Biology subjects

Martin-Fardon, R.

Publications and source records attributed to Martin-Fardon, R..

5 recordsLinked to original sources

bioRxiv2018

Exploring sex differences in the prevention of ethanol drinking by naltrexone in dependent rats during abstinence

BackgroundDespite considerable efforts, few drugs are available for the treatment of alcohol (ethanol [EtOH]) use disorders (AUDs). Ethanol directly or indirectly modulates several aspects of the central nervous system, including neurotransmitter/neuromodulator systems. Relapse vulnerability is a challenge for the treatment of EtOH addiction. Ethanol withdrawal symptoms create motivational states that lead to compulsive EtOH drinking and relapse even after long periods of abstinence. Among the therapeutics to treat AUDs, naltrexone (NTX) is a pharmacological treatment for relapse. The goal of the present study was to evaluate the effect of NTX on EtOH drinking in EtOH-dependent male and female rats during abstinence.\n\nMethodsWistar rats (males and females) were first trained to orally self-administer 10% EtOH. Half of them were then made dependent by chronic intermittent EtOH (CIE) vapor exposure, and the other half were exposed to air. Using this model, rats exhibit somatic and motivational signs of withdrawal. At the end of EtOH vapor (or air) exposure, the rats were tested for the effects of NTX (10 mg/kg, p.o.) on EtOH self-administration at three abstinence time points: acute abstinence (8 h, A-Abst), late abstinence (2 weeks, L-Abst), and protracted abstinence (6 weeks, P-Abst).\n\nResultsNTX decreased EtOH intake in nondependent rats, regardless of sex and abstinence time point. In post-dependent rats, the effects of NTX improved with a longer abstinence time (i.e., L-Abst and P-Abst) in males, whereas it similarly reduced EtOH drinking in females at all abstinence points.\n\nConclusionsThe data suggest that the therapeutic efficacy of NTX depends on the time of intervention during abstinence and sex. The data further suggest that EtOH dependence induces different neuroadaptations in male and female rats, reflected by differential effects of NTX. The results underscore the significance of considering the duration of EtOH abstinence and sex for the development of pharmacotherapeutic treatments for AUD.

neuroscience↗

bioRxiv2017

Dynorphin counteracts orexin in the paraventricular nucleus of the thalamus: cellular and behavioral evidence

The orexin (Orx) system is known to play a critical role in drug addiction and reward-related behaviors. The dynorphin (Dyn) system, conversely, promotes depressive-like behavior and plays a key role in the aversive effects of stress. Orexin and Dyn are co-released and have opposing functions in reward and motivation in the ventral tegmental area (VTA). Earlier studies showed that microinjections of OrxA in the posterior paraventricular nucleus of the thalamus (pPVT) exerted priming-like effects and reinstated cocaine-seeking behavior, suggesting that Orx transmission in the pPVT participates in cocaine-seeking behavior. The present study sought to determine whether Orx and Dyn interact in the pPVT. Using a cellular approach, brain slices were prepared for whole-cell recordings and to study excitatory transmission in pPVT neurons. The superfusion of OrxA increased spontaneous glutamatergic transmission by increasing glutamate release onto pPVT neurons, whereas DynA decreased glutamate release. Furthermore, the augmentation of OrxA-induced glutamate release was reversed by DynA. To corroborate the electrophysiological data, separate groups of male Wistar rats were trained to self-administer cocaine or sweetened condensed milk (SCM). After self-administration training, the rats underwent extinction training and were tested with intra-pPVT administration of OrxA{+/-}DynA under extinction conditions. OrxA reinstated cocaine-and SCM-seeking behavior, with a greater effect in cocaine animals. DynA selectively blocked OrxA-induced cocaine seeking vs. SCM seeking. The data indicate that DynA in the pPVT prevents OrxA-induced cocaine seeking, perhaps by reversing the OrxA-induced increase in glutamate release, identifying a novel therapeutic target to prevent cocaine relapse.

neuroscience↗

bioRxiv2017

Administration of orexin A in the posterior paraventricular nucleus of the thalamus promotes cocaine-seeking behavior and is associated with hypothalamic activation

