Imidazoline binding sites on receptors and enzymes: emerging targets for novel antidepressant drugs?

Clonidine, like many other imidazoline drugs, is usually thought of as a selective α2-adrenergic agonist and is approved for use as a centrally acting antihypertensive agent. In addition, clonidine is prescribed off-label to treat some cases of Tourette’s syndrome, and it may also have a role in the treatment of other psychiatric conditions, including obsessive–compulsive disorders, panic states, schizophrenia and affective disorders. However, the finding by Bousquet et al that clonidine also has high affinity for novel central nonadrenergic sites, and that binding to these sites contributes to clonidine’s hypotensive efficacy, has cast doubt upon the simplistic theories based solely upon the activity of clonidine at α2 receptors, and has led to the discovery and classification of novel imidazoline receptors and binding sites. Indeed, evidence is growing that favours the involvement of some of these sites in the pathophysiology of depression and, thus, the possibility exists that drugs that modify imidazolinergic systems may be of use in treating depression and perhaps some other psychiatric and cardiovascular conditions. Imidazoline binding sites have been subclassified into 3 major groups, based largely upon ligand selectivities and subcellular distribution. Perhaps the pharmacology and physiology of imidazoline I1 receptors (I1R) are best understood, whereas the available data with respect to I2 binding sites (I2BS) are somewhat confusing. I3 binding sites (I3BS) were identified more recently and have consequently been studied less extensively. In the rostral ventrolateral medulla, I1Rs are thought to act in concert with adrenergic receptors to exert central control over vascular tone. Of more interest in the present context is the presence of similar I1Rs in other brain areas and on the plasma membranes of platelets, which exhibit altered behaviour in several psychiatric disorders and normalize their behaviour following treatment with numerous therapeutics. The cDNA for a human I1R has recently been cloned, and the expressed protein was homologous with murine nischarin, which appears to be involved in cytoskeletal signalling. In human brain, I1Rs are distributed in a regional manner, with the highest densities being found in the striatum, pallidum, gyrus dentatus of the hippocampus, amygdala and substantia nigra. Receptor densities have been found to be different from controls in the brains of depressed subjects post mortem, and numerous studies have also confirmed a marked elevation of platelet I1R density in depressed patients, compared with control subjects. Furthermore, following chronic treatment with desipramine, fluoxetine, citalopram, imipramine, clomipramine or bupropion, receptor densities were reduced toward control values. In the last study, the measured reductions in re-