Differential effect of local infusion of serotonin reuptake inhibitors in the raphe versus forebrain and the role of depolarization-induced release in increased extracellular serotonin

Systemic administration of selective serotonin reuptake inhibitors (SSRIs) elicits larger increases in serotonin (5-HT) in raphe than in forebrain sites. Because serotonergic neuronal activity is suppressed, the mechanism underlying SSRI-induced increases in extracellular 5-HT is unclear. This study determined whether local infusion of SSRIs also elicited regionally selective increases in extracellular 5-HT, and whether changes depended on serotonergic neuronal depolarization. Conventional microdialysis methods were used to measure 5-HT in dorsal raphe (DRN), median raphe, nucleus accumbens (NAcc), and frontal cortex of unanesthetized rats. During infusion of SSRIs into each site, the maximum response was an approximately 6- to 7-fold increase in 5-HT in NAcc and frontal cortex, and an approximately 20-fold increase in DRN and median raphe. The larger increase in 5-HT in raphe was confirmed using zero-net-flux microdialysis. In NAcc, baseline 5-HT was 0.7 nM, and levels increased to a maximum of 3.1 nM during infusion of the SSRI citalopram. Baseline 5-HT in DRN was greater, 1.3 nM, and increased to 12.4 nM in response to citalopram. Consistent with evidence that autoreceptor activation inhibits serotonergic neuronal discharge, SSRI infusion into DRN produced a moderate decrease in 5-HT in NAcc. However, increases in 5-HT in DRN elicited by SSRI infusion were attenuated by 8-hydroxydipropylaminotetralin and tetrodotoxin. These data indicate that depolarization-dependent 5-HT release was not fully inhibited during SSRI infusion into DRN. In summary, SSRIs produce larger increases in extracellular 5-HT in raphe than in forebrain sites. Increases depend in part on depolarization-induced release, which may be greater in raphe than in forebrain.     

Disorder of the pineal gland associated with depression, peptic ulcers, and sexual dysfunction

Depression, peptic ulcers, and sexual dysfunction may be exacerbated by a deficiency of melatonin. Stress and dietary habits may lead to deficiencies of both serotonin and melatonin. Melatonin inhibits the release of cortisol via the release of vasotocin. Abnormal circadian rhythms of cortisol may occur in states of decreased melatonin. A circannual rhythm of melatonin has troughs associated with peaks in the incidence of peptic ulcers and psychotic depression. Psychotic depression is an apparent disorder of the locus ceruleus and/or dorsal raphe nucleus.     

Raphe magnus inhibition of primate T1-T4 spinothalamic cells with cardiopulmonary visceral input

Effects of stimulation of nucleus raphe magnus on upper thoracic spinothalamic tract neurons were determined. Experiments were performed on 15 monkeys (Macaca fascicularis) anesthetized with α-chloralose. Forty-two T₁?T₄ spinothalamic tract neurons with viscerosomatic inputs were studied. Stimulation of nucleus raphe magnus inhibited activity of all 42 neurons. Thirty-two of these cells had background activity. The magnitude of the inhibition of background activity was related to the raphe magnus stimulus current. Current strengths as low as 300 μA (100 Hz, 0.2 msec duration) completely inhibited most cells. Current thresholds averaged 80 ± 10 μA and were unrelated to the type of somatic or visceral input the cell received, or to the cell location. Conditioning stimuli applied to nucleus raphe magnus inhibited cell responses to electrical stimulation of cardiopulmonary sympathetic Aδ and C afferent fibers. However, in order to demonstrate preferential inhibition of responses to C fiber input it was necessary to use 200 msec trains of raphe stimuli which were concurrent with the cell response to sympathetic afferent stimuli. Twenty-five spinothalamic neurons were tested for responses to intracardiac injections of bradykinin and 17 cells increased their discharge rate. Stimulation of nucleus raphe magnus (280 ± 25 μA) near the peak of the response reduced activity of all 17 cells from 26 ± 3 to 4 ± 1 spikes/sec (P < 0.001). Raphe stimulation inhibited responses of 41 of 41 cells to noxious pinch and responses of 15 of 15 wide dynamic range and the 1 low threshold cell to blowing hair. The results establish the capacity of the raphe-spinal pathway to modulate activity of upper thoracic spinothalamic tract neurons including their response to potentially noxious cardiac stimuli. It is therefore possible that descending inhibitory systems may modulate ascending information related to cardiac pain and perhaps account for myocardial ischemic attacks which occur without pain.     

