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This study examines the activity of hippocampal CA, pyramidal neurons during conditioned fear stress (CFS)-induced freezing behavior in unanesthetized, unrestrained rats. The firing frequency of hippocampal CA1 pyramidal neurons was significantly decreased when conditioned rats exhibited freezing behavior. Firing frequency returned to the baseline after freezing behavior disappeared. The selective 5-hydroxytryptamine (5-HT)1A antagonists, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635), and N-tert-butyl-3-[4-(2-methoxyphenyl)piperazine-1-yl]-2-phenylpropamide (WAY-100135) and 5-HT depletion with parachlorophenylalanine (PCPA) completely abolished the decrease in firing frequency during CFS-induced freezing behavior. These results suggested that endogenous 5-HT inhibited the firing activity of hippocampal CA1 pyramidal neurons during CFS-induced freezing behavior mainly through stimulating 5-HT1A receptors.

Duloxetine, an inhibitor of both 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake processes, has been developed as a potential antidepressant drug. The present study was initiated to investigate the functioning of multiple components of the 5-HT and NA systems following the long-term administration of duloxetine. In rats treated for 21 days with duloxetine (20 mg/kg/day), the recovery times of dorsal hippocampus CA3 pyramidal neurons from microiontophoretic applications of 5-HT and NA were significantly increased, indicating ongoing reuptake blockade with the minipump in place delivering the drug. The remaining experiments were performed following a 48-h washout. Electrically evoked release of [3H]5-HT from preloaded slices was enhanced in the midbrain, presumably due to a desensitization of the somatodendritic 5-HT1D and 5-HT1A autoreceptors. In addition, evoked release of [3H]5-HT was increased in the hippocampus, which could have been due to the desensitization of the alpha2-adrenergic heteroreceptors located on the 5-HT terminals. In contrast, there was no change in the evoked release of [3H]5-HT in the frontal cortex despite decreased functioning of the 5-HT transporter found in this brain region. Similar to changes in 5-HT release, electrically evoked release of [3H]NA was enhanced in the hippocampus and frontal cortex of rats treated chronically with duloxetine. These increases in [3H]NA release were most likely due to the desensitization of the alpha2-adrenergic autoreceptor in the hippocampus and to the desensitization of the NA transporter in the frontal cortex, respectively. These data suggest that long-term administration of duloxetine is able to induce changes in the 5-HT and NA systems that lead to enhanced release of both 5-HT and NA in some limbic brain areas. Duloxetine, therefore, may be a useful antidepressant compound.

The present study was performed to examine an overall effect of endogenous serotonin (5-HT) on the spontaneous firing activity of the dorsal hippocampus CA1 pyramidal neurons in quiet awake rats. A selective 5-HT 1A antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide (WAY-100635: 0.03-0.2 mg/kg, s.c.) It has been shown that there are at least 14 serotonin (5-HT; 5-hydroxytryptamine) receptor subtypes over seven distinct receptor subfamilies. Among these seven receptor subfamilies, only the 5-HT 1 subfamily is inhibitory whereas the others are excitatory (see Hoyer et al. 1994; Glennon and Dukat 1995 for reviews). Several in situ hybridization studies have demonstrated that ten of these 14 receptor subtypes are detectable over the CA1 region of the rat hippocampus (see Andrade 1998 for review).In accordance with the distribution and exuberance of 5-HT receptors expressed in this area, several in vitro electrophysiological studies have demonstrated multiple actions of 5-HT on the excitability of the CA1 pyramidal neurons. These are the direct inhibitory and exci- 142 K. Kasamo et al. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 24 , NO . 2 tatory actions through stimulating 5-HT 1A and 5-HT 4 receptors on the pyramidal neurons, respectively. In addition, via inhibitory interneurons, 5-HT indirectly decreases and increases the excitability through stimulating 5-HT 2 and 5-HT 3 , and 5-HT 1A receptors, respectively (see Hoyer et al. 1994; Aghajanian 1995; Andrade 1998 for reviews). Given these extremely diverse actions of 5-HT demonstrated in vitro , endogenous 5-HT should produce multiple actions simultaneously on the excitability of the CA1 pyramidal neurons in vivo. These in vitro data have been obtained with the preparations isolated from various potentially confounding factors, such as the effects of activation of other receptor systems. Contrary, in vivo cells in the brain are exposed continuously to the various neurotransmitter, neuromodulator and hormonal stimuli. In any cell, these stimuli are integrated spatially and temporally. Furthermore, the intracellular signaling cascades are extensively interconnected. Moreover, even in vivo , the use of anesthesia drastically reduces the 5-HT tone (Jacobs 1985; as well as the spontaneous firing activity of the hippocampus pyramidal neurons (Blier et al. 1993). The reduction in the firing activity indicates that the use of anesthesia per se markedly decreases the excitability of hippocampal pyramidal neurons. Thus, an overall action of endogenous 5-HT on the firing activity of the pyramidal neurons in awake rats is unpredictable solely basing on the data obtained from in vivo studies with anesthetized animals and from in vitro experiments. Therefore, using awake animals is essential to scrutinize the influence of endogenous 5-HT. To our knowledge, such studies examining the net effect of endogenous 5-HT on cellular activity in the brain of awake rats have not been performed so far.Thus, the present study was carried out to...

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