Serotonergic Dorsal Raphe Nucleus Research Articles

Single-unit responses of serotonergic dorsal raphe nucleus neurons to environmental heating and pyrogen administration in freely moving cats

Single-unit activity of serotonergic neurons in the dorsal raphe nucleus was examined in response to environmental heating and pyrogen-induced fever in freely moving cats. In the heating study, ambient temperature was rapidly raised from a baseline of 25° to 43 ± 1°C and maintained at this level for 2 h. Cats displayed hyperthermia, intense panting, and signs of heat stress, however, the discharge rate of serotonergic neurons of the dorsal raphe nucleus was not significantly different from baseline at any time during heat exposure. Similarly, the activity of these neurons was not significantly altered at any time during an approximately 6-h long febrile response induced by the synthetic pyrogen muramyl dipeptide (50 μg/kg, i.v.). These results indicate that serotonergic unit activity in the dorsal raphe nucleus is not related to either the activation of behavioral or physiological mechanisms underlying heat defense, or to alterations in thermoregulatory mechanisms during the febrile response to exogenous pyrogen. Furthermore, because these neurons do not respond to an elevation in body temperature induced by either ambient heating or pyrogen, they do not appear to be directly temperature-sensitive. These results do not support a specific role for serotonergic neurons of the dorsal raphe nucleus in thermoregulation.

Serotonin neurons and sleep. I. Long term recordings of dorsal raphe discharge frequency and PGO waves.

Brain stem transection studies suggest that pontine neurons play a key role in regulating the mammalian sleep cycle. The serotonin (5-HT) hypothesis originally postulated that pontine 5-HT containing neurons directly initiated and maintained synchronized or NREM sleep and "primed" rapid eye movement (REM) sleep. Contrary to the predictions of this hypothesis, single unit recordings from the serotonergic dorsal raphe nucleus (DRN) have uniformly shown that DRN discharge rate is positively correlated with behavioral arousal but negatively correlated with both the NREM and REM phases of sleep. These findings required revision of the original 5-HT hypothesis and suggested instead that DRN discharge may influence the maintenance of behavioral arousal and, by ceasing to discharge, may contribute to the generation of NREM and REM sleep. The purpose of this paper was to quantitatively assess the strength of the correlation between DRN discharge, REM sleep, and PGO waves following the experimental perturbations of the sleep cycle. Since forced locomotor activity is known to powerfully alter the timing of sleep and wakefulness, the present experiments used forced activity in an attempt to dissociate DRN discharge from the sleep cycle. It was hypothesized that such dissociations would suggest DRN discharge is not involved in sleep cycle regulation. Contrastingly, preserved correlations would support the hypothesis of a possible causal relationship between DRN discharge, PGO waves activity, and the timing of sleep and wakefulness. Extracellular recordings were obtained from single cells in the DRN of intact, undrugged cats across greater than 300 sleep cycles with durations ranging from about 8 to 80 mins. Forced activity significantly reduced the amount of time spent in wakefulness and increased the number but not the duration of REM sleep epochs. The results revealed that DRN discharge rate was altered as a function of sleep cycle duration. In no case, however, was forced activity able to completely dissociate the characteristic DRN discharge rates from PGO waves or the ultradian sleep cycle. The inability of forced activity to disrupt the faithful relationships between DRN discharge, PGO waves, and sleep cycle phase thus provides a new form of correlative evidence consistent with the hypothesis that the DRN is involved in sleep cycle regulation.

Selective prefrontal cortical projections to the region of the locus coeruleus and raphe nuclei in the rhesus monkey

Descending cortical projections to the region of the noradrenergic locus coeruleus (LC) and the serotonergic dorsal and central superior raphe nuclei were analyzed in the rhesus monkey using anterograde labeling techniques. HRP pellets or tritiated leucine were injected into one of 7 cortical areas: the dorsolateral prefrontal cortex, the dorsomedial prefrontal cortex, the orbital prefrontal cortex, the parietal association cortex, somatosensory cortex, the anterior portion of the inferior temperal gyrus, and the posterior portion of the inferior temporal gyrus. Anterogradely labeled fibers were found in and adjacent to the LC and raphe nuclei only following the dorsolateral and dorsomedial prefrontal cortical injections. Terminal labeling was densest at rostral levels of the LC, particularly in the area directly medial to the nucleus. Labeled fibers could not be followed beyond caudal levels of the LC. The projections to the contralateral LC and raphe nuclei were similar to, but less dense than that to the ipsilateral region. Injections into cortical areas other than the dorsal prefrontal cortex resulted in anterograde labeling of the pontine nuclei or pyramids, but not the LC/raphe region. These data, in conjunction with studies in the rat, suggest that the dorsal prefrontal cortex may be only cortical area to have direct influence on the LC and raphe nuclei and secondary influence on the monoaminergic innervation of large areas of cerebral cortex.

Reduction of stimulation-produced analgesia by lysergic acid diethylamide, a depressor of serotonergic neural activity

MAYER Neurobiology and Anesthesiology Branch, National Institute of Dental Research, National Institutes of Health, Bethesda, Md. 20014 and Departments of Physiology and Pharmacology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Va. 23298 (U.S.A.) (Accepted November 18th, 1976) it is now well known that electrical stimulation of the mesencephalic centrai gray matter in the region of the dorsal raphe nucleus (DRN) produces a profound behavioral analgesia in rat22, 25, cat 26,z8 and monkey 11,a7. In man, stimulation of areas of the periaqueductal gray matter also relieves both chronic clinical and acute experimental pain aS. A number of observations suggest that serotonin participates in the production of this analgesia. Akil and Mayer a have shown that stimulation-produced analgesia (SPA) can be reduced in the rat by p-chlorophenylalanine (p-CPA), a serotonin syn- thesis inhibitor. Reduction in SPA was greater for stimulation sites closer to the DRN, a densely serotonergic neural aggregate 7, thereby further implicating an involvement of this monoamine. Reduction of SPA by p-CPA can also be reversed by the adminis- tration of 5-hydroxytryptophan (5-HTP), the precursor of serotonin 2. Electrical stimulation of the central gray matter has also been shown to have effects at an electrophysiological level. Liebeskind and coworkers ~a,20 have demon- strated in the cat that this stimulation inhibits the responsiveness of dorsal horn lamina V cells to noxious stimuli. They reported that D-lysergic acid diethylamide (LSD) antagonized this inhibition. Although stimulation at many sites within and adjacent to the central gray was effective in inhibiting the responses of lamina V cells to noxious stimuli, LSD greatly reduced the inhibitory effects of only stimulation sites in the immediate vicinity of the serotonergic DRN. Data are also available showing that the closer the electrode is to the DRN of the cat, the greater the magnitude of SPA at a given current intensity a0. These observations, coupled with the demonstration that LSD is a directly acting and potent inhibitor of neural activity of the serotonin-containing neurons of the DRN 14, led us to examine the behavioral effect of LSD on SPA. If LSD were to antagonize SPA it would: (1) provide additional data on the possible role of serotonin systems in this phenomenon and (2) demonstrate that previous electrophysiological observations of the effects of LSD on nociceptive neurons have a behavioral correlate. In these experiments, 90-day-old, male Holtzman rats were implanted with a