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PubMed1977

Behavioral sensitivity to LSD: dependency upon the pattern of central 5HT depletion.

Two experiments were carried out using a fixed ratio (FR) schedule of water reinforcement to determine the efficacy of two serotonin (5HT) depleting agents (p-chloroamphetamine, 5, 7-dihydroxytryptamine) in altering sensitivity to a low dose of LSD (0.02 MG/KG). The results showed that while both p-chloroamphetamine (PCA) and 5, 7 dihydroxytryptamine (5, 7 DHT) were efficacious in reducing whole brain 5HT, only 5, 7 DHT altered LSD sensitivity such that a 0.02 mg/kg dose of LSD given 12 days after 5, 7 DHT administration disrupted bar press behavior. This was not observed in animals given PCA within similar parameters. Moreover, 4 animals given PCA that did not show increased sensitivity to LSD, did show behavioral disruption to LSD (0.02 mg/kg when they were pretreated with p-chlorophenylalanine, Results are discussed on terms of a possible particular pattern of 5HT depletion that must be achieved before sensitivity to LSD is observed.

Animals↗

PubMed1997

Brain structures involved in the behavioral stimulant effect of central serotonin release.

Drugs such as p-chloroamphetamine or a combination of tranylcypromine and tryptophan release serotonin in the central nervous system and produce a behavioral serotonin syndrome. However, in the presence of methysergide or following destruction of descending spinal serotonergic projections by 5,7-dihydroxytryptamine, central serotonin release produces hyperlocomotion. This supports the hypothesis that release of serotonin in the brain promotes locomotion but that the expression of this effect can be blocked by concomitant intraspinal effects of serotonin release. Hyperlocomotion induced by serotonin release is attenuated or blocked by: (a) pretreatment with p-chlorophenylalanine; (b) acute surgical lesions of the basal diencephalon; (c) chronic lesions of the ventromedial midbrain tegmentum by local injection of 5,7-dihydroxytryptamine; and (d) acute surgical decortication. Medial decortication tends to be more effective then lateral decortication. Hyperlocomotion produced by methamphetamine is also attenuated or blocked by acute basal diencephalic lesions or decortication. It is suggested that ascending serotonergic and dopaminergic projections collaborate in the generation of spontaneous voluntary motor activity.

Animals↗

PubMed1982

5-hydroxytryptamine stimulates [3H]dopamine release from the fish retina.

Serotonin (5-hydroxytryptamine, 5-HT; 0.5 micro M and above) stimulated the release of [3H]dopamine ([3H]DA) from particulate fractions of the carp (Cyprinus carpio) retina. The 5-HT effect was dose- and Ca2+-dependent, and was structurally specific. A similar response was not elicited by the other indoles (5,6-dihydroxytryptamine, 5,7-dihydroxytryptamine, 5-hydroxytryptophan, or 5-hydroxyindoleacetic acid) examined. An increase in [3H]DA release was elicited by addition of 5-HT agonists (5-methoxytryptamine, 5-methoxy-N,N-dimethyltryptamine, and tryptamine), but not antagonized by three 5-HT antagonists (metergolin, methysergide, and spiperone). Either DA alone or noradrenaline (0.5 mM) produced a large increase in [3H]DA release from the particulate fractions, but this action was Ca2+-independent. Further, no significant release of [3H] gamma-aminobutyric acid could be evoked by 5-HT (0.5 mM) under similar experimental conditions. Taken together, the present data suggest that 5-HT stimulates [3H]DA release from the fish retina through a specific receptor-mediated mechanism on dopaminergic terminals, but not through an exchange or nonspecific phenomenon.

5-Methoxytryptamine↗

PubMed1984

Presynaptic nicotinic cholinergic receptors labeled by [3H]acetylcholine on catecholamine and serotonin axons in brain.

Nicotinic cholinergic receptor binding sites labeled by [3H]acetylcholine were measured in the cerebral cortices, thalami, striata, and hypothalami of rats lesioned by intraventricular injection of either 6-hydroxydopamine or 5, 7-dihydroxytryptamine. In addition, [3H]acetylcholine binding sites were measured in the cerebral cortices of rats lesioned by injection of ibotenic acid into the nucleus basalis magnocellularis. [3H]Acetylcholine binding was significantly decreased in the striata and hypothalami of both 6-hydroxydopamine- and 5,7-dihydroxytryptamine-lesioned rats. There was no change in binding in the cortex or thalamus by either lesion. Ibotenic acid lesions of the nucleus basalis magnocellularis, which projects cholinergic axons to the cortex, did not alter [3H]acetylcholine binding. These results provide evidence for a presynaptic location of nicotinic cholinergic binding sites on catecholamine and serotonin axons in the striatum and hypothalamus.