Hypothalamic orexin (Orx) neurons that project to the paraventricular nucleus of the thalamus (PVT) have received growing interest because of their role in drug-seeking behavior. When injected in the posterior PVT (pPVT), OrxA reinstated extinguished cocaine-seeking behavior in rats that had long access (LgA) to cocaine for 6 h/day after an intermediate period of abstinence (I-Abst, 2-3 weeks). Considering the long-lasting nature of drug-seeking behavior and that the PVT sends projections to the hypothalamus, the present study examined whether (i) OrxAs priming effect is preserved after a period of protracted abstinence (P-Abst, 4-5 weeks) in LgA rats and (ii) the neural activation pattern (i.e., Fos+ and Fos+/Orx+ cells) in the lateral hypothalamus (LH), dorsomedial hypothalamus (DMH), and perifornical area (PFA) following intra-pPVT OrxA administration that may explain OrxA-induced reinstatement in LgA animals. As reported previously, OrxA administration in the pPVT triggered cocaine-seeking behavior after I-Abst. With P-Abst, the priming effect of OrxA was absent. An intra-pPVT injection of OrxA produced a strong increase in neuronal activation (i.e., Fos expression) in the LH/DMH/PFA at I-Abst but not at P-Abst. The analysis of the activation (Fos+) of Orx neurons (Orx+) revealed an increase in Fos+/Orx+ expression in the LH/DMH/PFA at I-Abst only, thus paralleling the behavioral data. These data indicate that shortly after abstinence, PVT{leftrightarrow}LH/DMH/PFA connections are strongly recruited in animals with a history of cocaine dependence. The lack of effect at P-Abst suggests that the function of Orx receptors and connectivity of the PVT{leftrightarrow}LH/DMH/PFA circuit undergo significant neuroadaptations following P-Abst.\n\nSIGNIFICANCE STATEMENTA better understanding of the pathophysiological changes associated with cocaine addiction is needed to develop efficient pharmacotherapies. The paraventricular nucleus of the thalamus (PVT) and orexin (Orx) transmission within the PVT have been implicated in maladaptive (compulsive) behavior that is characteristic of drug addiction. The present study shows OrxA injections in the posterior PVT reinstates cocaine-seeking behavior in animals with a history of cocaine dependence, and this effect disappears after protracted abstinence, paralleled by the neuronal activation pattern in the hypothalamus. In subjects with a history of cocaine dependence, the function of Orx receptors and connectivity of the PVT{leftrightarrow} LH/DMH/PFA circuit undergo significant neuroadaptations.

neuroscience↗

bioRxiv2017

Knockdown of Hypocretin/Orexin Attenuates Extended-Access Cocaine Self-Administration in Rats

The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug-seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Longterm Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake during extended self-administration access, a model that mimics key features of compulsive cocaine-taking. In addition, Hcrt silencing decreased motivation for both cocaine and palatable food (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence to general measures of arousal-dependent behaviors. At the molecular level, longterm Hcrt knockdown moderately reduced the downstream expression of dynorphin (DYN) and melanin-concentrating hormone (MCH) in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low-effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling.

neuroscience↗

bioRxiv2017

Cebranopadol Blocks The Escalation Of Cocaine Intake And Conditioned Reinstatement Of Cocaine Seeking In Rats

Cebranopadol is a novel agonist of nociceptin/orphanin FQ peptide (NOP) and opioid receptors with analgesic properties that is being evaluated in clinical Phase 2 and Phase 3 trials for the treatment of chronic and acute pain. Recent evidence indicates that the combination of opioid and NOP receptor agonism may be a new treatment strategy for cocaine addiction. We sought to extend these findings by examining the effects of cebranopadol on cocaine self-administration (0.5 mg/kg/infusion) and cocaine conditioned reinstatement in rats with extended access to cocaine. Oral administration of cebranopadol (0, 25, and 50 g/kg) reversed the escalation of cocaine self-administration in rats that were given extended (6 h) access to cocaine, whereas it did not affect the self-administration of sweetened condensed milk (SCM). Cebranopadol induced conditioned place preference but did not affect locomotor activity during the conditioning sessions. Finally, cebranopadol blocked the conditioned reinstatement of cocaine seeking. These results show that oral cebranopadol treatment prevented addiction-like behaviors (i.e., the escalation of intake and reinstatement), suggesting that it may be a novel strategy for the treatment of cocaine use disorder. However, the conditioned place preference that was observed after cebranopadol administration suggests that this compound may have some intrinsic rewarding effects.

neuroscience↗