Showing papers on "Serotonin published in 1978"

Serotonergic component of neuroleptic receptors

Abstract: BINDING studies performed in vitro with 3H-haloperidol1–3, 3H-spiperone4–5, 3H-dopamine1–3,6 and 3H-apomorphine7,8 showed that the specific neuroleptic binding sites in the striatum are dopaminergic. The frontal cortex, however, was much more labelled by 3H-spiperone than by 3H-haloperidol9,10. The investigations reported here indicate that the neuroleptic receptor sites in the frontal cortex labelled by 3H-spiperone are predominantly serotonergic and virtually identical to those labelled by 3H-LSD. These conclusions were reached from a study of the relative binding affinities of a series of serotonin or dopamine agonists or antagonists for rat frontal cortex and striatal receptors. Significant correlations were obtained between the binding activities in the rat frontal cortex and in vivo potencies in the pharmacological anti-tryptamine test. Similarly, binding activities in the striatum were significantly correlated with the potencies in the anti-apomorphine test. We therefore suggest that serotonergic, as well as dopaminergic, receptors are involved in the mechanism of action of neuroleptic drugs.

Tricyclic antidepressants: long-term treatment increases responsivity of rat forebrain neurons to serotonin

Abstract: Long-term treatment of rats with clinically effective tricyclic antidepressant drugs induced a selective increase in the inhibitory response of forebrain neurons to serotonin applied by microiontophoresis. Long-term administration of some related drugs which lack antidepressant efficacy failed to induce such a change. The enhanced response to serotonin induced by the clinically active tricyclic drugs took 1 to 2 weeks to develop, a time course which correlates with the delayed onset of therapeutic effects in humans.

Method for the rapid determination of norepinephrine, dopamine, and serotonin in the same brain region

Abstract: A method is presented for the fluorometric analysis of norepinephrine, dopamine and serotonin. This procedure is a combination of an unpublished catecholamine assay developed by Hogans and of the o-phthaldialdehyde serotonin reaction reported by Maickel and Miller [9]. This procedure should greatly facilitate the correlation of neurotransmitter levels in brain regions with changes in behavior produced by experimental manipulations.

The effects of putative 5-hydroxytryptamine antagonists on the behaviour produced by administration of tranylcypromine and L-tryptophan or tranylcypromine and L-DOPA to rats

Abstract: 1 The putative 5-hydroxytryptamine (5-HT) receptor blocking drugs methysergide (10 mg/kg) and methergoline (5 mg/kg) were found to abolish some components of the hyperactivity syndrome, including head weaving and forepaw treading, which follow administration to rats of tranylcypromine (20 mg/kg) and L-tryptophan (100 mg/kg). Hyperactivity and hyper-reactivity were potentiated with a resultant increase in automated locomotor activity counts. In contrast (-)-propranolol (20 mg/kg) inhibited all features of the syndrome. The same results were obtained with these drugs when the behaviour was elicited by p-chloroamphetamine (10 mg/kg) or by tranylcypromine and tryptamine (10 mg/kg). 2 Methysergide and methergoline had similar effects on the syndrome produced by tranylcypromine and L-DOPA (50 mg/kg) whereas propranolol was without effect. 3 None of the putative 5-HT receptor antagonists affected brain 5-HT turnover as assessed by rate of accumulation of 5-HT following monoamine oxidase inhibition with tranylcypromine. 4 Microinjections of 5,7-dihydroxytryptamine into the spinal cord resulted in a 70% fall in cord 5-HT concentrations without an effect on brain 5-HT concentrations. The behavioural response to the putative 5-HT receptor agonist, 5-methoxy N,N-dimethyltryptamine (2 mg/kg), was potentiated in these animals suggesting that 5-HT receptors become supersensitive on denervation, and that some components of the behavioural syndrome are mediated by spinal cord 5-HT receptors. 5 Pretreatment with alpha-methyl p-tyrosine (2 X 200 mg/kg) delayed the onset of all components of the behaviour elicited by tranylcypromine/L-tryptophan by 60 min, indicating an involvement of catecholamines in the syndrome. 6 p-Chloroamphetamine-induced 5-HT depletion had no effect on any component of the tranylcypromine-L-DOPA behaviour.