Acetylcholine↗

PubMed1989

Evidence that central 5-hydroxytryptaminergic neurones are involved in the anxiolytic activity of buspirone.

1. A two-compartment exploratory test was used to assess the role of central 5-hydroxytryptaminergic neurones in the anxiolytic activity of buspirone in rats. 2. Buspirone 0.1 mg kg-1, administered subcutaneously 15 min before testing, significantly increased black-white transitions (BWT) in control rats but had no effect in animals injected intracerebroventricularly one week before with 150 micrograms 5,7-dihydroxytryptamine (in 20 microliters). 3. Infusion of buspirone in the median raphe (but not in the dorsal raphe) significantly enhanced BWT, at doses from 1 micrograms to 10 micrograms (in 0.5 microliters). Buspirone 5 and 10 micrograms, but not 1 microgram, administered in the median raphe, significantly enhanced motor activity of rats during the first 10 min of testing in the activity cages. 4. The effect on BWT of 5 micrograms buspirone in the median raphe was completely antagonized in animals which had received either 5,7-dihydroxytryptamine intraventricularly, 150 micrograms (in 20 microliters), one week before or an infusion of 0.1 microgram (in 0.5 microliter) (-)-propranolol in the same area 5 min before. (-)-Propranolol infused in the median raphe did not modify the effect of buspirone on locomotion. 5. Infusion of 5 micrograms buspirone (in 0.5 microliter) in the median raphe significantly enhanced punished responses in a conflict test with no effect on unpunished responding. Buspirone infused in the dorsal raphe had no effect on punished or unpunished responding over a wide dose range. 6. The results indicate that at the relatively low dose used in the present study buspirone produces an anxiolytic effect by acting on central 5-hydroxytryptaminergic neurones. It is likely that activation of 5-hydroxytryptamine1A-receptors in the median raphe is involved.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1980

A dopamine-5-hydroxytryptamine link in the hypothalamic pathways which mediate heat loss in the rat.

1. Intrahypothalamic injection of either dopamine or 5-hydroxytryptamine (5-HT) in a dose volume of 1 microliters caused a fall in core temperature in lightly restrained rats maintained at an ambient temperature of 17 +/- 1 degree C. 2. Haloperidol (6.5 n-mole), a dopamine antagonist, prevented the hypothermic effect of dopamine (65 n-mole), but was ineffective against the response to either intrahypothalamic 5-HT (114 n-mole) or oxotremorine (6.0 n-mole). 3. Methysergide (14 n-mole) and cryproheptadine (17 n-mole) blocked the effect of both 5-HT and dopamine. However, these same doses failed to antagonise the effect of oxotremorine. 4. Rats placed on 0.65 m below a 250 W infra-red lamp responded to the imposed heat load vasodilation of tail skin blood vessels, as indicated by an increased tail skin temperature. 5. Rats tested 2 weeks after bilateral intrahypothalamic injection of 5,6-dihydroxytryptamine (42 n-mole in 2 microliters) showed a significant reduction in their tail skin temperature response and were less able to withstand the imposed heat load. 6. Three serial sections (0.8 mm thick) were prepared from the preoptic area of the rat brain, one anterior, one posterior and one corresponding to the previously defined dopamine-sensitive site. 7. Pretreatment with 5,6-dihydroxytryptamine significantly reduced the 5-HT concentration in the dopamine sensitive site, but had no effect on the concentration of dopamine. This pretreatment blocked dopamine but not 5-HT-induced hypothermia. 8. The 5-hydroxyindoleacetic acid (5HIAA) concentration in the hypothalamus of the normal rat exposed to a heat load was found to be significantly elevated, whereas there was no change in the 5HIAA concentration in the cortex. 9. Slices of rat preoptic hypothalamus and hippocampus were incubated with [3H]5-HT (0.2-2 microM). These slices accumulated 5-HT with properties characteristic of a neuronal uptake process. 10. Perfusion with either dopamine (greater than 50 microM) or apomorphine (greater than 200 microM) enhanced the release of [3H]5-HT from the prelabelled hypothalamic slices, but failed to stimulate release from hippocampal slices. 11. The release of [3H]5-HT from preoptic slices by dopamine and apomorphine was antagonised by the dopamine antagonists haloperidol (2 microM) and (+) isomer of butaclamol (1 microM), the (-) isomer of butaclamol was inactive. 12. These results support the hypothesis of a dopamine-5HT link in the hypothalamic thermoregulatory pathways of the rat.

