Paradoxical actions of the serotonin precursor 5-hydroxytryptophan on the activity of identified serotonergic neurons in a simple motor circuit.

Neurotransmitter synthesis is regulated by a variety of factors, yet the effect of altering transmitter content on the operation of neuronal circuits has been relatively unexplored. We used electrophysiological, electrochemical, and immunohistochemical techniques to investigate the effects of augmenting the serotonin (5-HT) content of identified serotonergic neurons embedded in a simple motor circuit. The dorsal swim interneurons (DSIs) are serotonergic neurons intrinsic to the central pattern generator (CPG) for swimming in the mollusc Tritonia diomedea. As expected, treatment with the serotonin precursor 5-hydroxytryptophan (5-HTP) increased the intensity of serotonin immunolabeling and enhanced the potency of synaptic and modulatory actions elicited by the DSIs. It also greatly enhanced the ability of the DSIs to evoke rhythmic CPG activity. After 5-HTP treatment, microvoltammetric measurements indicated an increase in a putative 5-HT electrochemical signal during swim CPG activation. Paradoxically, the spiking activity of the serotonergic neurons decreased to a single burst at the onset of the rhythmic motor program, whereas the overall duration of the episode remained about the same. 5-HTP treatment gradually reduced the rhythmicity of the CPG output. Thus, more serotonin did not result in a more robust swim motor program, suggesting that serotonin synthesis must be kept within certain limits for the circuit to function correctly and indicating that altering neurotransmitter synthesis can have serious consequences for the output of neural networks.     

Effects of serotonin on crossed phrenic nerve activity in cervical spinal cord hemisected rats

The present study investigates the effect of 5-hydroxytryptophan (5-HTP), a serotonin precursor, on crossed phrenic nerve activity (CPNA) in rats subjected to a left C2 spinal cord hemisection. Electrophysiological experiments were conducted on anesthetized, vagotomized, paralyzed, and artificially ventilated rats to assess phrenic nerve activity. The left phrenic nerve lost rhythmic activity due to the disruption of the bulbospinal respiratory pathways following spinal cord hemisection. Activity was induced in the left phrenic nerve (CPNA) by temporary asphyxia. 5-HTP administration increased CPNA during asphyxia in the left phrenic nerve in a dose-dependent fashion. Specifically, in a group of eight animals, application of 5-HTP at 0.5, 1.0, and 2.0 mg/kg significantly increased CPNA by 102.2+/-18.5%, 200.8+/-58.1%, and 615.0+/-356.9% compared with predrug control values, respectively. 5-HTP-induced increases in CPNA were reversed by methysergide (2-6 mg/kg, i.v.), a serotonin receptor antagonist. The results suggest that serotonin is involved in the modulation of crossed phrenic nerve activity following spinal cord injury.     

Low brain uptake of L-[11C]5-hydroxytryptophan in major depression: a positron emission tomography study on patients and healthy volunteers

The precursor of serotonin, L-5-hydroxytryptophan (L-5-HTP), was radiolabelled with 11C in the beta-position, yielding [beta-11C]serotonin after decarboxylation, allowing positron emission tomography studies of L-5-HTP uptake across the blood-brain barrier. We studied 8 healthy volunteers and 6 patients with histories of DSM-III major depression, 2 with repeated examinations after clinically successful treatment. We report a significantly lower uptake of [11C]5-HTP across the blood-brain barrier in depressed patients, irrespective of phase of illness. The findings emphasize that serotonin is involved in depressive pathophysiology and support earlier suggestions that the transport of 5-HTP across the blood-brain barrier is compromised in major depression.     

The effects of zimeldine and alaproclate combined with a small dose of 5-HTP on waking and sleep stages in cats

Sleep and waking stages in cats were studied 8 h following administration of zimeldine and alaproclate, in combination with saline or 5-hydroxy-1-tryptophan (5-HTP). Both drugs in combination with saline reduced rapid eye movement sleep and ponto-geniculo-occipital wave activity, and the effects were potentiated with 5-HTP. After administration of zimeldine in combination with 5-HTP there was an increase in synchronized waking (W-2), followed by an increase in slow wave sleep (SWS), at first SWS-1 with spindles and then highly synchronized SWS-2. The changes were interpreted as reflecting a serotonergic deactivating effect expressed by an electroencephalographic synchronizing effect. This is consistent with earlier studies following serotonin depletion and serotonin precursor loading. After alaproclate in combination with 5-HTP there were changes in W-2 and SWS-1 suggestive of the same process but much less pronounced. The difference between the two serotonin uptake inhibitors is interpreted as being due to regional differences in their uptake inhibition.     

