Extinction vs. Abstinence: A Review of the Molecular and Circuit Consequences of Different Post-Cocaine Experiences

The intravenous cocaine self-administration model is widely used to characterize the neurobiology of cocaine seeking. When studies are aimed at understanding relapse to cocaine-seeking, a post-cocaine abstinence period is imposed, followed by “relapse” tests to assess the ability of drug-related stimuli (“primes”) to evoke the resumption of the instrumental response previously made to obtain cocaine. Here, we review the literature on the impact of post-cocaine abstinence procedures on neurobiology, finding that the prelimbic and infralimbic regions of the prefrontal cortex are recruited by extinction training, and are not part of the relapse circuitry when extinction training does not occur. Pairing cocaine infusions with discrete cues recruits the involvement of the NA, which together with the dorsal striatum, is a key part of the relapse circuit regardless of abstinence procedures. Differences in molecular adaptations in the NA core include increased expression of GluN1 and glutamate receptor signaling partners after extinction training. AMPA receptors and glutamate transporters are similarly affected by abstinence and extinction. Glutamate receptor antagonists show efficacy at reducing relapse following extinction and abstinence, with a modest increase in efficacy of compounds that restore glutamate homeostasis after extinction training. Imaging studies in humans reveal cocaine-induced adaptations that are similar to those produced after extinction training. Thus, while instrumental extinction training does not have face validity, its use does not produce adaptations distinct from human cocaine users.

Anesthesia and Surgery Induce a Functional Decrease Selectively in Excitatory Synaptic Transmission in Mouse Prefrontal Cortex Neurons

Postoperative delirium (POD), a syndrome of confusion and inattention, frequently occurs after anesthesia and surgery. However, the neuropathogenesis of POD remains mostly unknown. The prefrontal cortex (PFC) plays an essential role in cognitive processes. We therefore investigated how anesthesia and surgery induce neurofunctional changes in the PFC, and assessed whether intraoperative administration of dexmedetomidine, an alpha-2 agonist, could prevent the functional changes in the PFC. Laparotomy was performed in mice under isoflurane anesthesia. After a battery of behavioral tests measuring natural behaviors and learning and anxiety levels, PFC neuronal activities were recorded using whole-cell patch-clamp recordings. Effects of intraoperative dexmedetomidine were also examined. In the anesthesia/surgery group, the frequency of excitatory synaptic responses in PFC pyramidal neurons was decreased after the surgery without any changes in the response kinetics. On the other hand, neuronal intrinsic properties and inhibitory synaptic responses were not changed. Intraoperative dexmedetomidine or glutamate receptor antagonists, prevented the excitatory synaptic dysfunction induced by anesthesia and surgery. These findings suggest that anesthesia and surgery induce functional reductions selectively in excitatory synaptic responses in PFC pyramidal neurons, and intraoperative dexmedetomidine inhibits the plastic change in the PFC synaptic transmission.

The Therapeutic Impact of New Migraine Discoveries

Background: Migraine is one of the most disabling neurological conditions and associated with high socio-economic costs. Though certain aspects of the pathomechanism of migraine are still incompletely understood, the leading hypothesis implicates the role of the activation of the trigeminovascular system. Triptans are considered to be the current gold standard therapy for migraine attacks; however, their use in clinical practice is limited. Prophylactic treatment includes non-specific approaches for migraine prevention. All these support the need for future studies in order to develop innovative anti-migraine drugs. Objective: The present study is a review of the current literature regarding new therapeutic lines in migraine research. Methods: A systematic literature search in the database of PUBMED was conducted concerning therapeutic strategies in a migraine published until July 2017. Results: Ongoing clinical trials with 5-HT1F receptor agonists and glutamate receptor antagonists offer promising new aspects for acute migraine treatment. Monoclonal antibodies against CGRP and the CGRP receptor are revolutionary in preventive treatment; however, further long-term studies are needed to test their tolerability. Preclinical studies show positive results with PACAP- and kynurenic acid-related treatments. Other promising therapeutic strategies (such as those targeting TRPV1, substance P, NOS, or orexin) have failed to show efficacy in clinical trials. Conclusion: Due to their side-effects, current therapeutic approaches are not suitable for all migraine patients. Especially frequent episodic and chronic migraine represents a therapeutic challenge for researchers. Clinical and preclinical studies are needed to untangle the pathophysiology of migraine in order to develop new and migraine-specific therapies.

Preoptic area cooling increases the sympathetic outflow to brown adipose tissue and brown adipose tissue thermogenesis

Modest cold exposures are likely to activate autonomic thermogenic mechanisms due to activation of cutaneous thermal afferents, whereas central thermosensitive neurons set the background tone on which this afferent input is effective. In addition, more prolonged or severe cold exposures that overwhelm cold defense mechanisms would directly activate thermosensitive neurons within the central nervous system. Here, we examined the involvement of the canonical brown adipose tissue (BAT) sympathoexcitatory efferent pathway in the response to direct local cooling of the preoptic area (POA) in urethane-chloralose-anesthetized rats. With skin temperature and core body temperature maintained between 36 and 39°C, cooling POA temperature by ~1–4°C evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature, expired CO2, and heart rate. POA cooling-evoked responses were inhibited by nanoinjections of ionotropic glutamate receptor antagonists or the GABAA receptor agonist muscimol into the median POA or by nanoinjections of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamic nucleus (bilaterally) or into the raphe pallidus nucleus. These results demonstrate that direct cooling of the POA can increase BAT SNA and thermogenesis via the canonical BAT sympathoexcitatory efferent pathway, even in the face of warm thermal input from the skin and body core.