Ibogaine is a psychedelic extracted from the plant Tabernanthe iboga Baill. (Apocynaceae), natural from Africa, and has been proposed as a potential treatment for substance use disorders. In animal models, ibogaine reduces ethanol self-administration. However, no study to date has investigated the effects of ibogaine on ethanol-induced conditioned place preference (CPP). The present study aimed to investigate the effects of repeated treatment with ibogaine on the reinstatement of CPP to ethanol in male mice. The rewarding effects of ethanol (1.8 g/kg, i. p.) or ibogaine (10 or 30 mg/kg, p. o.) were investigated using the CPP model. Furthermore, we evaluated the effects of repeated treatment with ibogaine (10 or 30 mg/kg, p. o.) on the reinstatement of ethanol-induced CPP. Reinstatement was evaluated under two conditions: 1) during a priming injection re-exposure test in which animals received a priming injection of ethanol and had free access to the CPP apparatus; 2) during a drug-free test conducted 24 h after a context-paired re-exposure, in which subjects received an injection of ethanol and were confined to the compartment previously conditioned to ethanol. Our results show that ethanol, but not ibogaine, induced CPP in mice. Treatment with ibogaine after conditioning with ethanol blocked the reinstatement of ethanol-induced CPP, both during a drug priming reinstatement test and during a drug-free test conducted after re-exposure to ethanol in the ethanol-paired compartment. Our findings add to the literature suggesting that psychedelics, in particular ibogaine, may have therapeutic properties for the treatment of alcohol use disorder at doses that do not have rewarding effects per se.
Maternal separation (MS) stress is a predictive animal model for evaluating the effects of early stress exposure on alcohol use disorders (AUD). The extended amygdala (AMY) is a complex circuit involved in both stress- and ethanol-related responses. We hypothesized that MS stress may increase ethanol consumption in adulthood, as well as augment neuronal activity in extended AMY, in a sex-dependent manner. We aimed to investigate the influence of MS stress on the ethanol consumption of male and female mice, and the involvement of extended amygdala sub-nuclei in this process. The C57BL/6J pups were subjected to 180min of MS, from postnatal day (PND) 1 to 14. The control group was left undisturbed. On PND 45, mice (n=28) in cages were exposed to a bottle containing 20% ethanol (w/v) for 4h during the dark period of the light-dark cycle, for 3weeks. Afterward, mice underwent ethanol self-administration training in operant chambers under fixed ratio (FR) schedule. Then, subjects were tested under 2h sessions of a progressive-ratio (PR) schedule of reinforcement (the last ratio achieved was considered the breaking point), and at the end, a 4h session of FR schedule (binge-intake). An immunohistochemistry assay for Fos protein was performed in Nucleus Accumbens (NAcc), Bed Nucleus of Stria Terminalis (BNST), and AMY. Our results showed that in the third week of training, the female MS group consumed more ethanol than the respective control group. The MS group presented increased breakpoint parameters. Female control group and male MS group were more resistant to bitter quinine taste. Increased Fos-immunoreactive neurons (Fos-IR) were observed in the central nucleus of AMY, but not in NAcc nor BNST in male maternal-separated mice. Maternal separation stress may influence ethanol intake in adulthood, and it is dependent on the sex and reinforcement protocol.
Anxiety disorders involve several behavioral and autonomic reactions in face of aversive stimuli that may threaten life. These responses are modulated by different neurotransmitters and neural modulators in limbic system structures, such as hippocampus. Among the neurotransmitters involved, it has been attributed to corticotrophin releasing fator (CRF) an important role in regulating anxiety-related defensive behaviors, since the presence of CRFergic neurons and CRF receptors in extrahipolamic sites has been identified. When CRF binds to these Gs-protein coupled receptors it triggers a cascade of intracellular reactions involving the activation of the cAMP/Protein Kinase A (PKA) pathway. This study aimed to evaluate the role of the CRF neurotransmitter and PKA into the hippocampus of mice in anxiety-related behavioral responses when exposed to the Elevated Plus Maze (EPM) through the effects of CP 376395 376395, CRF1 antagonist, and H-89 microinjection, a PKA inhibitor, and rat exposure test (RET), through nuclear expression of Fos protein and effects CP 376395 microinjection. From EPM exposure results, it was possible to verify that the intra-ventral hippocampus (VH) treatment with CP 376395 increased the time in the open arms of the EPM at 3.0nmol dose, however, the 6.0nmol dose increased the number of unprotected head dipping when injected into the dorsal hippocampus (DH) and the number of protected head dipping when injected into VH. None of the doses promoted changes in the stretched-attend posture (SAP) behavior and arrival at the end of the open arms. Microinjection of H-89 at 2.5nmol dose in VH, but not in DH increased the time and number of entries in the open arms, but the 5.0nmol dose increased the number of entries in closed arms. Both doses reduced the expression of protected head dipping behavior on the same subregion. When exposed to RET, there was a decrease only in the number of Fos-positive cells in DH from mice repeatedly exposed to the rat in relation to the toy exposed group. On the other hand, in VH, there was an increase in Fos expression in the groups exposed to the rat in a single or repeated way, in relation to the control and toy exposed groups. The behavioral analysis of these animals revealed that the repeated exposure to the rat decreased the time spent on the surface of the apparatus, as well as the time of contact with the screen and climbing. The single exposure to rat also decreased the time climbing on the screen and increased the number of SAP. Microinjection of CP 376395 at 3.0 and 6.0nmol doses in VH increased the residence time on the surface of the RET, but only the dose of 6.0nmol was able to exert this effect in DH. In relation to the complementary behaviors, only the 3.0nmol dose, injected in VH, decreased the number of SAP. Thus, this study has demonstrated a CRF participation mainly into the VH, in the mediation of anxiety-like behaviors and, moreover, that cAMP/PKA pathway is also involved in the mediation of these effects.
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