Animals↗

PubMed1996

Selective depletion of spinal monoamines changes the rat soleus EMG from a tonic to a more phasic pattern.

1. To assess the role of descending monoaminergic pathways for motor activity long-lasting EMG recordings were performed from the adult soleus muscle before and after selective depletion of spinal monoamines. 2. Rats were chronically implanted with an intrathecal catheter placed in the lumbar subarachnoid space and gross-EMG recording electrodes in the soleus muscle. EMG recordings were performed in control conditions and at different times after intrathecal administration of either 40-55 micrograms 5,6-dihydroxytryptamine (5,6-DHT) and 40-55 micrograms 6-hydroxydopamine (6-OHDA) or 80 micrograms 5,7-dihydroxytryptamine (5,7-DHT) alone. The depletions were evaluated biochemically in brains and spinal cords after recordings. 3. In agreement with previous studies the intrathecal administration of neurotoxins caused a reduction of the noradrenaline (NA) and serotonin (5-HT) content of the lumbar spinal cord to about 2-3% of control, with little or no changes in the monoamine content of the cortex. 4. In non-treated chronically catheterized rats the integrated rectified gross EMG displayed long-lasting EMG episodes composed of phasic high-amplitude events and tonic segments of varying duration and amplitude. 5. After intrathecal administration of neurotoxins the number of long-lasting gross-EMG episodes, the mean episode duration, and the total EMG activity per 24 h, were reduced. These changes were accompanied by a simultaneous increase both in the number of short-lasting EMG episodes and the total number of EMG episodes per 24 h period. The changes were apparent 5-6 days after drug administration and fully developed after 2-3 weeks. 6. No changes in general movement ability were observed, except that the denervated animals had a tendency to a less errect posture. 7. These results indicate that descending monoaminergic pathways are important for the maintained motor output in tonic hindlimb muscles.

Animals↗

PubMed1986

Interaction of putative endogenous tryptolines with the hypothalamic serotonergic system and prolactin secretion in adult male rats.

The effect of 5-methoxytryptoline (5-MeOT), 5-hydroxytryptoline (5-OHT) and tryptoline (Tp), putative endogenous derivatives of the tryptamines, on plasma prolactin (PRL) concentrations has been investigated in the adult male rat. The possible involvement of the hypothalamic serotonergic system has been considered in the mediation of the hormonal effect of the tryptolines. Therefore, plasma PRL levels have been evaluated in rats receiving tryptolines after different pharmacological manipulations of central serotonergic function. Although the three compounds increased the plasma titers of PRL in a dose-dependent manner and enhanced the hypothalamic content of serotonin (5HT), they appear to affect the serotonergic system through different mechanisms. In particular, 5-OHT might act at a presynaptic level, since its hyperprolactinemic effect was antagonized both by the depletion of central 5HT content after p-chlorophenylalanine and by the degeneration of serotonergic terminals after 5,7-dihydroxytryptamine. In contrast, 5-MeOT behaved as if it had a postsynaptic site of action, being counteracted by the serotonergic postsynaptic antagonists metergoline and cyproheptadine. The unsubstituted tetrahydro-beta-carboline, Tp, is probably active at both pre- and postsynaptic sites. The enhancing effect of Tp on PRL secretion was antagonized by chronic treatment with p-chlorophenylalanine, while it was also maintained in 5,7-dihydroxytryptamine-lesioned rats. These findings suggest that tryptolines may play a functional role in PRL secretion by interacting with central serotonergic systems through different biochemical mechanisms.

5-Hydroxytryptophan↗

PubMed1981

Evidence that a serotonergic mechanism stimulates the secretion of pituitary beta-endorphin-like immunoreactivity in the rat.