Diagnosis and treatment in circadian rhythm sleep disorders

Circadian rhythm sleep disorders (CRSD) are characterized by misalignment between major sleep episode and desired sleep phase, or symptoms associated with internal desynchronization between endogenous circadian rhythm and overt sleep-wake rhythm. Endogenous circadian rhythm is mainly regulated by master circadian clock located in the suprachiasmatic nucleus. Light entrains the circadian clock according to a phase-response curve. Furthermore, social time cue affects human sleep-wake rhythm. Instructions concerning sleep hygiene including light environment play fundamental role for the treatment in CRSD. In addition, light therapy and oral melatonin administration have application to delayed sleep phase type. Diagnostic classification and treatment in each types of CRSD are reviewed in this article.     

Functional relationship between circadian rhythm and control of food intake

Living things on the earth including bacteria, plants and animals show circadian rhythms in their behaviors and physiological phenomena, and these circadian rhythms are usually synchronized with environmental changes having the period of 24 h on the earth. In mammals including human beings, the hypothalamic suprachiasmatic nucleus (SCN) functions as a master circadian oscillator, and generates a circadian rhythm of food intake. Sometimes the circadian oscillation of the SCN is disturbed with physical and psychological stressors. This review describes the functional relationship in respect to connections between the circadian oscillator in the SCN and food regulatory centers and neurons in the brain focusing on its mechanism in human beings, and a possible involvement of the circadian oscillator of the SCN in the abnormality of the appetite control.     

Effects of biogenic amines on raphe-spinal tract cells

Stimulation in the nucleus raphe magnus produces analgesia in behavioral paradigms and inhibits spinal cord nociceptive neurons. Similar effects result from stimulation of the periaqueductal gray (PAG). Such actions may be mediated via a synaptic link between PAG and nucleus raphe magnus or the adjacent reticular formation. In this study we have examined the effects of biogenic amines applied iontophoretically in the vicinity of nucleus raphe magnus neurons that project to the spinal cord in monkeys. Raphe-spinal tract (RST) neurons were identified by antidromic activation after stimulation of the dorsolateral funiculi at an upper lumbar level. The actions of serotonin, quipazine, norepinephrine, dopamine and acetylcholine (ACh) were tested against the background activity, the activity evoked by glutamate pulses or the excitation of RST cells by stimulation in the PAG. Serotonin, quipazine, norepinephrine and dopamine produced a current-dependent inhibition of background activity and the responses to glutamate pulses in all RST cells tested. No cases of excitation were found. By contrast, ACh enhanced activity produced by glutamate pulses in all RST cells observed. ACh also enhanced the background activity of all but one of the RST cells; however, ACh did not activate cells with little or no background discharge. Serotonin and norepinephrine often inhibited PAG excitation of RST cells. No facilitation of PAG excitation was observed. We conclude that the actions of serotonergic and catecholaminergic agonists on raphe-spinal cells are inhibitory whereas the effect of ACh is facilitatory.     

