The brain galanin receptors: targets for novel antidepressant drugs

Our present view that the mood disorders involve dysfunction of monoaminergic system is a result of important clinical and preclinical observations over the past 40 years. The therapeutic efficacy of drugs such as the tricyclic antidepressants (TCAs), monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs) and lately of SNRIs (serotonin and norepinephrine reuptake inhibitors) helped to shape our view that mood regulation involves the monoaminergic systems in some way. It is thus little surprising when the neuropeptide, galanin, is discovered to coexist with norepinephrine (NE) in locus coeruleus (LC) neurons and with serotonin (5-HT) in the dorsal raphe nucleus (DRN) neurons, a link between galanin mediated signaling and mood regulation is sought. Galanin receptors are expressed in brain structures that are involved in the regulation of mood such as frontal cortex, amygdala, hypothalamus, LC, DRN and hippocampus. It is almost an accident of research fate that the potent effects of galanin on cognitive performance and seizure threshold have led galanin research to focus on the hippocampus where the neuropeptide is present in cholinergic and noradrenergic afferents and where the receptor density is much lower than in the monoaminergic nuclei. Hopefully it is not too late to report on the recent inroads into the roles of galanin and of galanin receptor subtypes 2 and 3 (GalR2 and GalR3) in mood regulation in animal models as well as in human patients with major depression. A body of existing data suggests that GalR2 signaling leads to antidepressant-like, anticonvulsant and neurogenesis-promoting effects, a spectrum of activities that are commonly associated with efficacious antidepressants. Similarly, GalR3 antagonists exhibit anxiolytic and antidepressant-like activity, another clinically useful combination for the treatment of mood disorders. Since both GalR2 and GalR3 are G-protein coupled receptors (GPCRs), a favorite target class for drug development, we believe that the pace of developing galaninergic antidepressants will increase significantly from now on.