Suppressive effects ofl-5-hydroxytryptophan in a feline model of photosensitive epilepsy

We recently demonstrated that long-lasting photosensitivity is acquired as a result of kindling of the lateral geniculate nucleus (LGN), and that the LGN-kindled cat pretreated withd,l-allylglycine represents a useful model of epilepsy for drug studies. The present experiments studied anticonvulsant effects of a serotonin precursor,l-5-hydroxytryptophan (5-HTP), on photosensitivity in the LGN-kindled cat underd,l-allylglycine and on LGN-kindled seizures. 5-HTP suppressed both myoclonic responses and paroxysmal EEG discharges induced by photic stimulation in a dose-related manner. Photically-induced seizures were completely blocked 1.5–2 h after injection of 20 mg/kg 5-HTP. 5-HTP was also effective in reducing the afterdischarge duration and behavioral seizure stage in LGN-kindled seizures; following 40 mg/kg administration, no electroclinical seizures were elicited in the LGN-kindled cats. Serotonergic mechanisms may play an important role in epileptic photosensitivity; the 5-HTP suppressive effect on photosensitivity is at least partly due to reduced neuronal activity at the level of the LGN via serotonergic inhibition.     

Effects of chlorimipramine and protriptyline on the hyperactivity induced by 5-hydroxytryptophan after peripheral decarboxylase inhibition in mice

Summary DL-5-HTP in doses from 100 mg/kg is reported to increase the spontaneous motor activity in mice pretreated with L--hydrazino--methyl--(3, 4-dihydroxyphenyl)-propionic acid (MK-486), an inhibitor of peripheral aromatic aminoacid decarboxylase. Exogenously administered 5-HTP gives rise to accumulation of 5-HT in both central 5-HT-and catecholamine-neurons. The stimulant effect of DL-5-HTP may be mediated via increased activation of 5-HT receptors or, via displacement, increased activation of catecholamine receptors. In the present experiment pre-treatment with chlorimipramine, 25 mg/kg concomitant with MK-486 markedly potentiated the stimulant effect of DL-5-HTP on motor activity,i.e. the dose response curve was shifted to the left. DL-5-HTP, 75 mg/kg, induced in these animals a pronounced increase of the motor activity but had no significant effect on the brain concentrations of DA or NA. Pre-treatment with protriptyline-HCl, 25 mg/kg, concomitant with MK-486 did not potentiate the stimulant effect of DL-5-HTP. The results indicate that the DL-5-HTP induced motor activity is largely dependent on an increased activation of central 5-HT receptors.     

Suppression of annual testicular development in Indian Palm Squirrel,Funambulus pennanti by 8 hr temporal relationship of serotonin and dopamine precursor drugs

Summary Daily injections of 5-HTP (5-hydroxytryptophan, serotonin precursor) and L-DOPA (L-Dihydroxyphenylalanine, dopamine precursor) given 8 hour apart inhibited normal testicular growth in seasonally breeding Indian Palm Squirrel,Funambuluspennanti leading to complete gonadal atrophy, which was maintained till the end of the study. HCG administration induced higher degree of gonadal development but, when the two treatments (HCG + 8 hr relationship of 5-HTP and L-DOPA) were given simultaneously no significant difference was observed compared to control.Results indicate that induced suppression of gonadal function in a fashion similar to seasonal regression leading to non-breeding condition is the consequence of specific phase relationship (8 hr) between serotonergic and dopaminergic activities and not due to Serotonin or dopamine alone. This suggestion gets support from the finding that gonadal condition of squirrels receiving only 5-HTP (5-HTP control) or L-DOPA (DOPA control) was not different from control and exhibited normal testicular growth.It also seems that neurotransmitter precursor drugs given 8 hr apart possibly inhibited the activity of neuroendocrine-gonadal axis since this effect was overpowered by stimulatory effect of gonadotrophin. The findings strongly support the hypothesis that specific phase relation of circadian serotonergic and dopaminergic oscillations account for seasonal reproductive conditions.     