Chlordiazepoxide reduces in vivo serotonin release in the basal ganglia of encéphale isolé but not anesthetized cats: evidence for a dorsal raphe site of action

By using a push-pull cannula technique and an isotopic method for the estimation of [3H]serotonin continuously synthetized from [3H]tryptophan, the effects of a benzodiazepine, chlordiazepoxide, were investigated on the in vivo release of [3H]serotonin in the cat basal ganglia. Chlordiazepoxide injection (10 mg/kg i.p.) decreased striatal and nigral [3H]serotonin release and enhanced the [3H]amine release in the dorsal raphe. These changes were blocked by the continuous superfusion of the dorsal raphe with Ro 15-1788 (10(-5) M), a benzodiazepine receptor antagonist. Chlordiazepoxide (10(-5) M) applied to the dorsal raphe reduced nigral [3H]serotonin release while decreasing [3H]serotonin release locally in the dorsal raphe. Furthermore, the superfusion of serotonergic nerve terminals of the substantia nigra or the caudate nucleus with chlordiazepoxide (10(-5) M) never altered the local release of [3H]serotonin. These data strongly suggest that the (inhibitory) influences exerted by chlordiazepoxide on serotonergic transmission more likely involved cell bodies and/or dendrites rather than terminals of serotonergic neurons. Chlordiazepoxide-induced changes in [3H]serotonin release were only observed in "encéphale isolé" and not in halothane-anesthetized cats. Further experiments revealed that GABAergic neurons of the dorsal raphe could participate to such a differential reactivity of serotonergic cells to chlordiazepoxide. For instance, [3H]gamma-aminobutyric acid release in the dorsal raphe was enhanced by halothane anesthesia. These findings further suggest the possibility that the influence exerted by benzodiazepines on serotonergic transmission, perhaps through a gamma-aminobutyric acid-dependent process, can significantly be involved in the pharmacological actions of these drugs.     

Effects of repeated 3,4-methylenedioxymethamphetamine administration on neurotransmitter efflux and sensory-evoked discharge in the ventral posterior medial thalamus

3,4-Methylenedioxymethamphetamine (MDMA) is known to enhance tactile sensory perception, an effect that contributes to its popularity as a recreational drug. The neurophysiological basis for the effects of MDMA on somatosensation are unknown. However, MDMA interactions with the serotonin transporter (SERT) and subsequent enhancement of serotonin neurotransmission are well known. The rat trigeminal somatosensory system receives serotonergic afferents from the dorsal raphe nucleus. Because these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that administration of a challenge injection of MDMA (3 mg/kg i.p.) after repeated MDMA treatment (3 mg/kg per day for 4 days) elicits both serotonin and norepinephrine efflux in the ventral posterior medial (VPM) thalamus of Long-Evans hooded rats, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We evaluated the potential for repeated MDMA administration to modulate whisker-evoked discharge of individual neurons in this region. After surgically implanting stainless steel eight-wire multichannel electrode bundles, we recorded spike train activity of single cells while activating the whisker pathway using a piezoelectric mechanical stimulator. We found that repeated MDMA administration increased the spontaneous firing rate but reduced both the magnitude and duration of whisker-evoked discharge in individual VPM thalamic neurons. The time course of drug action on neuronal firing patterns was generally consistent with fluctuations in neurotransmitter efflux as shown from our microdialysis studies. On the basis of these results, we propose that single use and repeated administration of MDMA may "distort," rather than enhance, tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.     

Effects of histamine, H1- and H2-receptor antagonists on the activity of serotonergic neurons in the dorsal raphe nucleus

We investigated the effects of histamine applied by microiontophoresis onto serotonin-containing (serotonergic) cells recorded extracellularly in the dorsal raphe nucleus of the rat. Application of histamine at low iontophoretic currents (1-5 nA) produced a rapid depression of the firing of all serotonergic neurons tested. The H1-receptor antagonists mepyramine and diphenhydramine were unable to attenuate the histamine-induced response. Antagonism of the effect of histamine by the iontophoretic application of the H2-receptor antagonists cimetidine and metiamide was not possible to evaluate since both were found to exert potent inhibitory effects by themselves. In contrast, the nonimidazole-derived H2-receptor antagonist ranitidine, which had no effect by itself, selectively antagonized the histamine-induced depression of neuronal activity. Histidine, 3-methylhistamine and a variety of histamine agonists selective for H1- or H2-receptors were unable to mimic the effect of histamine in dorsal raphe. Histamine's effects may, in part, be mediated at a gamma-aminobutyric acid receptor complex as the gamma-aminobutyric acid antagonists bicuculline and picrotoxin rapidly and reversibly antagonized both the histamine- and the cimetidine-induced depression of serotonin cell firing; the glycine antagonist strychnine selectively blocked the inhibitory effect of glycine without altering the histamine-induced response. These data show an inhibitory effect of histamine on serotonin-containing neurons in the dorsal raphe; this effect may be partially mediated at a subtype of H2-receptor. These data further indicate that the inhibitory effects of histamine and cimetidine observed in the dorsal raphe nucleus may result, in part, from an action directly or indirectly at a gamma-aminobutyric acid receptor complex.     

