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.

Prenatal and postnatal cocaine exposure enhances the anxiety- and depressive-like behaviors in rats: An ontogenetic study.

BACKGROUND: Prenatal and postnatal exposure to drugs such as cocaine is a public health problem that causes deficits in brain development and function in humans and animals. One of the main effects of prenatal and postnatal cocaine exposure is increased vulnerability to developing the substance use disorder at an early age. Furthermore, the negative emotional states associated with cocaine withdrawal increase the fragility of patients to relapse into drug abuse. In this sense, prenatal and postnatal cocaine exposure enhanced the cocaine- and nicotine-induced locomotor activity and locomotor sensitization, and rats exposed prenatally to cocaine displayed an increase in anxiety- and depressive-like behaviors in adulthood (PND 60-70). OBJECTIVE: Therefore, the objective of this study was to determine the effect of prenatal and postnatal cocaine exposure on anxiety- and depressive-like behaviors at different ages (30, 60, 90, and 120 days of age) in rats. METHODS: The study was divided into two stages: prenatal and postnatal. In the prenatal stage, a group of pregnant female Wistar rats was administered daily from GD0 to GD21 cocaine (cocaine pre-exposure group), and another group of pregnant female rats was administered daily saline (saline pre-exposure group). In the postnatal stage, during lactation (PND0 to PND21), pregnant rats received administration of cocaine or saline, respectively. 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 depressive-like behaviors at different postnatal ages (30, 60, 90, and 120 days), representative of adolescence, adult, adulthood, and old age. RESULTS: The study found that prenatal and postnatal cocaine exposure generated age-dependent enhancement in anxiety- and depressive-like behaviors, being greater in older adult (PND 120) rats than in adolescent (PND 30) or adults (PND 60-90) rats. CONCLUSIONS: This suggests that prenatal and postnatal cocaine exposure increases anxiety- and depressive-like behaviors, which may increase the vulnerability of subjects to different types of drugs in young and adult age.

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.

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.

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.