Electrophysiological diversity of the dorsal raphe cells across the sleep-wake cycle of the rat.

Through their widespread projections to the entire brain, dorsal raphe cells participate in many physiological functions and are associated with neuropsychiatric disorders. In previous studies, the width of action potentials was used as a criterion to identify putative serotonergic neurons, and to demonstrate that cells with broad spikes were more active in wakefulness, slowed down their activity in slow wave sleep and became virtually silent during paradoxical sleep. However, recent studies reported that about half of these presumed serotonergic cells were not immunoreactive for tyrosine hydroxylase. Here, we re-examine the electrophysiological properties of dorsal raphe cells across the sleep-wake cycle in rats by the extracellular recording of a large sample of single units (n = 770). We identified two major types of cells, which differ in spike waveform: a first population characterized by broad, mostly positive spikes, and a second one displaying symmetrical positive-negative spikes with a large distribution of spike durations (0.6-3.2 ms). Although we found classical broad-spike cells that were more active in wakefulness, we also found that about one-third of these cells increased or did not change their firing rate during sleep compared with wakefulness. Moreover, 62% of the latter cells were active in paradoxical sleep when most of raphe cells were silent. Such a diversity in the neuronal firing behaviour is important in the light of the recent controversy regarding the neurochemical identity of dorsal raphe cells exhibiting broad spikes. Our results also suggest that the dorsal raphe contains subpopulations of neurons with reciprocal activity across the sleep-wake cycle.

Prophylactic and therapeutic effects of acute systemic injections of EMD 281014, a selective serotonin 2A receptor antagonist on anxiety induced by predator stress in rats.

We examined the effect of the selective serotonin 2A (5-HT(2A)) receptor antagonist 7-[4-[2-(4-fluoro-phenyl)-ethyl]-piperazine-1-carbonyl]-1H-indole-3-carbon itrile HCl (EMD 281014) [Bartoszyk, G.D., van Amsterdam, C., Bottcher, H., Seyfried, C.A., 2003. EMD 281014, a new selective serotonin 5-HT2A receptor antagonist. Eur. J. Pharmacol. 473, 229-230.] on change in affect following predator stress. Predator stress involved a 5 min unprotected exposure of rats to a domestic cat. Behavioral effects of stress were evaluated with hole board, plus maze, light/dark box and acoustic startle tests 1 week after stress. Predator stress increased anxiety-like behavior in the plus maze, light/dark box, and elevated response to acoustic startle. EMD 281014 (0.001, 0.01, 0.1, 1 or 10 mg/kg) and vehicle injection (ip) occurred either 10 min after predator stress (prophylactic testing), or 90 min prior to behavioral testing for the effects of predator stress (therapeutic testing 1 week after predator stress). In prophylactic testing, EMD 281014 prevented stress potentiation of startle in a dose dependent manner, though the most effective doses were midrange (0.01 and 0.1 mg/kg). Prophylactic administration of EMD 281014 also prevented stress-induced increase of open arm avoidance in the plus maze in a clear dose dependent manner (from 0.01 mg/kg onward). In therapeutic testing, EMD 281014 had no clear drug dependent effects on stress elevation of startle or on behavior of stressed rats in the elevated plus maze. Finally, EMD 281014 did not block the effects of stress on behavior in the light/dark box when given prophylactically or therapeutically. Findings implicate 5-HT(2A) receptors in initiation of some but not all lasting changes in anxiety-like behavior following predator stress. Potential clinical significance of findings are discussed.