A pharmacological approach was used to investigate serotonergic control of the secretion of pituitary beta-endorphin-like immunoreactivity (beta-END-LI) in the rat. The administration of 75 or 200 mg/kg L-tryptophan (ip, over 30 min) increased brain serotonin by 17% and 19%, respectively, and increased circulating beta-END-LI from 0.30 +/- .06 to 0.56 +/- 0.7 and 0.64 +/- 0.8 ng/ml, respectively. D,L,5-Hydroxytryptophan (30 mg/kg, ip, over 30 min) produced a 4.9-fold increase in brain serotonin content and a 3.4-fold rise in plasma beta-END-LI. The administration of a serotonin reuptake blocker, fluoxetine (10 mg/kg, ip, over 15 min), elevated basal levels of plasma beta-END-LI from a control value of 0.38 +/- 0.02 to 1.21 +/- 0.32 ng/ml. Exposure to ether increased circulating beta-END-LI to 1.08 +/- 0.18 ng/ml, and fluoxetine treatment further increased this rise to 1.69 +/- 0.09 ng/ml (P less than 0.05). Quipazine, a serotonin receptor agonist, evoked a dose-related (2.5-5.0 mg/kg, ip) increase in circulating beta-END-LI levels by 15-45 min post injection. By contrast, intraventricular injection of the neurotoxin 5,7-dihydroxytryptamine (75 microgram free base, for 10 days) caused a 77% depletion of brain serotonin and attenuated the rise in beta-END-LI levels in response to immobilization (3.28 +/- 0.20 vs. 1.83 +/- 0.25 ng/ml). A higher dose of 5,7-dihydroxytryptamine (200 microgram free base, for 10 days) significantly decreased resting levels of beta-END-LI from 0.65 +/- 0.14 to 0.36 +/- 0.08 ng/ml. We conclude that brain serotonin neurons exert a stimulatory influence over the basal secretion of pituitary beta-END-LI and mediate, in part, the stress-induced release of this hormone.

Animals↗

PubMed1999

Involvement of brain serotonergic terminals in the antinociceptive action of peripherally applied calcitonin.

We investigated the antinociceptive effect of systemic injection of calcitonin and its mechanisms of action in rats. Subcutaneous injection of [Asu(1,7)]eel calcitonin (ECT, 4 U x kg(-1) x day(-1)) daily for 7 days suppressed nociceptive hypersensitivity induced by formalin (and by carrageenan); the effect was gradually increased by the repeated injections and significant effects were observed after administration for more than 4 days. The antinociceptive action of ECT (4 U x kg(-1) x day(-1) for 7 days) was inhibited by intracerebroventricular injection of the serotonergic neurotoxin 5,7-dihydroxytryptamine and serotonin-receptor antagonists methiothepin, cyproheptadine and ketanserin; methysergide showed an inhibitory tendency. Intrathecal injections of 5,7-dihydroxytryptamine, methiothepin, cyproheptadine and ketanserin were without effects on the ECT action. The results suggest the involvement of serotonin in the brain, but not in the spinal cord, in the ECT antinociception. Intracerebroventricular or intrathecal injection of the catecholaminergic neurotoxin 6-hydroxydopamine and intracerebroventricular injection of the alpha-adrenoceptor antagonist phentolamine were also without effects on the ECT action. A subcutaneous infusion of the opioid receptor antagonist naloxone inhibited the antinociceptive action of morphine, but not that of ECT. Thus, adrenergic and opioidergic systems may not play important roles in the ECT antinociception. The present results suggest that repeated systemic injection of ECT produces analgesia and that the brain serotonergic terminals are involved in this action.

Adrenergic alpha-Antagonists↗

PubMed1984

Brain part monoamines in the neuroendocrine mechanisms activated by immobilization stress in the rat.

The long suspected and recently demonstrated abnormality in neuroendocrine control in patients with severe depression indicates that the neurochemical and neuroanatomical analysis of the neuroendocrine response to stress may provide valuable information in understanding the etiology of severe endogenous depression. Rats were immobilized for 1, 2, 3 or 5 hours consecutively or 2 hours per day for 5 days, sacrificed and plasma corticosterone (as an index of the release of adrenocorticotropic hormone from the pituitary) and brain part noradrenaline, dopamine, and serotonin concentrations were determined fluorometrically. Plasma corticosterone and brain part monoamines were also measured in other rats given 2 hour immobilization stress one week after the intraventricular injection of the neurotoxins 6-hydroxydopamine and/or 5,6-dihydroxytryptamine. Plasma corticosterone increased by 30% to 50% after all periods of stress and serotonin was increased in all brain parts after 1, 2 or 3 hours of stress but not after 5 hours or chronic stress. Forebrain dopamine was decreased by 30% after 1 hour stress, slowly increased with increasing duration of stress becoming a marked increase of 85% over controls after prolonged or chronic stress. The destruction of catecholamine nerve terminals with 6-hydroxydopamine prevented the stress induced rise in brain part serotonin but had no effect on the plasma corticosterone response to immobilization stress. Destruction of serotonin nerve terminals with 5,6-dihydroxytryptamine potentiated by 50% the stress induced rise in plasma corticosterone. Plasma corticosterone after 2 hours immobilization stress was the same as controls in rats given both neurotoxins. These data support the hypothesis that ACTH release is stimulated by serotonergic neural activity.

