Effects of acute and chronic treatment with fluoxetine on regional glucosecerebral metabolism in rats: implications for clinical therapies

The wide therapeutic spectrum of fluoxetine (e.g., antidepressant, antipani c, antiphobic, antiobsessive, analgesic, antimigraine) requires long-term a dministration and adaptive changes. To test whether adaptation involves the serotonin (5-HT) transporters, we measured the effects of fluoxetine on th e regional cerebral metabolic rate for glucose (rCMRglc) in control rats or in rats pretreated for 2 weeks with fluoxetine (8 mg/kg, i.p., daily, 2 da ys wash out); rCMRglc was measured in 56 brain regions, using the quantitat ive [C-14]deoxyglucose technique, at 30 min after i.p. administration of fl uoxetine 0.4, 4 or 40 mg/kg, i.p., to non-pretreated rats or fluoxetine 4 m g/kg to pretreated rats. In non-pretreated rats, fluoxetine reduced rCMRglc in a dose-dependent fashion in 4 (7%, mean decrease 11%) 28 (50%, mean dec rease 23%) and 37 (66%, mean decrease 32%) brain regions. In chronic fluoxe tine-pretreated rats, fluoxetine decreased rCMRglc to a substantially lesse r degree (eight regions, 14%; mean decrease, 10%). Subcortical brain region s (i.e., hypothalamic paraventricular, locus coeruleus and basal ganglia nu clei) that mediate the physiological responses to stress were very sensitiv e to fluoxetine acutely and subsensitive after chronic treatment. As kineti c tolerance to fluoxetine does not occur during chronic administration, the diminished rCMRglc responsivity to fluoxetine reflects dynamic, adaptive t olerance of 5-HT transporters and, consequently, increased synaptic 5-HT co ncentrations; the findings suggest that fluoxetine may be therapeutic by in creasing the 5-HT-negative modulation upon areas that drive the abnormally hyperactive responses to stress found in several neuropsychiatric condition s. (C) 2000 Elsevier Science B.V. All rights reserved.