Antiepileptic drugs (AEDs) have many benefits but also many side effects, including aggression, agitation, and irritability, in some patients with epilepsy. This article offers a comprehensive summary of current understanding of aggressive behaviors in patients with epilepsy, including an evidence-based review of aggression during AED treatment. Aggression is seen in a minority of people with epilepsy. It is rarely seizure related but is interictal, sometimes occurring as part of complex psychiatric and behavioral comorbidities, and it is sometimes associated with AED treatment. We review the common neurotransmitter systems and brain regions implicated in both epilepsy and aggression, including the GABA, glutamate, serotonin, dopamine, and noradrenaline systems and the hippocampus, amygdala, prefrontal cortex, anterior cingulate cortex, and temporal lobes. Few controlled clinical studies have used behavioral measures to specifically examine aggression with AEDs, and most evidence comes from adverse event reporting from clinical and observational studies. A systematic approach was used to identify relevant publications, and we present a comprehensive, evidence-based summary of available data surrounding aggression-related behaviors with each of the currently available AEDs in both adults and in children/adolescents with epilepsy. A psychiatric history and history of a propensity toward aggression/anger should routinely be sought from patients, family members, and carers; its presence does not preclude the use of any specific AEDs, but those most likely to be implicated in these behaviors should be used with caution in such cases.

Background: Melatonin (MLT) is a pleiotropic neurohormone controlling many physiological processes and whose dysfunction may contribute to several different diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes and pain. Melatonin is synthesized by the pineal gland during the night and acts through 2 G-protein coupled receptors (GPCRs), MT₁ (MEL1a) and MT₂ (MEL1b). Although a bulk of research has examined the physiopathological effects of MLT, few studies have investigated the selective role played by MT₁ and MT₂ receptors. Here we have reviewed current knowledge about the implications of MT₂ receptors in brain functions. Methods: We searched PubMed, Web of Science, Scopus, Google Scholar and articles reference lists for studies on MT₂ receptor ligands in sleep, anxiety, neuropsychiatric diseases and psychopharmacology, including genetic studies on the MTNR1B gene, which encodes the melatonin MT₂ receptor. Results: These studies demonstrate that MT₂ receptors are involved in the pathophysiology and pharmacology of sleep disorders, anxiety, depression, Alzheimer disease and pain and that selective MT₂ receptor agonists show hypnotic and anxiolytic properties. Limitations: Studies examining the role of MT₂ receptors in psychopharmacology are still limited. Conclusion: The development of novel selective MT₂ receptor ligands, together with further preclinical in vivo studies, may clarify the role of this receptor in brain function and psychopharmacology. The superfamily of GPCRs has proven to be among the most successful drug targets and, consequently, MT₂ receptors have great potential for pioneer drug discovery in the treatment of mental diseases for which limited therapeutic targets are currently available.

The pathophysiological function of the G-protein coupled melatonin MT₁ and MT₂ receptors has not yet been well-clarified. Recent advancements using selective MT₁/ MT₂ receptor ligands and MT₁/MT₂ receptor knockout mice have suggested that the activation of the MT₁ receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT₂ receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT₁ knockout mice have an increase in NREM sleep and a decrease in REM sleep, while MT2 knockout mice a decrease in NREM sleep. The localization of MT₁ receptors is also distinct from MT2 receptors; for example, MT₂ receptors are located in the reticular thalamus (NREM area), while the MT₁ receptors in the Locus Coeruleus and lateral hypothalamus (REM areas). Altogether, these findings suggest that these two receptors not only have a very specialized function in sleep, but that they may also modulate opposing effects. These data also suggest that mixed MT₁-MT₂ receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT₁/MT₂ non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT₁ and MT₂ receptors have specific roles in the modulation of sleep, and consequently, selective ligands with agonist, antagonist, or partial agonist properties could have therapeutic potential for sleep; while the MT₂ agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT₁ agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT₁ but not MT₂ receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT₁ and/or MT₂ receptors as targets for neuropsychopharmacology drug development.

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT _2A , but not N -methyl-D-aspartate (NMDA) and 5-HT _1A , synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons ( Raptor ^f/f :Camk2alpha-Cre ), the prosocial effects of LSD and the potentiation of 5-HT _2A /AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC ( Raptor ^f/f :Gad2-Cre ), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT _2A /AMPA receptors and mTOR signaling. The activation of 5-HT _2A /AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

Melatonin activates two brain G-protein coupled receptors, MT₁and MT₂, whose differential roles in the sleep–wake cycle remain to be defined. The novel MT₂receptor partial agonist,N-{2-[(3-methoxyphenyl) phenylamino] ethyl} acetamide (UCM765), is here shown to selectively promote non-rapid eye movement sleep (NREMS) in rats and mice. The enhancement of NREMS by UCM765 is nullified by the pharmacological blockade or genetic deletion of MT₂receptors. MT₂, but not MT₁, knock-out mice show a decrease in NREMS compared to the wild strain. Immunohistochemical labeling reveals that MT₂receptors are localized in sleep-related brain regions, and notably the reticular thalamic nucleus (Rt). Microinfusion of UCM765 in the Rt promotes NREMS, and its systemic administration induces an increase in firing and rhythmic burst activity of Rt neurons, which is blocked by the MT₂antagonist 4-phenyl-2-propionamidotetralin. Since developing hypnotics that increase NREMS without altering sleep architecture remains a medical challenge, MT₂receptors may represent a novel target for the treatment of sleep disorders.