The cannabinergic system is implicated in the upregulation of central NGF protein by psychotropic drugs

Abstract

Rationale: Studies on the regulation of nerve growth factor (NGF) levels by psychotropics are limited in scope and the mechanism(s) remain elusive which merit further elucidation.

Objectives: We aimed to perform a more comprehensive investigation on the possible effects of pharmacologically heterogeneous groups of psychotropic drugs on NGF contents in the brain regions involved in the modulation of emotions. As a mechanistic approach, we looked at the role of the cannabinergic system which is linked to depression and/or antidepressant effect and appears to interact with neurotrophin signaling.

Methods: Following psychotropic treatment, NGF or endocannabinoid (eCB) contents were quantified by Bio-Rad protein assay and isotope-dilution liquid chromatography/mass spectrometry, respectively. In case of any significant change, the effects of pretreatment with the CB(1) receptor neutral antagonist AM4113 were investigated.

Results: Single injection of nortriptyline, isocarboxazid, citalopram, diazepam, risperidone (2.5, 5, and 10 mg/kg, each), and fluphenazine (0.25, 0.5, and 1 mg/kg) into rats did not alter NGF or eCB contents. Following 4-week treatment, all drugs except diazepam elevated NGF or eCB levels in dose-dependent and brain region-specific fashion. Pretreatment with the highest dose of AM4113 (5.6 mg/kg) prevented psychotropic-induced NGF or eCB elevation. AM4113 had no effect by itself.

Conclusions: The cannabinergic system is implicated in the mechanisms of action of certain psychotropic drugs including the upregulation of brain NGF levels. This provides a better understanding of the pathophysiological mechanisms underlying neuropsychiatric disorders, leading to novel drug design.