may be a useful therapeutic agent to reduce cocaine abuse; additionally, they suggest that MT1 and MT2 receptors could be therapeutic targets, useful for the treatment of drug abuse disorder.

Effect of the morphine/heroin vaccine on opioid and non-opioid drug-induced antinociception in mice.

Pain is a common symptom in patients with opioid use disorder (OUD), which increases synthetic and illicit synthetic opioid abuse and even fatalities due to opioid overdose. Many FDA-approved drugs are available for the treatment of OUD, however, the use of these medications is limited, mainly due to the development of various side effects. Active vaccination is a new therapeutic approach but the resulting antibodies may compromise the use and efficiency of opioid and non-opioid drugs. In this study, we evaluated whether the antibodies produced by the morphine/heroin vaccine (M-TT) would alter the antinociceptive effects of opioid and non-opioid drugs. Female Balb-c mice were immunized with the M-TT vaccine. A solid-phase antibody-capture ELISA was used for monitoring antibody titer responses after each booster dose in vaccinated animals, followed by tail-flick testing. This study found that the M-TT vaccine did not affect the antinociception induced by different doses of morphine or the ability of non-opioid and synthetic opioid drugs to decrease thermal pain. Moreover, the combination of vaccination and naloxone increased the time-course of morphine antagonism relative to either vaccination or naloxone alone. These results suggest that the antibody titers generated by the M-TT vaccine 1) are capable of reducing morphine-induced antinociception and 2) are selective enough not to alter antinociception induced by non-opioid or synthetic drugs. These characteristics support its potential as a treatment agent for patients with symptoms of pain comorbid to OUD.

Mirtazapine reduces the expression of cocaine-induced locomotor sensitization in male and female Wistar rats.

BACKGROUND: Epidemiological studies have described that women are more vulnerable to the reinforcing effects of cocaine. In animals, the findings are similar: female rats show higher levels of cocaine self-administration and increased cocaine-induced locomotor activity. In contrast, women with depression respond better to treatment with antidepressants, however their therapeutic response to tetracyclic antidepressants is lower. Several studies have shown that mirtazapine-a tetracyclic antidepressant-decreases the behavioral effects of cocaine in male rats. The objective of this study was to evaluate the efficacy of daily dosing of mirtazapine on cocaine-induced locomotor activity and sensitization in naive female rats compared to male rats. METHODS: Male and female Wistar rats were daily dosed with 10 mg/kg of cocaine. During extinction, cocaine was withdrawn and the groups received daily mirtazapine (30 mg/kg, i.p.) or saline. Tamoxifen was administered during the antagonism phase. After each administration, locomotor activity for each animal was recorded for 30 min in transparent Plexiglass activity chambers. RESULTS: In this study, a higher cocaine locomotor response was found in females than in males and the mirtazapine was equally effective in decreasing cocaine-induced locomotor activity and the expression of locomotor sensitization in male and female rats. In addition, co-administration of mirtazapine and tamoxifen enhanced the efficacy of mirtazapine in female rats. CONCLUSION: The results suggest that mirtazapine may be considered an effective therapeutic option for the treatment of cocaine use disorder in men and women.

Melatonin decreases cocaine-induced locomotor activity in pinealectomized rats

Objective: Several studies have shown that the time of day regulates the reinforcing effects of cocaine. Additionally, melatonin and its MT1 and MT2 receptors have been found to participate in modulation of the reinforcing effects of such addictive drugs as cocaine. Loss of the diurnal variation in cocaine-induced locomotor sensitization and cocaine-induced place preference has been identified in pinealectomized mice. In addition, several studies in rodents have shown that administration of melatonin decreased the reinforcing effects of cocaine. The objective of this study was to evaluate the effect of melatonin on cocaine-induced locomotor activity in pinealectomized rats at different times of day (zeitgeber time [ZT]4, ZT10, ZT16, and ZT22). Methods: Naïve, pinealectomized Wistar rats received cocaine at different times of day. Melatonin was administered 30 min before cocaine; luzindole was administered 15 min prior to melatonin and 45 min before cocaine. After administration of each treatment, locomotor activity for each animal was recorded for a total of 30 min. Pinealectomy was confirmed at the end of the experiment through melatonin quantitation by ELISA. Results: Cocaine-induced locomotor activity varied according to the time of day. Continuous lighting and pinealectomy increased cocaine-induced locomotor activity. Melatonin administration decreased cocaine-induced locomotor activity in naïve and pinealectomized rats at different times of day. Luzindole blocked the melatonin-induced reduction in cocaine-induced locomotor activity in pinealectomized rats. Conclusion: Given its ability to mitigate various reinforcing effects of cocaine, melatonin could be a useful therapy for cocaine abuse.

Prenatal and postnatal cocaine exposure enhances the induction and expression of locomotor sensitization to cocaine in rats.