CLUSTER AND TRIGEMINAL AUTONOMIC CEPHALALGIAS

The suprachiasmatic nucleus (SCN) of the hypothalamus has been termed the master circadian pacemaker of mammals. Recent discoveries of damped circadian oscillators in other tissues have led to the hypothesis that the SCN synchronizes and sustains daily rhythms in these tissues. We studied the effects of constant lighting (LL) and of SCN lesions on behavioral rhythmicity and Period 1 (Per 1) gene activity in the SCN and olfactory bulb (OB). We found that LL had similar effects on cyclic locomotor and feeding behaviors and Per 1 expression in the SCN but had no effect on rhythmic Per 1 expression in the OB. LL lengthened the period of locomotor and SCN rhythms by approximately 1.6 hr. After 2 weeks in LL, nearly 35% of rats lost behavioral rhythmicity. Of these, 90% showed no rhythm in Per 1-driven expression in their SCN. Returning the animals to constant darkness rapidly restored their daily cycles of running wheel activity and gene expression in the SCN. In contrast, the OB remained rhythmic with no significant change in period, even when cultured from animals that had been behaviorally arrhythmic for 1 month. Similarly, we found that lesions of the SCN abolished circadian rhythms in behavior but not in the OB. Together, these results suggest that LL causes the SCN to lose circadian rhythmicity and its ability to coordinate daily locomotor and feeding rhythms. The SCN, however, is not required to sustain all rhythms because the OB continues to oscillate in vivo when the SCN is arrhythmic or ablated.
Comments: As the central generator for cluster appears to be near the hypothalamic circadian nuclei (May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology. 2000;55:1328-1335), it behooves us to follow the work on understanding the training of circadian and circannual rhythms in order to better understand cluster. Stewart J. Tepper     

The Future of Multilocus Linkage Analysis

The brain's biological clock located in the suprachiasmatic nucleus (SCN) generates circadian rhythms of physiology and behaviour of approximately 24 hours. The clock needs, however, like a watch that runs too fast or too slow, daily adjustment and the most important stimulus for this adjustment is the environmental light/dark cycle, a process know as photoentrainment. It is well established that the eye contains a separate anatomical and functional system mediating light information to the clock. Until recently, the photopigment responsible for light entrainment of the circadian system has been elusive but recent studies have provided evidence that melanopsin, a recently identified opsin, could be the circadian photopigment. This conclusion is based on the observation that melanopsin is expressed exclusively in retinal ganglion cells projecting to the SCN, a projection known as the retinohypothalamic tract (RHT) and that these ganglion cells are intrinsically photosensitive. Melanopsin is present in the plasma membrane of soma, dendrites and axons forming an extensive photoreceptive network in the entire retina. Although these findings make melanopsin a strong candidate as a circadian photopigment, a number of functional experiments are needed before the role of melanopsin is finally proven.     

Melanopsin: a novel photopigment involved in the photoentrainment of the brain's biological clock?