Effects of serotonin synthesis inhibition on sleep in hippocampectomized rats

In adult rats an anterodorsal bilateral hippocampectomy produced an increase in motor activity without modification of the amount of the different sleep stages. In hippocampectomized rats p-chlorophenylalanine produced an insomnia which can be reversed by 5-HTP. These results show that the insomnia produced by brain serotonin depletion is not a result of the hyperactivity produced by the treatments which cause such depletion.     

Effect of chronic treatment with 5-hydroxytryptophan on cortical serotonin receptors in the rat

L-5-Hydroxytryptophan (5-HTP) is a clinically useful antimyoclonic drug that is thought to act at serotonin (5-HT) receptors after decarboxylation to 5-HT. However, the chronic effects of 5-HTP on central 5-HT receptors and the activity of 5-HTP at 5-HT receptor subtypes have not been previously reported. In rats treated 28 but not 7 consecutive days with high doses of 5-HTP (50-200 mg/kg), cortical 5-HT2 (-20%) and 5-HT1 (-11%) sites were downregulated without altered receptor affinity, but only the changes in 5-HT2 sites were significant. In naive frontal cortex in vitro, however, 5-HTP and 5-HT were more active at 5-HT1 sites, and 5-HTP was inactive at 5-HT2 sites. The differential effects of high-dose 5-HTP on 5-HT receptors suggest that 5-HT2 receptor downregulation may be relevant either to the antimyoclonic effect of chronic 5-HTP therapy in posthypoxic myoclonus or to development of tolerance.     

Effects of increased endogenous serotonin on the in vivo binding of [11C]DASB to serotonin transporters in conscious monkey brain

Using a combination of positron emission tomography (PET) and the microdialysis technique, the effects of increased endogenous serotonin (5-hydroxytryptamine; 5-HT) on the binding of [(11)C]DASB to 5-HT transporters (5-HTT) were investigated in the conscious monkey brain. Five rhesus monkeys (Macaca mulatta) were scanned with [(11)C]DASB under the control condition and the increased endogenous 5-HT condition, in which 5-hydroxy-L-tryptophan (5-HTP) was administered (20 mg/kg, i.v.) before the PET scan. Compared with the control scan, the 5-HTP administration significantly decreased the binding potential (BP) (BP = B(max)/K(d)) of [(11)C]DASB in several brain regions. The mean % decrease of BP was biggest in the caudate and putamen. Two monkeys were scanned with [(11)C]5-HTP to assess the amino acid decarboxylase (AADC) activity in the brain, resulting in the high activity in the caudate and putamen. Microdialysis measurements showed that although 5-HTP administration (20 mg/kg, i.v.) increased the extracellular 5-HT levels in both the prefrontal cortex and caudate, the increase of the 5-HT level in the caudate was 27 times higher than that in the prefrontal cortex. These results suggest that the caudate and putamen, both of which show high AADC activity, convert 5-HTP to 5-HT at a high rate, and the increased 5-HT competes with [(11)C]DASB for the 5-HTT.     

The effects of SP-111, a water-soluble THC derivative, on neuronal activity in the rat brain

The serotonin precursor, 5-hydroxytryptophan (5-HTP), can induce a behavioral syndrome characterized by rigidity, splayed feet, tremor, head weaving, salivation and forepaw treading. This response to 5-HTP was markedly potentiated in adult rats treated intracisternally with 5,7-dihydroxytryptamine (5,7-DHT) during development. Prevention of the 5,7-DHT-induced reduction of brain norepinephrine with pargyline or desipramine did not diminish the potentiation of 5-HTP, suggesting that noradrenergic fibers are not contributing to the altered 5-HTP response. It was also found that treatments with 5,7-DHT potentiated the release of prolactin and the disruption of responding in a fixed-ratio operant task induced by 5-HTP. Other experiments indicated that 5,7-DHT treatments potentiated 5-HTP without affecting the action of L-dihydroxyphenylalanine. In addition, administration of the decarboxylase inhibitor, R0-4-4602, at a dose that inhibits enzyme activity in brain, blocked the 5-HTP-induced behavioral syndrome in 5,7-DHT-treated rats, indicating that 5-HTP must be converted to serotonin for 5-HTP to alter behavior. Thus, the present studies indicate that destruction of serotonergic fibers during development can produce permanent changes in central serotonergic mechanisms.     