[3h]glycogen hydrolysis in brain slices: responses to neurotransmitters and modulation of noradrenaline receptors

Abstract: — Different agents have been investigated for their effects on [C3H]glycogen synthesized in mouse cortical slices. Of these noradrenaline, serotonin and histamine induced clear concentration-dependent glycogenolysis. [C3H]Glycogen hydrolysis induced by noradrenaline appears to be mediated by beta-adrenergic receptors because it is completely prevented by timolol, while phentolamine is ineffective. It seems to involve cyclic AMP because it is potentiated in the presence of isobutylmethylxanthine; in addition dibutyryl cyclic AMP (but not dibutyryl cyclic GMP) promotes glycogenolysis. Lower concentrations of noradrenaline were necessary for [C3H]glycogen hydrolysis (EC50= 0.5μM) than for stimulation of cyclic AMP accumulation (EC50= 8μM). After subchronic reserpine treatment the concentration-response curve to noradrenaline was significantly shifted to the left (EC50= 0.09 ± 0.02 μM as compared with 0.49 ± 0.08 μM in saline-pretreated mice) without modifications of either the basal [C3H]glycogen level, maximal glycogenolytic effect, or the dibutyryl cAMP-induced glycogenolytic response. In addition to noradrenaline, clear concentration-dependent [3H]glycogen hydrolysis was observed in the presence of histamine or serotonin. In contrast to the partial [3H]glycogen hydrolysis elicited by these biogenic amines, depolarization of the slices by 50 mM K+ provoked a nearly total [C3H)glycogen hydrolysis.

Specificity of a rat behavioral model for serotonin receptor activation.

Abstract: Pharmacological stimulation of central serotonin (5-HT) receptors causes a behavioral syndrome characterized by simultaneous side-to-side head weaving or head tremor, forepaw padding and splayed hindlimbs. This syndrome has been proposed and used as a model for 5-HT receptor activity. Questions have been raised about the possible involvement of catecholamines. This study was designed to differentiate behavioral signs contributed by 5-HT from those that might be due to catecholamines. Depletion of catecholamines by alpha-methyl-p-tyrosine, or depletion of 5-HT by either p-chlorophenylalanine or 5,7-dihydroxytryptamine, did not prevent the syndrome caused by 5-methoxy-N,N-dimethyltryptamine, a 5-HT receptor agonist. Pretreatment with methysergide, but not phenoxybenzamine or pimozide, prevented the syndrome caused by 5-methoxy-N,N-dimethyltryptamine. Conversely, 5-HT depletion prevented the syndrome caused by monoamine oxidase inhibitor and levodopa; behavioral response was restored in p-chlorophenylalanine-pretreated rats by 5-hydroxytryptophan. Methysergide prevented the syndrome caused by monoamine oxidase inhibitor and levodopa, but phenoxybenzamine or pimozide did not. Intraventricular 5-HT or dopamine also caused the behavioral syndrome after monoamine oxidase inhibition. p-Chlorophenylalanine pretreatment prevented the syndrome caused by dopamine, but did not prevent the syndrome caused by 5-HT. Our results suggest that systemic levodopa or intraventricular dopamine produces the behavioral signs through 5-HT mechanisms; endogenous catecholamine mechanisms are not involved directly in either the cause or expression of the behavioral syndrome.

Systemic administration of beta-endorphin: potent hypotensive effect involving a serotonergic pathway.

