Anxiety-like behaviors produced by acute fluoxetine: prevention by wheel running and 5-HT2C receptor blockade
Authors: *B. N. GREENWOOD, P. S. STRONG, L. BROOKS, M. FLESHNER; Dept Integrative Physio, Univ. Colorado, Boulder, CO Abstract:
Exposure to an uncontrollable stressor produces anxiety-like behaviors such as exaggerated fear and shuttle box escape deficits. Anxiety-like behaviors produced by uncontrollable stress are dependent on serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN). Although selective 5-HT reuptake inhibitors (SSRIs) can reduce anxiety after chronic treatment, acute SSRI administration is associated with an increase in anxiety consistent with an acute increase in 5-HT neurotransmission. The current studies tested the hypothesis that both uncontrollable tail shock and acute administration of fluoxetine would sensitize 5-HT neurons in the DRN, indexed by double c-Fos / TpH2 immunohistochemistry, and would produce similar anxiety-like behaviors in adult, male Ficher-344 rats. Wheel running prevents the 5-HT-hyperactivating and behavioral consequences of uncontrollable stress; therefore, the effect of wheel running on fluoxetine-induced behaviors was also examined. Both moderate (10.0 mg/kg) and high (20.0 mg/kg) doses of fluoxetine produced exaggerated freezing and interfered with shuttle box escape relative to saline or low dose fluoxetine (2.5 mg/kg). Fluoxetine-induced behaviors were similar to, but of a smaller magnitude than, those produced by uncontrollable shocks and were blocked by pretreatment with the 5-HT2C receptor antagonist SB 242084 (1 mg/kg). Acute fluoxetine
administration produced anxiety-like behaviors in sedentary rats only. Wheel running for 6 weeks prevented the typical behavioral consequences of acute fluoxetine (10 mg/kg). Contrary to our prediction, neither acute fluoxetine nor uncontrollable shocks sensitized DRN 5-HT neurons as indexed by the c-Fos response to 5 brief foot shocks administered 1 hour after fluoxetine or 24 hours after stress. Instead, fluoxetine and uncontrollable shocks both blocked the 5-HT-activating effects of 5 shocks in the mid and caudal, dorsal DRN, suggesting that manipulations that rapidly increase 5-HT in the DRN can render DRN 5-HT neurons non-reactive to future excitation. Thus, 5-HT-dependent behavioral consequences of uncontrollable stress could be mediated by terminal or post-synaptic events and not by sensitization of neuronal firing as previously thought. Results are consistent with the idea that exercise can produce resistance against the anxiogenic effects of acute increases in 5-HT and suggest that acute behavioral effects of antidepressants can depend on history of physical activity.
Disclosures: B.N. Greenwood, None; P.S. Strong, None; L. Brooks, None; M. Fleshner, None. Support:
[Authors]. [Abstract Title]. Program No. XXX.XX. 2008 Neuroscience Meeting Planner. Washington, DC: Society for Neuroscience, 2008. Online.
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