Regulation of central corticosteroid receptors following short-term activation of serotonin transmission by 5-hydroxy-L-tryptophan or fluoxetine

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis function characterized by a decreased negative feedback capacity are often associated with affective disorders and are corrected by treatment with antidepressant drugs. To gain a better understanding of the effects of the antidepressant drug fluoxetine, a specific serotonin (5-HT) reuptake inhibitor, on central corticosteroid receptors, the effects of short-term activation of serotonin transmission on central corticosteroid receptor expression were analysed in adrenalectomized (ADX) rats either supplemented or not with corticosterone. Serotonin transmission was stimulated either by a single injection of the 5-HT precursor, 5-hydroxy-L-tryptophan (5-HTP), or by a 2-day treatment with fluoxetine. In ADX rats, administration of 5-HTP decreased hippocampal mineralocorticoid (MR) and glucocorticoid (GR) receptor numbers 24 h later, while their respective mRNAs were unchanged and these effects of 5-HTP were mediated by 5-HT2 receptors. In the hypothalamus, GR mRNAs and binding sites decreased 3 h and 24 h after 5-HTP, respectively. By contrast, fluoxetine treatment increased hippocampal MR and GR mRNAs and MR binding sites while GR number remained unchanged. In ADX rats supplemented with corticosterone, 5-HTP and fluoxetine treatment had the same effects on corticosteroid receptors compared to those observed in non supplemented ADX rats: 5-HTP decreased hippocampal MR and GR and hypothalamic GR while fluoxetine treatment increased hippocampal MR. These results show that short-term stimulation of 5-HT transmission by 5-HTP decreases hippocampal and hypothalamic corticosteroid receptor numbers through a corticosterone-independent mechanism. It is hypothesized that the delayed maximal increase in extracellular 5-HT contents after fluoxetine treatment, due to negative feedback regulations induced by the activation of 5-HT1A and 5-HT1B autoreceptors, is not the primary cause for the delayed normalization of corticosteroid receptor numbers that regulates the HPA axis functioning.     

Functional changes in the descending antinociceptive system of morphine-dependent rats

Functional changes of the descending antinociceptive system were studied in morphine-dependent rats by two types of experiments: (a) by recording the effects produced on nociceptive responses of the somesthetic thalamus by stimulation of the nucleus raphe magnus (NRM), and (b) by analyzing changes in the tonic activity of neurons in the periaqueductal gray matter (PAG). Poststimulus time histograms indicated that the input of A-alpha, A-delta, and C fibers into the spinal cord was conveyed via the spinothalamic tract (STT) to particular neurons of the nucleus ventralis posterolateralis (nVPL). Spikes of their responses were grouped in a short-latency burst followed by late spikes that occurred at the appropriate intervals for the arrival of the excitations originally initiated in the A-delta and C fibers. Only the histograms with late peaks were evaluated for the influence of the antinociceptive system. Stimulation of the NRM prior to stimulation of the sciatic nerve promptly suppressed the late (A-delta and C-fiber) peaks in morphine-naive animals. In morphine-dependent rats, NRM stimulation had little or no effect on the histograms. 5-Hydroxytryptophan (5-HTP) had no effect on the nVPL neurons in morphine-naive rats, but in the morphine-dependent rats it renewed the ability of NRM stimulation to suppress the late activity. The tonic activity of the PAG neurons was significantly higher in morphine-dependent compared with that of the morphine-naive animals. Naloxone had a differential effect on the activity of the PAG neurons with regard to the two types of animals: it decreased the PAG activity drastically in the morphine-dependent rats. Apparently, the high tonic activity induced in the PAG by repeated administration of morphine acts on the descending antinociceptive fibers of the NRM and exhausts the synaptic transmitter substance, serotonin, in the NRM terminals, thus decreasing the ability of these terminals to block A-delta and C-fiber excitation of the STT. By assisting the synthesis of serotonin, 5-HTP renews the capacity of the NRM fibers to counteract STT excitation, and thus reinstates the normal function of the antinociceptive system.     

