Clonidine is an α2-adrenergic receptor agonist that also activate the imidazoline 1 receptor, increasing downstream catecholamine synthesis. Clonidine exhibits antihypertensive, neuromoduatory, cognition enhancing, antinociceptive, analgesic, and antipsychotic activities. In hypertensive rats, clonidine increases baroreceptor sensitivity and decreases blood pressure and heart rate. In other animal models, clonidine inhibits long term potentiation (synaptic plasticity) and decreases excitatory postsynaptic potentials (EPSPs) in the medial prefrontal cortex (mPFC), a potential mechanism behind clonidine’s ability to decrease glutamate release. Clonidine also improves spatial memory impairments in vivo. This compound is occasionally used clinically for its antipsychotic benefits and is most often used to treat attention deficit hyperactive disorder (ADHD) as a result of its actions that stem from binding postsynaptic α2-adrenergic receptors. In vitro, clonidine inhibits Nav1.7 Na+ channels. In vivo, clonidine decreases mechanical and thermal pain in a model of chronic constriction injury-induced neuropathy, likely due to its ability to downregulate expression of phosphorylated NMDA receptor subunit 1 (pNR1). Clonidine also displays some sedative activity and induces downstream activation of histamine H2 receptors.