Prenatal and postnatal exposure to cocaine can affect the development and function of the central nervous system in offspring. It also produces changes in cocaine-induced dopamine release and increases cocaine self-administration and cocaine-induced conditioned place preference. Further, prenatal cocaine exposure involves greater risk for development of a substance use disorder in adolescents. Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on locomotor sensitization in rats. A group of pregnant female Wistar rats were administered daily from day GD0 to GD21 with cocaine (cocaine pre-exposure group) and another group pregnant female rats were administered daily with saline (saline pre-exposure group). During lactation (PND0 to PND21) pregnant rats also received cocaine administration or saline, respectively. Of the litters resulting of the cocaine pre-exposed and saline pre-exposed pregnant female groups, only the male rats were used for the recording of the locomotor activity induced by different doses of cocaine (1, 5, 10, 20 and 40 mg/Kg/day) during the induction and expression of locomotor sensitization at different postnatal ages (30, 60, 90 and 120 days), representative of adolescence and adult ages. The study found that prenatal and postnatal cocaine exposure enhanced locomotor activity and locomotor sensitization, and such increase was dose- and age-dependent. This suggests that prenatal and postnatal cocaine exposure can result in increased vulnerability to cocaine abuse in young and adult humans.

Mirtazapine decreased induction and expression of cocaine + nicotine-induced locomotor sensitisation in rats.

Objectives: Concurrent abuse of cocaine and nicotine is considered a public health problem. To date, no effective therapy has been known to reduce the reinforcing effects of concurrent use of cocaine and nicotine. Mirtazapine, an antagonist of the α2-adrenoceptor and the 5-HT2A/C and the 5-HT3 receptors has proven effective in reducing the cocaine, nicotine and methamphetamine behavioural effects in humans and animals. Our study evaluated the effect of mirtazapine on enhancing locomotor activity during the induction and expression of locomotor sensitisation induced by a cocaine + nicotine mixture.Methods: Wistar rats were dosed with cocaine, nicotine or cocaine + nicotine combination. Mirtazapine (30 mg/kg, i.p.) was administered during the extinction phase.Results: Mirtazapine decreased cocaine + nicotine-induced locomotor activity and induction and expression of locomotor sensitisation. In addition, we found that co-administration of mecamylamine and mirtazapine significantly enhanced the effect of mirtazapine on cocaine + nicotine-induced locomotor activity during induction and expression of behavioural sensitisation.Conclusions: Our results suggest that mirtazapine demonstrated efficacy in decreasing the psycho-stimulant effects of concurrent use of cocaine and nicotine.

Melatonin decreases cocaine-induced locomotor activity in pinealectomized rats.

OBJECTIVE: Several studies have shown that the time of day regulates the reinforcing effects of cocaine. Additionally, melatonin and its MT1 and MT2 receptors have been found to participate in modulation of the reinforcing effects of such addictive drugs as cocaine. Loss of the diurnal variation in cocaine-induced locomotor sensitization and cocaine-induced place preference has been identified in pinealectomized mice. In addition, several studies in rodents have shown that administration of melatonin decreased the reinforcing effects of cocaine. The objective of this study was to evaluate the effect of melatonin on cocaine-induced locomotor activity in pinealectomized rats at different times of day (zeitgeber time [ZT]4, ZT10, ZT16, and ZT22). METHODS: Naïve, pinealectomized Wistar rats received cocaine at different times of day. Melatonin was administered 30 min before cocaine; luzindole was administered 15 min prior to melatonin and 45 min before cocaine. After administration of each treatment, locomotor activity for each animal was recorded for a total of 30 min. Pinealectomy was confirmed at the end of the experiment through melatonin quantitation by ELISA. RESULTS: Cocaine-induced locomotor activity varied according to the time of day. Continuous lighting and pinealectomy increased cocaine-induced locomotor activity. Melatonin administration decreased cocaine-induced locomotor activity in naïve and pinealectomized rats at different times of day. Luzindole blocked the melatonin-induced reduction in cocaine-induced locomotor activity in pinealectomized rats. CONCLUSION: Given its ability to mitigate various reinforcing effects of cocaine, melatonin could be a useful therapy for cocaine abuse.

Melatonin does not produce sedation in rats: A chronobiological study.

Background: Melatonin has been associated with a wide variety of cellular, neuroendocrine, and neurophysiological processes. Clinical studies have reported the use of melatonin as an agent that exerts sedative-hypnotic effects. However, evidence of the sedative-hypnotic effects of different doses of melatonin is inconsistent, and available data regarding its night/day-time sedative effects are limited. The purpose of this study was to evaluate the effects of melatonin administered at different times of day on the magnitude of the sedative-hypnotic activity of different melatonin doses (5, 10, 30, and 50 mg/kg) in rats.Methods: Sedation was assessed in Wistar rats behaviorally, using rota-rod, spontaneous locomotor activity, and fixed-bar tests at different times of day (ZT4, ZT10, ZT16, and ZT22).Results: Our results showed that, compared to trazodone, acute and chronic dosing of ≤5 mg melatonin produced mild, transient sedative effects, mainly in the light period. Nevertheless, doses of ≥10 mg/kg did not cause sustained sedative effects.Conclusion: These results suggest that melatonin may be used for sedation induction, mainly in preoperative patients.