Temporal synergism of neurotransmitter affecting drugs and seasonal reproductive responses of Indian Palm Squirrel,Funambulus pennanti

Summary Daily injections of L-dihydroxyphenylalanine (L-DOPA, dopamine precursor) given 12 hour after 5-hydroxytryptophan (5-HTP, serotonin precursor) eliminated annual testicular regression in seasonally breeding sub-tropical Palm Squirrel that undergoes seasonal changes in responsiveness to day-length and humidity. Other temporal relations (L-DOPA given 0, 4, 8, 16 and 20 hours after 5-HTP administration) decreased/delayed the rate of regression and maintained the reproductive system at intermediate level. 12-hour-relation maintained full breeding condition (maximum gonad and accessory sex organs) unlike control, which exhibited complete atrophy of primary and accessory sex organs.It seems likely that these injections entrained the circadian serotonergic and dopaminergic oscillations and the interaction/phase relation of these two systems through their many circadian expressions (neural/hormonal) accounts for the seasonal interpretation of environmental factors. It is suggested that response in the present study is not a pharmacological effect of drugs but temporal synergism of neural acitivities affected the seasonality of reproduction as only 12-hour-relation of 5-HTP and L-DOPA maintained breeding activity during post reproductive phase of annual gonad cycle in Palm Squirrel.     

Inhibition of 5,7-dihydroxytryptamine-induced supersensitivity to 5-hydroxytryptophan in mice by treatment with cycloheximide.

Intracisternal injection of 5,7-dihydroxytryptamine (5,7-DHT) following treatment with desmethylimipramine induced development of behavioral supersensitivity to the intraperitoneally administered serotonin precursor 5-hydroxytryptophan (5-HTP) in the mouse. This behavioral syndrome, characterized by tremor and muscle twitches (myoclonus), showed a clear dose-response relationship with 5,7-DHT as well as with 5-HTP. Mice lesioned with a low dose of 5,7-DHT (20 micrograms) or a placebo were treated repeatedly with a protein synthesis inhibitor, sycloheximide (45 mg/kg, s.c., every 12 h for up to 10 days). This treatment resulted in a reversible decrease of cerebral protein synthesis varying between 70 and 20% with time between treatments. The myoclonic response to 5-HTP in animals pretreated with 5,7-DHT and by cycloheximide showed a decrease in intensity within 24 h when evaluated quantitatively by an electronic activity monitor, the results of which were confirmed by direct observation. Cycloheximide also exerted a similar, though smaller, effect following full development of sensitivity to 5-HTP over 10 days. These effects may de mediated by inhibition of rapidly turning over serotonin receptor proteins, although their interpretation is somewhat obscured by possible toxic effects of cycloheximide.     

Further studies on the activation of rat median raphe serotonergic neurons by inescapable sound stress

Previous studies, using a biochemical measure of serotonergic neuronal function, show that inescapable, randomly presented sound pulses activate serotonergic neurons in the rat median raphe but not dorsal raphe nucleus. The present study reveals that this activation also occurs in serotonin projection areas, in hippocampus, nucleus accumbens and cortex but not in caudate nucleus. The selectivity of this response is examined by comparing the response to sound stress with that produced by morphine, a treatment known to selectively activate dorsal raphe but not median raphe serotonergic neurons. Two approaches are used in Sprague-Dawley rat to measure the activation of serotonergic neurons: (1) determination ex vivo of accumulation of 5-hydroxytryptophan (5-HTP) in tissue from the dorsal and median raphe nuclei, hippocampus, cortex, caudate nucleus, and nucleus accumbens following in vivo inhibition of aromatic amino acid decarboxylase; and (2) measurement of extracellular serotonin levels in hippocampus, caudate nucleus, and nucleus accumbens. Sound stress increases 5-HTP accumulation in median raphe nucleus, hippocampus, cortex, and nucleus accumbens, but not dorsal raphe nucleus or caudate nucleus. Sound stress also enhances extracellular serotonin levels in hippocampus and nucleus accumbens, but not caudate nucleus. In contrast, the morphine treatment enhances 5-HTP accumulation in dorsal raphe nucleus, cortex and caudate nucleus, but not in median raphe nucleus, hippocampus or nucleus accumbens. Furthermore, it increases extracellular serotonin levels in only the caudate nucleus. The combined effects of sound stress and morphine on 5-HTP accumulation are identical to those obtained by each treatment individually. These findings provide further support for the presence of serotonergic neurons within the median raphe nucleus that have a unique response profile. These neurons may have an important role in responses or adaptations to stress.     