The brain's biological clock located in the suprachiasmatic nucleus (SCN) generates circadian rhythms of physiology and behaviour of approximately 24 hours. The clock needs, however, like a watch that runs too fast or too slow, daily adjustment and the most important stimulus for this adjustment is the environmental light/dark cycle, a process know as photoentrainment. It is well established that the eye contains a separate anatomical and functional system mediating light information to the clock. Until recently, the photopigment responsible for light entrainment of the circadian system has been elusive but recent studies have provided evidence that melanopsin, a recently identified opsin, could be the circadian photopigment. This conclusion is based on the observation that melanopsin is expressed exclusively in retinal ganglion cells projecting to the SCN, a projection known as the retinohypothalamic tract (RHT) and that these ganglion cells are intrinsically photosensitive. Melanopsin is present in the plasma membrane of soma, dendrites and axons forming an extensive photoreceptive network in the entire retina. Although these findings make melanopsin a strong candidate as a circadian photopigment, a number of functional experiments are needed before the role of melanopsin is finally proven.     

The electrophysiology of cluster headache

Cluster headache (CH) is a neurovascular headache disease characterized by recurrent, strictly unilateral, severe pain attacks. Despite its typical clinical features, including circadian rhythm of the attacks and ipsilateral autonomic dysfunction, the underlying pathophysiology of CH is still unclear. Electrophysiological data point to central disinhibition of the trigeminal nociceptive system as one of the key mechanisms of CH pain. Therefore, altered habituation pattern and changes within trigeminal-facial neuronal circuits due to central sensitization seem to be involved. One biochemical correlate is probably represented in dysfunctions of serotonergic raphe nuclei-hypothalamic pathways. Structural and functional imaging data show an alteration of hypothalamic structures in CH patients, supporting the hypothesis that the hypothalamus, according to its function as a circadian pacemaker, plays a pivotal role in CH pathology. Cortical and brainstem reflexes are reviewed to illuminate the pathophysiology of CH.     

Stress-induced alterations of somatodendritic 5-HT1A autoreceptor sensitivity in the rat dorsal raphe nucleus — in vitro electrophysiological evidence

Summary— Somatodendritic 5-HT_1A autoreceptors play a key role in the control of the electrical and metabolic activity of serotoninergic neurons in the dorsal raphe nucleus. These neurons also possess intracellular glucocorticoid receptors which may be involved in the well established modulation of serotonin (5-hydroxytryptamine, 5-HT) metabolism by corticosterone in stressed animals. The possible mediation by somatodendritic 5-HT_1A autoreceptors of such corticosterone-dependent changes in serotoninergic neuron activity was investigated using an in vitro electrophysiological approach. 5-HT_1A autoreceptor-mediated inhibition of the firing of serotoninergic neurons was examined in brain stem slices from rats whose serum corticosterone concentrations had been markedly increased (+ 100–200%) by two different stressful conditions. Immobilization for 30 or 90 min (restraint stress) did not modify the concentration-dependent inhibition of the firing of serotoninergic neurons by the 5-HT_1A receptor agonist ipsapirone. In contrast, placing the rats in novel uncontrolled environmental conditions for 16 h significantly reduced the cell response to ipsapirone, indicating a decreased sensitivity of somatodendritic 5-HT_1A autoreceptors. Such a change was not observed in adrenalectomized rats subjected to the same stressful conditions. These data show that some forms of stress can reduce the 5-HT_1A autoreceptor-dependent inhibitory control of the electrophysiological activity of serotoninergic neurons in the dorsal raphe nucleus. Both the nature and duration of stress seem to be critical factors for triggering the (corticosterone-dependent) mechanism(s) responsible for the functional desensitization of 5-HT_1A autoreceptors in stressed rats.     

MDMA (3,4-methylenedioxymethamphetamine)-mediated distortion of somatosensory signal transmission and neurotransmitter efflux in the ventral posterior medial thalamus

