A substantial proportion of raphe neurons are glutamatergic. However, little is known about how these glutamatergic neurons modulate the forebrain. We investigated how glutamatergic median raphe nucleus (MRN) input modulates the medial prefrontal cortex (mPFC), a critical component of fear circuitry. We show that vesicular glutamate transporter 3 (VGLUT3)–expressing MRN neurons activate VGLUT3- and somatostatin-expressing neurons in the mPFC. Consistent with this modulation of mPFC GABAergic neurons, activation of MRN (VGLUT3) neurons enhances GABAergic transmission in mPFC pyramidal neurons and attenuates fear memory in female but not male mice. Serotonin plays a key role in MRN (VGLUT3) neuron–mediated GABAergic plasticity in the mPFC. In agreement with these female-specific effects, we observed sex differences in glutamatergic transmission onto MRN (VGLUT3) neurons and in mPFC (VGLUT3) neuron–mediated dual release of glutamate and GABA. Our results demonstrate a cell type–specific modulation of the mPFC by MRN (VGLUT3) neurons and reveal a sex-specific role of this neuromodulation in mPFC synaptic plasticity.

The onset of several neuropsychiatric disorders including anxiety disorders coincides with adolescence. Consistently, threat extinction, which plays a key role in the regulation of anxiety-related behaviors, is diminished during adolescence. Furthermore, this attenuated threat extinction during adolescence is associated with an altered synaptic plasticity in the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for threat extinction. However, the mechanism underlying the altered plasticity in the IL-mPFC during adolescence is unclear. Given the purported role of vasoactive intestinal polypeptide expressing interneurons (VIPINs) in disinhibition and hence their potential to affect cortical plasticity, we examined whether VIPINs exhibit an adolescence-specific plasticity in the IL-mPFC. We observed an increase in GABAergic transmission and a decrease in excitability in VIPINs during adolescence. Male mice show a significantly higher VIPIN-pyramidal neuron GABAergic transmission compared with female mice. The observed increase in GABAergic transmission and a decrease in membrane excitability in VIPINs during adolescence could play a role in the altered plasticity in the adolescent IL-mPFC. Furthermore, the suppression of VIPIN-mediated GABAergic transmission in females might be relevant to sex differences in anxiety disorders.

BackgroundA growing body of literature suggests that migraineurs, particularly those with aura, have an increased risk for ischemic stroke, but not via enhanced atherosclerosis. The theory that micro-emboli induced ischemia provokes cortical spreading depression (ie, symptomatic aura) in migraineurs but transient ischemic attacks in others highlights a potential role for hypercoagulability as a link between migraine (with aura) and stroke. AimOur objective is to summarize the literature evaluating the association of migraine with various acquired or inheritable thrombophilic states, including those related to elevated estrogen levels, endothelial activation and dysfunction, antiphospholipid antibodies (aPL), deficiency of coagulation inhibitors, and presence of certain genetic polymorphisms. FindingsAlthough definitive studies are lacking, a preponderance of available evidence links migraine, and especially aura, to increased levels of estradiol (eg, oral contraceptive pill [OCP] use, pregnancy), thrombo- and erythrocytosis, von Willebrand factor (vWF) antigen, fibrinogen, tissue plasminogen activator (tPA) antigen, and endothelial microparticles. Studies of a link to migraine are conflicting for aPL, homocysteine, Protein S, and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism. No association with migraine was found in meta-analyses of Factor V Leiden, and of prothrombin gene mutation. Within a large, young ischemic stroke sample, migraine with aura was associated with a thrombophilic state and with patent foramen ovale (PFO). In the non-stroke population, meta-analyses show an association of PFO and migraine with aura (MA), but two population-based studies do not support the link. RecommendationsFor persons with MA and (1) a personal history or family history of thrombosis, or (2) MRI evidence of micro-vascular ischemia or of stroke, an evaluation for hypercoagulability is warranted. In cases of MA alone, consider screening for markers of endothelial activation (eg, vWF, high sensitivity c-reactive protein [hs CRP], and fibrinogen). Rigorous management of other stroke risk factors is paramount, but efficacy of anti-thrombotic agents in the treatment of migraine is unproven. Closure of PFO is not routinely recommended based on negative randomized trials.

3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative commonly abused for its psychotropic and mood-elevating effects. These subjective effects are primarily mediated by a release of serotonin and dopamine. MDMA is also known to elicit prolonged toxic effects toward serotonergic nerve terminals, and more recently, has been shown to reduce the number of gamma-aminobutyric acid (GABA) neurons in the hippocampus of rats. In this chapter, this novel GABAergic toxicity and the potential underlying mechanisms are discussed in detail. The primary mechanism presented here is glutamate excitotoxicity, as MDMA has been shown to promote excessive glutamate release specifically in the hippocampus, and the glutamate receptors expressed by GABA neurons in this brain region are especially vulnerable to overstimulation. If conclusively linked by further studies, glutamate signaling and GABA toxicity may provide a mechanism for the observed cognitive impairments and increased seizure vulnerability evoked by MDMA exposure.