Abstract: In normal adult rats anesthetized with urethane, intravenous injections of beta-endorphin (30--150 micrograms kg-1) induced a transient fall of blood pressure followed by a small hypertension and a prolonged hypotension. Prior administration of naloxone completely blocked these effects, whereas naloxone, given 1 hr after beta-endorphin, did not reverse the prolonged depressor phase of the opioid peptide. The effects of beta-endorphin on the arterial blood pressure were greatly reduced in animals pretreated with p-chlorophenylalanine, a specific depletor of serotonin. Moreover, in rats pretreated with potent serotonin antagonists such as cyproheptadine, mianserin, and metergoline, beta-endorphin did not produce a significant hypotension. Furthermore, the depressor effect of beta-endorphin was potentiated by fluoxetine, a specific serotonin uptake inhibitor. These observations suggest the participation of a serotonergic pathway in the action of beta-endorphin on the arterial blood pressure.

A suspension culture of pinealocytes: regulation of N-acetyltransferase activity.

Abstract: A method to prepare suspension cultures of highly viable pinealocytes is described. Pineal glands of neonatal or adult rats can be used; the best yield is obtained from neonatal glands. Morphological examination of the cells indicates that they have a normal, healthy appearance and retain some structures typical of neonatal pinealocytes. During the first 24 h of culture, the cells aggregate into small clusters; after several days, larger aggregates can be seen. Biochemical studies indicate that adrenergic stimulation of these cells causes a 30- to 100-fold increase in serotonin N-acetyltransferase activity, a response which is unique to the pineal gland. The relative order of potency of several adrenergic agonists is l-isoproterenol greater than l-norepinephrine greater than or equal to l-epinephrine greater than phenylephrine. Serotonin, tyramine, histamine, carbachol, gamma-aminobutyric acid, cocaine, and desmethylimipramine are inactive. Studies using adrenergic and metabolic inhibitors indicate that the regulation of N-acetyltransferase in these cells has the same characteristics of that seen in adult tissue. In addition, these cells synthesize protein and RNA from radioactive precursors, convert tryptophan to serotonin, and N-acetylate endogenous serotonin.

Effects of insulin and streptozotocin–nduced diabetes on brain tryptophan and serotonin metabolism in rats

Abstract: — Previous work by other authors has shown hat insulin administration increases brain tryptophan levels and serotonin (5–HT) metabolism. The present study partially replicates these results and tests whether these effects could be due to insulin-induced hypoglycemic stress, since stressers such as immobilization or food deprivation also increase brain tryptophan and 5-HT metabolism. Ingestion of a dextrose solution by rats administered insulin (2 I.U./kg) prevents the extreme fall in blood glucose concentration and rise in plasma corticosterone following insulin injections alone. This treatment, however, produces a larger increase in brain tryptophan (30%) than insulin-injected rats allowed only tap water. The greater accumulation of brain tryptophan may reflect an additive effect of the endogenously released insulin to that exogenously administered, since ingestion of the dextrose solution could trigger insulin secretion. In addition, brain tryptophan and 5-HT metabolism were measured in streptozotocin-diabetic rats maintained on several different feeding schedules to control for the effects of hyperphagia. All groups of diabetics showed significant decreases of approx 30% in brain tryptophan concentrations, while 5-HT metabolism was unchanged. This deficit in brain tryptophan is reversed within 2 h after insulin administration (2 I.U./kg). These results indicate that changes in brain tryptophan and 5-HT metabolism following insulin injections are not due to hypoglycemic stress, and that brain tryptophan is low in diabetics but increases above normal after administration of insulin. The results are discussed with respect to the effects of insulin on plasma levels of the neutral amino acids and a possible direct effect of insulin on the uptake of tryptophan by brain.

Fenfluramine and brain serotonin.