MDMA (3,4-methylenedioxymethamphetamine, Ecstasy) is reported to enhance tactile sensory perception, an effect that is believed to contribute to its popularity as a recreational drug. To date, no literature exists that addresses the neurophysiological mechanisms underlying the effects of MDMA on somatosensation. However, MDMA interactions with the serotonin transporter protein (SERT) are well known. The rat trigeminal somatosensory system has been studied extensively and receives serotonergic afferents from the dorsal raphe nucleus. Given that these fibers express SERT, they should be vulnerable to MDMA-induced effects. We found that short-term low-dose MDMA administration (3 mg/kg i.p.) led to a significant increase in 5-hydroxytryptamine (5-HT) efflux in the ventral posterior medial (VPM) thalamus, the main relay along the lemniscal portion of the rodent trigeminal somatosensory pathway. We further evaluated the potential for MDMA to modulate whisker-evoked discharge (WED) of individual neurons in this region. After surgically implanting stainless steel 8-wire multichannel electrode bundles, we recorded spike train activity from single cells of halothane-anesthetized rats while mechanically activating the whisker pathway. We found that short-term low-dose MDMA (3 mg/kg i.p.) increased the spontaneous firing rate but reduced the magnitude and duration of WED in individual VPM thalamic neurons. It is noteworthy that the time course of drug action on neuronal firing patterns was generally consistent with increased 5-HT efflux as shown from our microdialysis studies. Based on these results, we propose the working hypothesis that MDMA may "distort" rather than enhance tactile experiences in humans, in part, by disrupting normal spike firing patterns through somatosensory thalamic relay circuits.     

Neurotransmitters and the pharmacology of the suprachiasmatic nuclei.

The suprachiasmatic nucleus is the major component of the biological clock responsible for the generation and the regulation of circadian rhythms in behavioral and physiological functions. The SCN acts as an endogenous circadian pacemaker that becomes entrained to the light/dark cycle. Although many neuropeptides and neurotransmitters have been localized within and around the SCN, their role in the generation of the circadian signal still has to be elucidated. There are some data about the transmitters that are involved in the mechanism of entrainment. The way the SCN modulates the homeostatic control systems that are involved in the control of behaviour, also needs more clarification.     

Effects of 3,4-dihydroxymethamphetamine and 2,4,5-trihydroxymethamphetamine, two metabolites of 3,4-methylenedioxymethamphetamine, on central serotonergic and dopaminergic systems.

The effects of 3,4-dihydroxymethamphetamine (DHM) and 2,4,5-trihydroxymethamphetamine (THM) on central serotonergic and dopaminergic systems were investigated to determine if these metabolites share the neurochemical properties of 3,4-methylenedioxymethamphetamine. THM (50-200 micrograms) or DHM (135 micrograms) was administered i.c.v. to rats; 5 days later, cortical, striatal and hippocampal tryptophan hydroxylase (TPH) activity were decreased by THM in a dose-dependent manner, whereas DHM was without effect in these brain structures. The concentration of serotonin in the brain structures contralateral to the side of THM injection was also decreased, but to a lesser degree. THM (100 and 200 micrograms) increased TPH activity to 155% of control in the dorsal raphe, whereas a dose of 50 micrograms increased TPH activity to 132% of control in the median raphe nucleus. THM also markedly reduced striatal tyrosine hydroxylase activity, but did not alter enzyme activity in the substantia nigra; DHM increased striatal tyrosine hydroxylase activity to 115% of control. These results suggest that THM, but not DHM, is toxic to both dopaminergic and serotonergic nerve terminals. Although THM could not be established as the neurotoxic metabolite explaining 3,4-methylenedioxymethamphetamine (MDMA) toxicity, its properties may prove useful in elucidating amphetamine toxicity.     

New hypnotics ramelteon for the treatment of insomniacs with circadian rhythm disturbance

Ramelteon is a new class of sleep agent that selectively binds to the melatonin type 1 (MT1) and type 2 (MT2) receptors in the suprachiasmatic nucleus (SCN), instead of binding to GABA-A receptors such as with traditional hypnotics benzodiazepines. Ramelteon exhibits not only acute sleep-promoting effect but also circadian phase-shifting effect via MT1 and MT2 receptors respectively, and has been revealed to contribute to the treatment of acute and chronic insomnia in patients with circadian rhythm sleep disorders(sleep-wake rhythm disorders) or with inappropriate timing of sleep habits. Optimal administration plan for insomniac patients to induce these characteristic sleep-modulating effects by ramelteon was discussed.