5-OH-tryptophane in migraine: Clinical and neurophysiological considerations

Summary The clinical effects of the protracted treatment with 5-OH Tryptophane (5-HTP) of some patients with chronic migraine are compared with other patients treated with acetylsalicylic acid.The pain threshold was neurophysiologically determined in migraneous patients whose response to 5-HTP therapy was specially good.The results with 5-HTP can be accounted for by an action of the substance on the serotonin turnover with activation of the serotoninergic antinociceptive system.

---

Zusammenfassung Eine Gruppe von chronischen Migränikern wurde mit 5-OH-Tryptophan behandelt und mit einer Gruppe von mit Aspirin behandelten Patienten verglichen. Die Schmerzschwelle wurde bei einer Gruppe von Migränikern, die auf die 5-OH-Tryptophan-Therapie gut angesprochen hatten, mit neurophysiologischen Techniken untersucht.Es wird angenommen, daß die Wirkung des 5-OH-Tryptophans auf eine Beeinflussung des Serotoninstoffwechsels durch eine Aktivierung des serotoninergischen antinociceptiven Systems interpretiert werden muß.

     

Neuropharmacology of Progressive Myoclonus Epilepsy: Response to 5-Hydroxy-L-Tryptophan

Summary: Low concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF) of patients with progressive myoclonus epilepsy (PME) suggest hypofunctional serotonergic neurotransmission. To study this hypothesis, we enrolled 6 patients with PME [Unverricht-Lundborg disease (U-L), mitochondria1 encephalomyopathy, or Lafora disease] in a controlled, double-blinded, dose-ranging, cross-over add-on pilot clinical trial of 5-hydroxy-L-tryptophan (L- 5-HTP) plus carbidopa after 2 other patients had received open-label L-5-HTP for compassionate use. Prestudy CSF 5-HIAA concentrations were low (<20 ng/ml) in 6 patients regardless of the etiology of PME. One patient with U-L disease showed clinical improvement and a fivefold increase in CSF 5-HIAA, and 1 with Lafora disease showed a twofold increase in CSF 5-HIAA without improvement. A patient with Lafora disease reported enough improvement in myoclonus-evoked convulsions to continue chronic use of the drug. One patient with mitochondria1 encephalomyopathy developed status epilepticus during treatment with L-5-HTP.As a group, patients had no statistically significant changes in myoclonus evaluation scale scores, subjective and objective measures of ataxia, seizure frequency, antiepileptic drug (AED) levels, or routine blood tests. These data suggest a serotonergic abnormality regardless of the underlying etiology of PME, but one that seldom responds to acute treatment with L-5-HTP.     

Estradiol and progesterone influence a serotonin mediated behavioral syndrome (myoclonus) in female guinea pigs: Comparison with steroid effects on reproductive behavior

L-5-hydroxytryptophan (L-5-HTP)-induced myoclonus was used as a behavioral index of central serotonergic activity. Estradiol benzoate (EB) and progesterone (P) influenced the induction of myoclonus by L-5-HTP. When L-5-HTP was injected 46 h after EB, myoclonus was enhanced. P blocked this effect on EB when 100 or 125 mg/kg L-5-HTP (but not 80 mg/kg) was given 6 h after P in EB-primed animals. When L-5-HTP was given 3 or 11-15 h after P in EB-primed animals, there was no inhibitory effect of P on myoclonus. In fact, at the lowest dose (80 mg/kg), L-5-HTP increased myoclonus when given 3 h after P in EB-primed animals. The inhibitory effects of P in EB-primed females on myoclonus were temporally correlated with the display of lordosis, suggesting that the neural progestin receptor mechanisms that have been proposed to mediate P effects on lordosis are also involved in the inhibitory effects of P on myoclonus.     

Effect of 5-hydroxytryptophan on H-reflex recovery curves in normal subjects and patients with affective disorders

The effect of the serotonin precursor DL-5-hydroxytryptophan (5-HTP) on the Hoffmann reflex recovery curve (HRRC) was studied in normal subjects and patients with affective illness. 5-HTP significantly decreased the HRRC in normal controls and in depressed and manic patients receiving treatment with lithium or antidepressants. 5-HTP increased the HRRC in unmedicated depressed and manic patients. These results provide further evidence for a serotonergic abnormality in the affective disorders.