Catrin Sinner

Nitric oxide modulates the release of serotonin in the rat hypothalamus

To investigate the effect of nitric oxide (NO) on the release of serotonin and its main metabolite, 5-hydroxyindoleacetic acid (5-HIAA), the posterior hypothalamus of the conscious rat was superfused through a push-pull cannula with drugs which either liberate NO, or inhibit NO synthase (NOS). The NO donors, linsidomine, diethylamine/nitric oxide (DEA/NO), S-nitroso-N-acetylpenicillamine (SNAP), S-nitroso-glutathione (SNOG) and sodium nitroprusside influenced the release of serotonin in a biphasic way. Low concentrations of drugs diminished, while higher concentrations of these compounds enhanced the outflow of serotonin. The NOS inhibitors N(G)-methyl-L-arginine methyl ester (L-NAME) and 7-nitroindazole (7-NINA) enhanced the serotonin release. A high concentration of L-NAME slightly diminished the outflow of serotonin. Inhibition of the guanylyl cyclase by oxodiazolo[4, 3]quinoxaline-one (ODQ) abolished the changes in serotonin outflow induced by both low and high concentrations of linsidomine. The extracellular concentration of the 5-HIAA was not influenced by the compounds used. These data suggest that endogenous NO modulates the release of serotonin in a biphasic and cGMP-dependent way.

Hyperforin enhances the extracellular concentrations of catecholamines, serotonin and glutamate in the rat locus coeruleus

Hyperforin is the main antidepressant component of hypericum perforatum (St. Johns Wort). Using the push-pull superfusion technique we tested whether hyperforin influences extracellular concentrations of neurotransmitters in the rat locus coeruleus. Hyperforin (10 mg/kg, i.p.) not only enhanced the extracellular levels of the monoamines dopamine, noradrenaline and serotonin, but also that of the excitatory amino acid glutamate. The levels of the main serotonin metabolite 5-hydroxyindolacetic acid, as well as those of the amino acids GABA, taurine, aspartate, serine and arginine, were not influenced. Together with in vitro studies, our findings suggest that the antidepressant property of hyperforin is due to enhanced concentrations of monoamines and glutamate in the synaptic cleft, probably as a consequence of uptake inhibition.

Airjet and FG-7142-induced Fos expression differs in rats selectively bred for high and low anxiety-related behavior

We reported recently that two rat lines bred for either high (HAB) or low (LAB) anxiety-related behavior display differential Fos expression in restricted parts of the fear/anxiety circuitry when exposed to mild anxiety evoked in exploratory anxiety tests. Since different forms of anxiety are thought to activate different parts of the anxiety circuitry, we investigated now whether (1) an aversive stimulus which elicits escape behavior (airjet) and (2) the anxiogenic/panicogenic drug FG-7142 would reveal further differences in Fos expression as a marker of neuronal activation between HAB and LAB rats. Both airjet exposure and FG-7142 induced Fos expression in both lines in various anxiety-related brain areas. HAB rats, which displayed exaggerated escape responses during airjet exposure, exhibited increased Fos expression in brain areas including the hypothalamus, periaqueductal gray and locus coeruleus, as well as blunted Fos activation in the cingulate cortex in response to airjet and/or FG-7142. The results corroborate previous findings showing that trait anxiety affects neuronal excitability in hypothalamic and medial prefrontal areas. Furthermore, by using airjet as well as FG-7142, we now reveal that enhanced trait anxiety is also associated with neuronal hyperexcitability in the locus coeruleus and the periaqueductal gray, suggesting that investigation of an array of different anxiogenic stimuli is important for the detection of altered neuronal processing in trait anxiety.

Release of glutamate and GABA in the amygdala of conscious rats by acute stress and baroreceptor activation: differences between SHR and WKY rats

To reveal the functional importance of amino acid neurotransmission in the amygdala (AMY) of conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, the in vivo release of glutamate (GLU) and GABA in this brain structure was studied using the push-pull superfusion technique. Basal GLU and GABA release rates in the AMY were comparable in SHR and WKY rats, although arterial blood pressure (BP) in SHR (152+/-6 mmHg) was higher than in WKY rats (102+/-4 mmHg). Neuronal depolarization by superfusion with veratridine enhanced the release of GLU and GABA to a similar extent in both rat strains. On the other hand, exposure to noise stress (95 dB) for 3 min led to a tetrodotoxin-sensitive increase in GLU release in the AMY of SHR, but not WKY rats. The concurrent pressor response to noise was enhanced in SHR as compared to WKY rats. A rise in BP induced by intravenous infusion of phenylephrine for 9 min had no effect on amino acid release in the AMY of both strains. The data suggest an exaggerated stress response of glutamatergic neurons in the AMY of SHR as compared with WKY rats, which might be of significance for the strain differences in the cardiovascular and behavioural responses to stress. The results also show that, in both rat strains, glutamatergic and GABAergic neurons in the AMY are not modulated by baroreceptor activation. Moreover, hypertension in adult SHR does not seem to be linked to a disturbed synaptic regulation of glutamatergic or GABAergic transmission in the AMY.

Conditioned fear and inescapable shock modify the release of serotonin in the locus coeruleus

The aim of the present study was to investigate the importance of the serotonergic transmission in the locus coeruleus (LC) to conditioned fear. Rats were conditioned to fear by exposing them to noise signal (N), light signal (L) and electric foot shock (S) for 4 days. Control rats were exposed to the same events without receiving S. The LC was superfused with artificial cerebrospinal fluid (aCSF) through a push-pull cannula, and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) was determined in the superfusate. Motility, blood pressure (BP) and heart rate (HR) were telemetrically recorded. (1) The process of moving animals from their home cage into the grid-floor chamber transiently increased the release rate of 5-HT and the outflow of 5-HIAA in control and naive rats. In conditioned rats, 5-HT release was similarly increased during transfer but was permanently decreased in the grid-floor chamber. Control rats showed phases of enhanced motility in the chamber, while conditioned animals displayed continuous immobility. In naive rats, enhanced motility persisted in the novel environment. (2) Exposure of rats to N+L+S increased the release of 5-HT and the outflow of 5-HIAA to the same extent in conditioned and naive rats. These changes were associated with elevated motility, rise in BP and tachycardia. (3) In conditioned subjects, exposure to N+L in the fifth day led to a pronounced and sustained decrease in the release rate of 5-HT and to tachycardia, while no effects were observed in control rats or naive rats. The findings suggest that conditioned fear attenuates serotonergic neurotransmission within the LC. Telemetric recording of HR proves to be a valuable index for fear and stress processes.

Peripheral chemoreceptor activation enhances 5-hydroxytryptamine release in the locus coeruleus of conscious rats.

Intravenous bolus injection of KCN (40 microg) elicited brief but pronounced tachypnea, bradycardia and pressor response, and led to a 37% increase in 5-hydroxytryptamine (serotonin) (5-HT) release in the locus coeruleus (LC) of freely moving rats. Slow infusion of KCN (15 microg/min) for 10 min induced only a slight pressor response, but increased the respiration rate (+39 breaths/min), as well as 5-HT release in the LC (+60%) throughout the infusion. In rats with transected chemoreceptor afferents, neither injection or infusion of KCN changed 5-HT release, suggesting that in intact animals, the effect on extracellular 5-HT was due to activation of peripheral chemoreceptors. In summary, we report that peripheral chemoreceptor activation enhances 5-HT release in the LC, indicating that 5-HT might be involved in the modulation of LC activity by ascending chemosensory information.