Antidepressant drugs
Serotonin selective uptake inhibitors (SSRIs), tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are the most commonly prescribed antidepressant drugs. Treatment with fluoxetine, the archetypal SSRI, potentiated THC-induced hypothermia in rats [91], but did not change THC-induced behavioral effects—freezing behavior, social interaction or exploration, and preference for outer or inner zones [92]. Fluoxetine increased CB1 binding density in the prefrontal cortex, without altering AEA or 2-AG levels in rat brains [93]. Chronic fluoxetine also increased WIN55212-2-stimulated [35S]GTPγS binding in the rat prefrontal cortex [94]. Conversely, treatment with citalopram reduced HU210-stimulated [35S]GTPγS binding in the rat hypothalamus and hippocampus [95].
Treatment with fluoxetine prevented synaptic defects in mice induced by chronic unpredictable stress (the CUS protocol included inversion of day/night light cycle, 45° tilted cage, cage rotation, tube restraint, predator sounds, strobe lights, food and water deprivation, cold environment, and wet bedding), and CUS preserved eCB- and WIN55,212-2-stimulated CB1 signaling [96]. In the hands of Mato et al. [97], fluoxetine in rats enhanced the inhibition of adenylyl cyclase by WIN55212-2, but did not alter WIN55212-2-stimulated [35S]GTPγS binding or CB1 density measured with [3H]CP55,940. They proposed that fluoxetine enhanced WIN55212-2 signaling through Gαi2 and Gαi3 subunits and not through Gαo subunits.
Treatment with the TCA desipramine increased CB1 binding density in the hippocampus and hypothalamus, without significantly altering AEA or 2-AG levels in rat brains [98]. The CUS protocol altered CB1 density in rat brains, and these changes were attenuated by concurrent treatment with imipramine [99]. Desipramine-induced weight gain was reduced by cotreatment with SR141716A, suggesting an eCB pathway [100].
Treatment with the MAOI tranylcypromine increased CB1 binding density in the prefrontal cortex and hippocampus, and increased 2-AG but decreased AEA levels in the prefrontal cortex [93]. Repeated electroconvulsive shock treatment (EST) for depression produced complex and regionally specific effects. Generally EST downregulated CB1 binding density and AEA levels in the cortex, but enhanced cannabinoid-stimulated [35S]GTPγS binding in the amygdala [101].
In summary, the effects of antidepressant drugs or treatments upon the eCB system are not definitive, but likely result in CB1 upregulation, at least in some brain regions. Preclinical studies suggest agonist trafficking may be responsible for variable responses.