ANTIDEPRESSANT INTERACTIONS WITH CORTICOTROPIN-RELEASING FACTOR IN THE NORADRENERGIC NUCLEUS LOCUS-CERULEUS

Corticotropin-releasing factor (CRF) has been implicated as a neurotransmitter in the noradrenergic nucleus, locus coeruleus (LC), and is thought to be hypersecreted in depression. Therefore, the hypothesis that antidepressants interfere with CRF neurotransmission in the LC was tested. The acute and chronic effects of desmethylimipramine (DMI), sertraline (SER), phenelzine (PHE), mianserin (MIA), and cocaine (COC) were quantified on LC spontaneous discharge, LC sensory-evoked discharge, LC activation by intracerebroventricular (i.c.v.)-administered CRF, and LC activation by stress in halothane-anesthetized rats. No consistent effect of the drugs on LC spontaneous discharge rate or sensory responsiveness was observed after acute administration. LC spontaneous discharge rates in rats chronically administered the drugs were similar to rates recorded in matched controls, with the exception of PHE and COC. In these rats, LC spontaneous discharge rates were lower than those of untreated rats. Interestingly, LC responses to repeated sciatic nerve stimulation (as measured by the ratio of evoked-to-tonic LC discharge rate) were enhanced in rats chronically administered SER and PHE. This is opposite to the reported effects of i.c.v.-administered CRF. This was not observed with chronic administration of DMI, MIA, or COC. The most striking effect associated with chronic administration of DMI and MIA was the attenuation of LC activation by hemodynamic stress. Because this activation requires CRF release in the LC region, and because none of the antidepressants altered LC activation by i.c.v.-administered CRF, the data suggest that chronic administration of either antidepressant, DMI or MIA, results in attenuation of stress-elicited CRF release in the LC. Thus, four pharmacologically distinct antidepressants have the potential to interfere with CRF function in the LC after chronic administration. SER and PHE may functionally antagonize CRF by producing opposite effects, and DMI and MIA may attenuate CRF release and subsequent LC activation. The results suggest that interference with CRF function in the LC may be one common mechanism of antidepressant action.