Adrenocorticotropic Hormone↗

PubMed1975

Microspectrofluorimetric analysis of the formaldehyde induced fluorescence in midbrain raphe neurons.

The formaldehyde induced fluorescence in perikarya localized in the midbrain rephe nuclei was investigated using the Falck-Hillarp technique in combination with qualitative (spectral analysis) and quantitative microspectorfluorimetry. The spectral evidence obtained after various pharmacological and lesion experiments with the neurotoxic compounds 5,6-dihydroxytryptamine and 5,7-dihydroxytryptamine, strongly favours the view that the vast majority of the perikarya in the cell groups B-7, B-8 and B-9 (according to Dahlström and Fuxe) are 5-hydroxytryptamine neurons, defined as structures capable of synthesizing, metabolizing, and storing 5-hydroxytryptamine. The spectral data indicate that the 5-hydroxytryptamine neurons might contain in addition to 5-hydroxytryptamine another indolealkylamine, possibly tryptamine, in low concentrations. The perikarya were shown to be able to take up and accumulate exogenously administered 6-hydroxytryptamine provided that monoamine oxidase was inhibited. Quantitative microfluorimetric analysis disclosed that the tryptophan hydroxylase inhibitor p-chlorophenylalanine was unable to block effectively this enzyme in the 5-hydroxytryptamine perikarya, although acutely a partial blockade was observed. The 5-hydroxytryptamineerogenously to the action of p-chlorophenylalanine and this might be associated with different states of neuronal activity. The difference in potency of p-chlorophenylalanine as regards tryptophan hydroxylase inhibition in perikarya and in nerve terminals may be related to different properties of tryptophan hydroxylase in various parts of the neuron and/or to a high turnover of the enzyme in the perikarya.

5-Hydroxytryptophan↗

PubMed1990

Serotonergic afferent regulation of the basic physiology and pharmacological responsiveness of nigrostriatal dopamine neurons.

The electrophysiological responsiveness of nigrostriatal dopamine (DA) neurons to dorsal raphe stimulation and to systemic administration of serotonin (5-HT) selective compounds was examined in chloral hydrate-anesthetized rats. Electrical stimulation of the dorsal raphe selectively inhibited the firing rate of slowly firing (less than 4 spikes/sec) DA neurons. The 5-HT-1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine preferentially increased the firing rate of slowly firing DA neurons, but did not alter the responsiveness of these cells to quinpirole-induced inhibition of firing rate. This increase in firing rate was not observed following depletion of brain 5-HT by the neurotoxin 5,7-dihydroxytryptamine. The 5-HT-1B agonists trifluoromethylphenylpiperazine and M-chlorophenylpiperazine had only weak inhibitory effects on the firing rates of DA neurons, and also failed to alter the responsiveness of DA neurons to quinpirole-induced inhibition. Depletion of brain 5-HT (greater than 80%) by either para-chlorophenylalanine or 5,7-dihydroxytryptamine eliminated the rate-dependent nature of quinpirole-induced inhibition of nigrostriatal DA neurons, while having limited effects on the basal electrophysiological activity of these cells. These data suggest that 5-HT systems exert subtle influences on the activity and pharmacological responsiveness of nigrostriatal DA neurons.

Animals↗

PubMed1989

Morphine, capsaicin and K+ release purines from capsaicin-sensitive primary afferent nerve terminals in the spinal cord.

