New perspectives on the molecular pharmacology of affective disorders

Abstract

Research with antidepressants has emphasized the importance of a delayed deamplification of the linked serotonin (5HT)/norepinephrine (NE) receptor coupled adenylate cyclase system in brain. The basic phenomena of regulation of receptor number and function of the beta adrenoceptor linked adenylate cyclase system in brain are well established, with NE regulating beta adrenoceptors in the high agonist affinity conformation (linked to adenylate cyclase and down-regulated by antidepressants), and with 5HT regulating those receptors in the low agonist affinity conformation. The biochemical effector systems of NE and 5HT are discussed and it is concluded that the final common pathway of signal transduction is protein kinase mediated phosphorylation of cellular proteins. Glucocorticoid receptors are located in the perikarya of aminergic cell bodies and may exert their effects by modifying the genomic expression of the diffusely projecting stress-responsive monoamine systems. The molecular neurobiology of beta adrenoceptors, with its implication for genetic and immunologic investigations, is briefly discussed and further research on stimulus-transcription coupling and regulation of gene expression in brain is suggested as an exciting new direction in central receptor research relevant to the psychopharmacology of affective and other disorders.

Early Changes in Prefrontal Activity Characterize Clinical Responders to Antidepressants

“…Receptor downregulation has been reported as part of the response to chronic antidepressant administration since the 1970s (cf. Sulser 1989), but may also be detected within several hours of the administration of a single dose of an antidepressant (Newman-Tancredi et al 1996), suggesting the plausibility of detecting meaningful changes after only two doses. Induction of specific genes (e.g., c-fos) has been elicited with a single exposure to antidepressants (Dahmen et al 1997;Beck 1995;Muck-Seler et al 1996).…”

“…Some individuals do have early symptomatic improvement, and this has been reported to predict further improvement over the next several weeks (Nierenberg et al 1995). Reports have suggested that some physiologic changes are seen shortly after initiation of treatment (Sulser 1989;Beck 1995;Dahmen et al 1997). No clinically practical physiologic predictor of treatment response has yet been identified with these techniques, however, and the relationship of early physiologic changes to eventual clinical outcome remains incompletely understood.…”

Galanin – 25 years with a multitalented neuropeptide

“…This led to the search for long-term adaptive changes which could be compatible with clinical evidence. Studies in rodents have shown that long-term treatment with antidepressants produces changes in intracellular signalling mechanisms [21] and multiple alterations in monoaminergic receptors [20,22], transcription factors [23,24] as well as an increase in hippocampal neurogenesis [25,26]. Even if a temporal correlation exists between some of the adaptive changes in monoamine mechanisms and clinical responses, the prolonged changes in monoaminergic signalling cannot explain the major limitations in the therapeutic efficacy of current antidepressant drugs, namely that about 30 -40 % of patients do not respond well to current antidepressants.…”

Levoprotiline ((?)-oxaprotiline) effects on inositol phosphate generation in human peripheral lymphocytes

“…Levoprotiline ((-)-oxaprotiline) is a new atypical antidepressant (Wendt and Binz, 1990), with the unique feature that it does not modify either [3-adrenergic or the serotonergic neurotransmission after single or repeated treatments (Delini-Stula et al, 1982). Changes in at least one of both systems are exerted by nearly all antidepressant drugs including the levoprotiline-enantiomer (+)-oxaprotiline, and are believed to be involved in their mechanism of action (Peroutka and Snyder, 1980;Blier etal., 1987;Sulser, 1990). The current lack of known biochemical effects of LPT which can explain its antidepressant efficacy prompted us to investigate possible LPT effects on the phosphoinositide signalling system.…”