Abstract: It has been 10 years since Duhalt and Verdavainne and Opitz found a decrease in serotonin [5-hydroxytryptamine (5-HT)I in brain a few hours after injecting animals with fenfluramine (N-ethyl-a-methyl-3-trifluoromethyl-,9phenylethylamine) , a drug used mainly as an anorexigen in man. However, the long-lasting nature of the reduction in brain 5-HT caused by fenfluramine was only recently described.:', .* Brain 5-HT remains below the normal concentration for at least 30 days after a single injection of a high dose, for example, 15 mg/kg, of fenfluramine.:jf4 A similar long-term decrease in brain 5-HT can also be achieved by repeated administration of fenfluramine in smaller amounts, such as 5 mg/kg/day for 5 days.' According to Harvey and McMaster,:' fenfluramine has a neurotoxic action on serotonergic cells of the B9 group, perhaps accounting for the compound's long-lasting effect on brain 5-HT. On the other hand, it would appear that fenfluramine also has prominent effects on serotonergic terminal processes. Pretreatment with chlorimipramine, an inhibitor of the uptake mechanism for 5-HT at the cell membrane,5 prevents the short-term reduction of brain 5-HT caused by fenfluramine.6 Garattini et al.' suggest that chlorimipramine prevents the access of fenfluramine into serotonergic terminals, thereby preventing the reduction in brain 5-HT. Fenfluramine inhibits the uptake and promotes the release of [:jH]-5-HT in vitro, using slices of cerebral cortex,X an area of the brain devoid of serotonergic cell bodies. In this paper, evidence is presented that indicates that the long-term decrease in brain 5-HT results primarily from an action of fenfluramine on serotonergic brain terminals. We show also that the 5-HT uptake inhibitor fluoxetine given after fenfluramine can terminate its action, suggesting that continued uptake for several hours is required for fenfluramine to exert a long-lasting effect on the concentration of 5-HT in the brain. Studies are also included on the relationship of the concentration of fenfluramine and norfenfluramine in brain to the prolonged depletion of 5-HT.

Postsynaptic Serotonin-Sensitive Adenylate Cyclase in the Central Nervous System: I. Development and Distribution of Serotonin and Dopamine-Sensitive Adenylate Cyclases in Rat and Guinea Pig Brain

Abstract: Postsynaptic serotonin-sensitive adenylate cyclase with an apparent affinity of 1 µM for serotonin (5-HT) was detected in various structures of the central nervous system in the rat and the guinea pig. At birth, the regional distribution of this enzyme in the rat brain was closely correlated with the topographical distribution of the serotoninergic innervation in young (9-day-old) as well as adult animals. Electrolytic raphe lesions made on the fourth day after birth, which produced 90% degeneration of serotoninergic innervation in rat colliculi, did not alter the characteristics (apparent affinity and maximal activity) of the serotonin-sensitive adenylate cyclase in this area. This suggests that the serotonin-sensitive adenylate cyclase is associated with postsynaptic serotoninergic receptors in the brain. During development, in both the rat and the guinea pig, the amount of cyclic 39,59-AMP formed in response to an optimal concentration of serotonin in a given area remained constant. This is in contrast to the amount of cyclic AMP formed in response to an optimal concentration of dopamine, which increased 6-fold in the rat striatum between the second and 23rd days after birth. The lack of correlation between the regional distribution of the dopamine-sensitive adenylate cyclase and serotoninergic innervation and between the serotonin-sensitive adenylate cyclase and dopaminergic innervation further emphasizes that the serotonin- and dopamine-sensitive adenylate cyclases are each associated with specific receptors in the rat brain.

Thiamine deficiency Selective impairment of the cerebellar serotonergic system

Abstract: To explore the role of thiamine deficiency in synaptic transmission, the high-affinity uptake and release systems for putative neurotransmitters were studied in synaptosomal preparations isolated from the telencephalon, hypothalamus, and cerebellum of rats made thiamine deficient by diet or pyrithiamine. There was significant decrease in the uptake of serotonin by the synaptosomal preparations of the cerebellum. Although thiamine and its phosphorylated forms added in vitro did not restore the decreased serotonin uptake, the administration of the vitamin in vivo resulted in a significant reversibility of the inhibition of serotonin uptake, coinciding with dramatic clinical improvement. The study supports the possibility of an important serotonergic innervation of the cerebellum and suggests a selective involvement of this system in the pathogenesis of some of the neurologic manifestations of thiamine deficiency.

