Abstract
3,4-Methylenedioxymethamphetamine (MDMA) and its derivatives, 2,5-dimethoxy-4-bromo-amphetamine hydrobromide (DOB) and para-methoxyamphetamine (PMA), are recreational drugs whose pharmacological effects have recently been attributed to serotonin 5HT2A/C receptors. However, there is growing evidence that the oxytocin (OT)/vasopressin system can modulate some the effects of MDMA. In this study, MDMA (2.5–10 mg/kg), DOB (0.5 mg/kg), or PMA (0.005, 0.1, or 0.25 mg/kg) were administered intramuscularly to adult zebra fish, alone or in combination with the V1a vasopressin antagonist, SR49059 (0.01–1 ng/kg), before carrying out conditioned place preference (CPP), social preference, novel tank diving, and light–dark tests in order to evaluate subsequent rewarding, social, and emotional-like behavior. The combination of SR49059 and each drug progressively blocked: (1) rewarding behavior as measured by CPP in terms of time spent in drug-paired compartment; (2) prosocial effects measured on the basis of the time spent in the proximity of a nacre fish picture; and (3) anxiolytic effects in terms of the time spent in the upper half of the novel tank and in the white compartment of the tank used for the light–dark test. Antagonism was obtained at SR49059 doses which, when given alone, did not change motor function. In comparison with a control group, receiving vehicle alone, there was a three to five times increase in the brain release of isotocin (the analog of OT in fish) after treatment with the most active doses of MDMA (10 mg/kg), DOB (0.5 mg/kg), and PMA (0.1 mg/kg) as evaluated by means of bioanalytical reversed-phase high-performance liquid chromatography. Taken together, these findings show that the OT/vasopressin system is involved in the rewarding, prosocial, and anxiolytic effects of MDMA, DOB, and PMA in zebra fish and underline the association between this system and the behavioral alterations associated with disorders related to substance abuse.
Highlights
New psychoactive substances are available in various formulations and are mainly used as legal substitutes for traditional drugs of abuse
Post hoc analysis showed a significant increase in postconditioning time after treatment with MDMA 10 mg/kg, dimethoxy-4bromo-amphetamine hydrobromide (DOB) 0.5 mg/kg, or PMA 0.1 mg/kg, whereas SR49059 completely blocked MDMA, DOB, and PMA-induced conditioned place preference (CPP)
This study investigated the modulatory role of vasopressin receptor (V1a)-like subtype receptors on MDMA, DOB, and PMA-induced rewarding, Table 2 | Effect of SR40059 on anxiety-like behavior in zebra fish
Summary
New psychoactive substances are available in various formulations and are mainly used as legal substitutes for traditional drugs of abuse. It has been demonstrated that the repeated administration of psychostimulants to rodents [2, 4,5,6,7,8] and humans [9] can lead to addiction, induce changes in emotional states such as fear, anxiety, and depression, interfere with social behavior, and cause cognitive impairment. It has been found that the repeated administration of cocaine and methamphetamine are anxiogenic in mice performing the elevated plus maze task [2], lead to cognitive deficit in rats when using the novel object recognition test, and induce depressivelike behavior as evaluated by the forced swimming task [4]. No working memory deficit has yet been documented in rats prenatally exposed to MDMA in the Morris water maze when a fixed platform schedule is used, they do show perseverative behavior using a cued platform schedule [8]. The repeated use of MDMA by humans has been associated with sleep, mood, and anxiety disturbances, increased impulsiveness, memory deficits and attention problems, which may persist for up to 2 years after cessation [9]
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