1. Schematic representation of brain targets common to the neurobiology and pharmacology of epilepsy and aggression.
Schematic representation of brain targets common to the neurobiology and pharmacology of epilepsy and aggression. All of the targets illustrated in the figure are described in the main text. (A) Example of a prototypical excitatory (glutamate)/inhibitory (GABA) synapse modulating the activity of a forebrain postsynaptic neuron. Postsynaptic targets include glutamate (NMDA, AMPA, and kainite receptors) and GABAA receptors. SV2A is a membrane glycoprotein that regulates neurotransmitter release from secretory vesicles. Voltage-gated K+, Na+, and Ca2+ channels modulate the action potential and resting membrane potential thus controlling neuronal firing activity. GABA transaminase catabolizes GABA into succinic semialdehyde. (B) Schematic representation of synaptic interactions between 5-HT, norepinephrine, and DA neurons with their projections to the forebrain postsynaptic neurons. On the presynaptic level, the autoreceptors mediating the inhibitory action of these three neurotransmitters are indicated. Notably, autoreceptors are targets for aggression treatment. The α2-adrenoceptor agonist clonidine is used to manage aggression, the D2 autoreceptor antagonist haloperidol is an antipsychotic with antiaggressive properties, and the 5-HT1A autoreceptor agonist eltoprazine has demonstrated potent antiaggressive properties in preclinical studies. The enzyme MAO, which catabolizes the monoamines DA, norepinephrine, and 5-HT, is located on the outer membrane of mitochondria, and MAO inhibitors are widely used in mood disorders. On the postsynaptic level, the monoaminergic receptor subtypes implicated in the pathophysiology and pharmacology of epilepsy and aggression are indicated. (C) A schematic simplification of the Akt/GSK3 and mTOR signaling pathways is shown; these pathways are regulated by G protein–coupled receptors, which may be involved in the neurobiology and in the treatment of both aggression and seizures. Furthermore, processes in the nucleus have also been implicated in aggression and epilepsy: DNA transcription, and epigenetic modifications of DNA such as methylation of the C-5 position of the cytosine ring, and histone modification (deacetylation of histones by histone deacetylases). GSK3, glycogen synthase kinase 3; HDAC, histone deacetylase; Me, methylation; mTOR, mammalian target of rapamycin.
Martin J. Brodie et al. Pharmacol Rev 2016;68:
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