The effect of serotonin precursors on alpha- and gamma-motoneuron activity.

Abstract: The effects of the 5-hydroxytryptamine (5-HT) precursors, 5-hydroxytryptophan (5-HTP) and tryptophan on alpha- and gamma-motoneuron discharges were examined in the spinal cat with a deafferented cord. The injection of 75 mg/kg of dl-5-HTP resulted in a doubling of the spontaneous discharge rate of gamma-motoneurons and the induction of spontaneous alpha-motoneuron activity. These effects of 5-HTP were reversed by the 5-HT antagonists, cinanserin (4 mg/kg) and methysergide (2 mg/kg). Tryptophan alone (100 mg/kg) exhibited minimal effects of motoneuron activity, but in animals pretreated with pargyline it significantly excited alpha- and gamma-motoneurons. Recordings of alpha- and gamma-motoneuron activity in gastrocnemius and semitendinosus nerves revealed that 5-HTP increased alpha- and gamma-motoneuron activity in both flexor and extensor nerves. Reversal of the effects of 5-HTP by 5-HT antagonists suggests that these effects were mediated by 5-HT. The fact that the 5-HTP effects were observed in preparations with an open gamma-loop indicates that the effects on the alpha-motoneurons are not mediated via the gamma-motoneuron facilitation, but results from a central activation.

Serotonin shifts the phase of the circadian rhythm from the Aplysia eye.

Abstract: A putative neurotransmitter, serotonin, may be used to transmit temporal information in the eye of Aplysia, because it can shift the phase of the circadian rhythm of spontaneous optic nerve impulses from the eye and the eye contains a significant quantity of serotonin. Serotonin acts either directly on the cell, or cells, containing the circadian pacemaker or on cells electronically coupled to the pacemaker cells.

The effect of beta-alanine on motor behaviour, body temperature and cerebral monoamine metabolism in rat.

Abstract: Intracerebroventricular (ICV) injection of beta-alanine produced a decrease in rectal temperature, inhibition of exploratory behaviour and motility, and changes in the metabolism of cerebral monoamines. Dopa and 5-HTP accumulation after inhibition of L-aromatic amino acid decarboxylase, NSD 1015 (3-hydroxybencylhydrazine HCl, 100 mg/kg i.p.) was found to be significantly increased in all the dissected cerebral regions of animals treated with beta-alanine, as compared to the controls. Levels of tyrosine and tryptophan did not show any significant change. Endogenous levels of dopamine (DA), noradrenaline (NA), serotonin (5-HT) and 5-hydroxyindolacetic acid (5-HIAA), did not change. After inhibition of the catecholamines synthesis with alpha-methyltryrosine (alpha-MT), dopamine depletion was retarded and noradrenaline accelerated, but without reaching statistical significance. After intraperitoneal (i.p.) injection of beta-alanine, significant changes in motor behaviour were found. Body temperature and metabolism of brain catecholamine were unchanged. This lack of effect could be explained by poor penetration through the blood-brain barrier.

Iron Deficiency in the Rat: Biochemical Studies of Brain Metabolism

Abstract: Studies were performed to determine the effects of iron deficiency on brain metabolism in rats. Concentrations of cytochrome pigments, oxidative phosphorylation, and catalase and monoamine oxidase activities in brain tissue were unaffected by iron deficiency. However, activities of aldehyde oxidase, a key enzyme in the pathway of serotonin degradation, were significantly reduced, and concentrations of serotonin and total 5-hydroxyindole compounds were elevated in brain tissue of iron-deficient animals. Aldehyde oxidase activities and concentrations of 5-hydroxyindole compounds in brain tissues returned to approximately normal values one week after treatment of iron deficient animals with iron dextran.