In the present study the neuronal source of adenosine released by K+, morphine and norepinephrine (NE) from the spinal cord was investigated. Intrathecal pretreatment with 5,7-dihydroxytryptamine and 6-hydroxydopamine reduced spinal 5-hydroxytryptamine and NE levels, respectively, but had no effect on adenosine release from dorsal spinal cord synaptosomes evoked by K+ or morphine. NE-evoked release of adenosine was unaffected by 5,7-dihydroxytryptamine but increased by 6-hydroxydopamine. Subcutaneous pretreatment of neonatal or intrathecal pretreatment of adult rats with capsaicin increased nociceptive thresholds and reduced the release of adenosine evoked by K+ and morphine but not NE from dorsal spinal cord synaptosomes. Intrathecal capsaicin also inhibited morphine-evoked release of adenosine in vivo. K+ and morphine released only small amounts of adenosine from ventral spinal cord synaptosomes whereas NE released significant amounts. Exposure of dorsal, but not ventral, spinal cord synaptosomes to capsaicin produced a dose- and Ca++-dependent release of adenosine, which was reduced by capsaicin pretreatment (neonatal and adult) and inhibition of ecto-5'-nucleotidase. Capsaicin also released endogenous ATP from dorsal spinal cord synaptosomes. These results suggest that primary afferent nerve terminals in the dorsal horn of the spinal cord release adenosine in response to morphine and K+, and a nucleotide (possibly ATP) in response to capsaicin. Adenosine does not appear to be released from the terminals of descending aminergic pathways. The source of purines released by NE is less certain.

Adenosine↗

PubMed1989

Serotonin depletion potentiates gastric secretory and motor responses to vagal but not peripheral gastric stimulants.

Vagal stimulation is known to release gastrointestinal serotonin. The effect of depletion of serotonin stores on vagally stimulated gastric acid secretion and motility was studied in rats. Pretreatment of rats with parachlorophenylalanine (p-CPA) did not alter basal gastric acid and serotonin secretion but produced a 57% reduction in the intraluminal gastric release of serotonin and a 43 to 100% potentiation of the gastric acid secretory response elicited by intracisternal injection of the stable thyrotropin-releasing hormone analog, RX 77368, in conscious pylorus-ligated rats or urethane-anesthetized rats with an acute gastric fistula. Dose-response studies revealed that the gastric acid secretion induced by submaximal but not high doses of RX 77368 was elevated significantly by p-CPA pretreatment. p-CPA also enhanced the gastric acid output produced by submaximal, but not high doses of the vagal stimulant baclofen, [beta-(p-chlorophenyl)-gamma-aminobutyric acid]. In contrast, p-CPA pretreatment had no effect on gastric acid secretion stimulated by bethanechol, histamine or pentagastrin. Selective depletion of central serotonin stores by pretreatment with the neurotoxin 5,7-dihydroxytryptamine given alone, or combined with parachloroamphetamine did not alter RX 77368-stimulated gastric acid secretion. In addition, gastric contractility stimulated by intracisternal injection of RX 77368 was significantly enhanced by p-CPA but not by 5,7-dihydroxytryptamine pretreatment, whereas the contractile response to carbachol was not altered by p-CPA pretreatment. These results suggest that depletion of peripheral but not central serotonergic stores potentiate gastric acid secretion and contractility induced by vagally, but not peripherally acting gastric stimulants. Thus, peripheral serotonin may exert an inhibitory tone on vagally stimulated gastric acid secretion and motility in the rat.

Animals↗

PubMed1989

Evidence for involvement of 5-hydroxytryptamine1 receptors in antidepressant-like drug effects on differential-reinforcement-of-low-rate 72-second behavior.

Previous work in this laboratory has suggested that antagonist action of 5-hydroxytryptamine2 (5-HT2) receptors and agonist action of 5-HT1 receptors results in antidepressant-like effects (increased reinforcement rate and decreased response rate) in rats performing under the differential-reinforcement-of-low-rate 72-sec schedule (DRL 72-s) of reinforcement. Serotonergic mediation of antidepressant drug effects on DRL 72-s behavior was assessed with a series of 5-HT agonists, and blockade of the effects of the antidepressant drugs clorgyline and fluoxetine (which presumably indirectly stimulate 5-HT1 receptors) was attempted in separate experiments with the 5-HT1 and 5-HT2 antagonist methysergide and the 5-HT neurotoxin 5,7-dihydroxytryptamine. Direct 5-HT1A agonists 8-hydroxy-2-(di-n-propylamino)tetralin and 5-methoxy-N,N-dimethyltryptamine and the 5-HT precursor 5-hydroxytryptophan all increased the reinforcement rate. The 5-HT1B and 5-HT1C agonists m-chlorophenylpiperazine and 1-(m-trifluoromethylphenyl)piperazine did not increase the reinforcement rate. The 5-HT2 agonist and 5-HT3 antagonist quipazine also did not increase the reinforcement rate. The monoamine oxidase inhibitor clorgyline and the 5-HT uptake inhibitor fluoxetine increased the reinforcement rate and decreased the response rate as seen with other antidepressant drugs on the DRL 72-s schedule. Methysergide antagonized the reinforcement rate increasing effects of both clorgyline and fluoxetine. Depletion of brain 5-HT with i.v.t. 5,7-dihydroxytryptamine blocked the antidepressant-like effects of clorgyline. These results suggest that central 5-HT1A receptors are involved in mediating the antidepressant-like effects of some drugs on DRL 72-s behavior. These results provide evidence that stimulation of 5-HT1A receptors and antagonism of 5-HT2 receptors lead to an antidepressant-like effect on the DRL 72-s schedule and implies that these two receptors may be important in mediating clinical drug effects in depression.

