Proceedings of The Physiological Society
University of Bristol (2005) J Physiol 567P, PC66
Anxiogenic drug treatment increases serotonin metabolism in specific anxiety-related forebrain circuits
Evans, Andrew; Abrams, Jolane; Bouwknecht, J. Adriaan; Knight, David; Shekhar, Anantha; Lowry, Christopher A.;
1. Henry Welcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Bristol, United Kingdom. 2. Department of Psychiatry and Pharmacology & Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.
FG-7142, a benzodiazepine receptor inverse partial agonist, elicits anxiety-like behaviour in rats (Dorow et al. 1983). FG-7142 and other anxiogenic drugs have been shown to induce c-Fos expression in a distributed anxiety-related neural system, including a select subpopulation of midbrain neurons in the dorsal raphe nucleus (Singewald & Sharp, 2000; Singewald et al. 2003). The present study was designed to test the hypothesis that serotonin metabolism is altered in forebrain regions identified as targets of anxiogenic drugs based on these previous studies. Wistar rats were given one of four treatments (vehicle, 1.675, 3.75, or 7.5 mg/kg FG-7142; intraperitoneal injection, n=5). One hour following treatment, rats were humanely killed and brains were dissected and frozen on dry ice. Brains were sectioned at 300 μm and 16 forebrain regions were microdissected and analysed for tryptophan, serotonin and 5-hydroxy-3-indoleacetic acid (5-HIAA) concentrations using high pressure liquid chromatography with electrochemical detection. Multifactorial repeated measures ANOVA revealed a main effect of dose on tryptophan (p = 0.009), serotonin (p = 0.048) and 5-HIAA (p = 0.045) concentrations and region on tryptophan (p < 0.001), serotonin (p < 0.001) and 5-HIAA (p < 0.001) concentrations. Post-hoc pair-wise comparisons of means revealed the most robust effects in the prelimbic cortex with the highest dose of FG-7142 resulting in elevated 5-HIAA (p = 0.028; 122.9% baseline), serotonin (p = 0.021; 134.6% baseline), and tryptophan (p = 0.009; 127.0% baseline). In addition, FG-7142 (7.5 mg/kg) increased tryptophan concentrations in the primary motor cortex (p = 0.015; 138.2%), medial amygdaloid nucleus (p = 0.016; 131.3%), and the dorsomedial hypothalamus (p = 0.039; 138.4%). An intermediate dose of FG-7142 (3.8 mg/kg) elevated serotonin concentrations in the infralimbic cortex (p = 0.028; 140.3%) and dorsomedial hypothalamus (p = 0.049; 139.6%). These data demonstrate that FG-7142 alters serotonin metabolism in select forebrain regions previously identified as sites for convergent actions of multiple anxiogenic drugs. In addition, these data highlight the effects of FG-7142 on tissue concentrations of tryptophan and serotonin metabolism in the prelimbic region of the prefrontal cortex. In the context of anxiety, the medial prefrontal cortex has been shown to play a critical role in mediating the differential effects of controllable and uncontrollable stress on stress-related behavior and brainstem serotonergic systems implicated in the potentiation of conditioned fear (Amat et al. 2005).
Where applicable, experiments conform with Society ethical requirements