3,4-methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA-treated rats, which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA-treated rats. We hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A receptors. The increased activation of 5HT2A receptors promotes the production of prostaglandin E2 (PGE2) and subsequent activation of EP1 receptors in the dentate gyrus. EP1 receptor activation leads to eventual excitotoxicity and loss of PV interneurons resulting in reduced inhibition and lowered seizure threshold resulting in increased seizure susceptibility.

Opinion statement Maltreatment during childhood increases vulnerability to a host of health disorders, including migraine. Putative mechanisms linking maltreatment and migraine include stress-induced dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, as well as disruption of other stress-mediating homeostatic systems, including those involving endocannabinoids, monoamine neurotransmitters, oxytocin, and inflammation. Prolonged elevation of glucocorticoids alters the neural architecture of the limbic system, resulting in the structural as well as functional changes described in both maltreatment and in migraine. Although treatment trials for migraine have not stratified participants by abuse history, strategies, such as cognitive behavioral therapy, which alter stress responsivity, may be particularly effective in this subgroup. Some therapies involving the endocannabinoid, serotonergic, oxytonergic, and inflammatory systems are under investigation for migraine. Anti-epileptic drugs such as valproate and topiramate, which are FDA approved for migraine treatment, are also known to interfere with epigenetic changes induced by stress. Discerning the role for this mechanism in treatment of maltreated migraineurs may introduce another therapeutic avenue.

MDMA is a widely abused psychostimulant which causes a rapid and robust release of the monoaminergic neurotransmitters dopamine and serotonin. Recently, it was shown that MDMA increases extracellular glutamate concentrations in the dorsal hippocampus, which is dependent on serotonin release and 5HT2A/2C receptor activation. The increased extracellular glutamate concentration coincides with a loss of parvalbumin-immunoreactive (PV-IR) interneurons of the dentate gyrus region. Given the known susceptibility of PV interneurons to excitotoxicity, we examined whether MDMA-induced increases in extracellular glutamate in the dentate gyrus are necessary for the loss of PV cells in rats. Extracellular glutamate concentrations increased in the dentate gyrus during systemic and local administration of MDMA. Administration of the NMDA receptor antagonist, MK-801, during systemic injections of MDMA, prevented the loss of PV-IR interneurons seen 10 days after MDMA exposure. Local administration of MDL100907, a selective 5HT2A receptor antagonist, prevented the increases in glutamate caused by reverse dialysis of MDMA directly into the dentate gyrus and prevented the reduction of PV-IR. These findings provide evidence that MDMA causes decreases in PV within the dentate gyrus through a 5HT2A receptor-mediated increase in glutamate and subsequent NMDA receptor activation.

The subthalamic nucleus (STN) is a part of the basal ganglia (BG) and thus has a role in modulating voluntary motor function. Dysfunction of STN neuronal activity is thought to underlie a variety of movement disorders. For example, in Parkinson's disease (PD), abnormalities in STN activity correlate

3,4-Methylenedioxymethamphetamine (MDMA; Ecstasy) is a popular drug of abuse with well-documented acute effects on serotonergic, dopaminergic, and cholinergic transmitter systems, as well as evidence of long-term disruption of serotoninergic systems in the rat brain. Recently, it was demonstrated that MDMA evokes a delayed and sustained increase in glutamate release in the hippocampus. The purpose of the present study was to determine the role of inflammatory mediators in the MDMA-induced increase in glutamate release, as well as the contribution of inflammatory pathways in the persistent neurochemical toxicity associated with repeated MDMA treatment. Treatment with the non-selective cyclooxygenase (COX) inhibitor ketoprofen and the COX-2 selective inhibitor nimesulide attenuated the increase in extracellular glutamate in the hippocampus evoked by repeated MDMA exposure (10 mg/kg, i.p., every 2 h); no attenuation was observed in rats treated with the COX-1 selective inhibitor piroxicam. Reverse dialysis of a major product of COX activity, prostaglandin E 2 , also resulted in a significant increase in extracellular glutamate in the hippocampus . Repeated exposure to MDMA diminished the number of parvalbumin-positive GABA interneurons in the dentate gyrus of the hippocampus, an effect that was attenuated by ketoprofen treatment. However, COX inhibition with ketoprofen did not prevent the long-term depletion of 5-HT in the hippocampus evoked by MDMA treatment. These data are supportive of the view that cyclooxygenase activity contributes to the mechanism underlying both the increased release of glutamate and decreased number of GABA interneurons in the rat hippocampus produced by repeated MDMA exposure.

Amphetamines are a class of psychostimulant drugs that are widely abused for their stimulant, euphoric, empathogenic and hallucinogenic properties. Many of these effects result from acute increases in dopamine and serotonin neurotransmission. Subsequent to these acute effects, methamphetamine and 3,4 methylenedioxymethamphetamine (MDMA) produce persistent damage to dopamine and serotonin nerve terminals. This review summarizes the numerous interdependent mechanisms including excitotoxicity, mitochondrial damage and oxidative stress that have been demonstrated to contribute to this damage. Emerging non-neuronal mechanisms by which the drugs may contribute to monoaminergic terminal damage, as well as the neuropsychiatric consequences of this terminal damage are also presented. Methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) have similar chemical structures and pharmacologic properties compared to other abused substances including cathinone (khat), as well as a relatively new class of novel synthetic amphetamines known as ‘bath salts’ that have gained popularity among drug abusers.