Animals↗

PubMed1982

Characterization of serotonin uptake in cultured neuroblastoma cells. Difference between differentiated and nondifferentiated cells.

Neuroblastoma cells clone N-2a, differentiated by serum deprivation, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 1.27 microM and the Vmax 720 fmoles/min/10(6) cells. The uptake was temperature-dependent and partially sodium-dependent, and was inhibited by ouabain and by selected metabolic inhibitors (sodium azide, 2,4-dinitrophenol, and iodoacetamide). Fluoxetine and desmethylimipramine (DMI) were equally effective inhibitors of [3H]5-HT uptake (IC50 = 13.7 microM and 13.6 microM). The uptake was structurally specific, since unlabeled 5-HT was a better inhibitor of [3H]5-HT uptake than norepinephrine (NE) (IC 50 = 0.6 microM and 9.4 microM). The neurotoxins 6-hydroxydopamine and 5,6-dihydroxytryptamine were cytotoxic to differentiated N-2a cells, causing time- and concentration-dependent inhibition of [3H]thymidine incorporation into DNA, 5,7-Dihydroxytryptamine had little cytotoxic effect. Non-differentiated N-2a cells, supplemented with 5% fetal calf serum, were also found to take up [3H]5-HT by a concentration-, temperature-, and energy-dependent process. The apparent Km of uptake was 0.96 microM and the Vmax was 619 fmoles/min/10(6) cells. However, in nondifferentiated cells [3H]5-HT uptake was not sodium-dependent, not inhibited by ouabain, less effectively inhibited by fluoxetine and DMI (IC50 = 148 microM and 107 microM), and not selectively inhibited by unlabeled 5-HT as compared with NE (IC50 = 7.9 microM and 6.0 microM).

Animals↗

PubMed1982

Characterization of serotonin uptake in cultured pheochromocytoma cells. Comparison with norepinephrine uptake.

PC-12 cells, derived from a rat pheochromocytoma, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 0.39 microM and the Vmax was 0.40 pmole/min/10(6) cells. The uptake was temperature-dependent, partially sodium-dependent, and inhibited by selected metabolic inhibitors (sodium azide, 2,4-dinitrophenol, and iodoacetamide), PC-12 cells also accumulated tritiated norepinephrine ([3H]NE) by a saturable process, with an apparent Km of 1.13 microM and a Vmax of 1.72 pmole/min/10(6) cells. This NE uptake process was also temperature- and sodium-dependent and inhibited by metabolic inhibitors and ouabain. Desmethylimipramine (DMI, IC50 = 3.8 microM) was a better inhibitor of [3H]NE uptake than fluoxetine (IC50 = 24.6 microM). The NE uptake process was structurally specific, since unlabeled NE was a better inhibitor of [3H]NE uptake than 5-HT (IC50 = 19.6 and 171 microM, respectively). However, [3H]5-HT uptake in PC-12 cells appeared to be a less structurally specific process, as it was equally inhibited by unlabeled 5-HT and NE (IC50 4.9 microM and 4.3 microM, respectively). DMI was also a better inhibitor of [3H]5-HT uptake than fluoxetine (IC50 = 85 and 411 microM, respectively). The neurotoxins 6-hydroxydopamine and 5,6-dihydroxytryptamine were cytotoxic to PC-12 cells, causing a time- and concentration-dependent inhibition of [3H]thymidine incorporation into DNA. 5,7-Dihydroxytryptamine had little cytotoxic effect toward PC-12 cells in culture.

Adrenal Gland Neoplasms↗