Evidence that serotonin mediates some behavioral effects of amphetamine.

Abstract: In the rat, d-amphetamine sulfate (15--80 mg/kg) causes numerous behavioral effects including simultaneous side-to-side head weaving or head tremor, forepaw padding and splayed hindlimbs. These signs are strikingly similar to a behavioral syndrome caused by intense serotonin (5-HT) receptor activation. Experiments were designed to determine whether some of the numerous effects of amphetamine on behavior can be ascribed to actions of the drug on 5-HT mechanisms. Catecholamine depletion with alpha-methyl-p-tyrosine did not prevent the amphetamine syndrome. However, 5-HT depletion with 5,7-dihydroxytryptamine or with p-chlorophenylalanine did prevent the syndrome. The degree of syndrome inhibition by p-chlorophenylalanine was correlated with the extent of 5-HT depletion. Normal responsiveness to amphetamine in p-chlorophenylalanine-treated rats was restored by 5-hydroxytryptophan, the precursor of 5-HT. Furthermore, methysergide, a 5-HT receptor blocker, prevented the amphetamine syndrome, whereas catecholamine blockers, phenoxybenzamine and pimozide, were ineffective. The results suggest that when amphetamine causes the signs of the syndrome it does so by activating 5-HT receptors in the brain, probably by displacement of endogenous 5-HT.

Developmental organization of raphe serotonin neuron groups in the rat.

Abstract: The pre- and early postnatal development of serotonin neurons in the rat brainstem was studied using the fluorescence histochemical method. The technique utilized does not require drug pretreatment to visualize an intense serotonin fluorophore localized in neuronal perikarya, dendrites, and axons. All the serotonin neuron groups develop as bilateral nuclei which extend from the midbrain through the medulla. Six of the nine groups undergo a midline fusion from embryonic day 18 (E 18) through postnatal day 6 (P 6) in a rostrocaudal gradient. Cells of the nucleus raphe dorsalis fuse first (by P 1), whereas the serotonin neurons located in nucleus raphe pallidus do not fuse until P 6. This gradient is comparable to the one described for the first observable fluorescence in the serotonin neurons groups. After final cell division, the serotonin neurons undergo a primary migration from the ventricular zone along the midline, where they are situated during embryogenesis, and a secondary migration extending into postnatal life which concludes with fusion in the midline. The bilateral origins of the serotonin cell groups are maintained in the adult. This is expressed by the apparent ipsilateral projections of some of the raphe neurons determined recently in our laboratory utilizing autoradiographic and horseradish peroxidase techniques.

Angiotensin regulates release and synthesis of serotonin in brain.

Abstract: Angiotensin II released serotonin from neuron terminals and accelerated synthesis of the serotonin. This increase in synthesis depended on the activation of tryptophan hydroxylase. A biphasic effect was observed: at high doses the stimulatory effect depended on conversion of angiotensin II to angiotensin III. At low doses an inhibitory effect was found, possible dependent on an angiotensin II metabolite. These actions represent a subtle regulation of the open-loop serotonin system.

Histochemical, pharmacological and microspectrofluorometric analysis of new sites of serotonin localization in the rat hypothalamus.

Abstract: Histopharmacological and microspectrofluorometric analysis was applied to the rat hypothalamus for the identification of serotonin. Neuronal perikarya, especially certain of those of the endocrinologically important arcuate nucleus, were seen to contain a yellow histofluorescence which possessed spectral characteristics consistent with the serotonin fluorophor. Serotonin was localized also within varicosities of various hypothalamic nuclei, as well as within an ependymally associated network of fibers. Pharmacological administration of the serotonin precursor, tryptophan, resulted in the identification of serotonin histofluorescence and spectra within hypothalamic neurons yielding evidence that these neurons possess the capacity to synthesize serotonin. These newly described cells may be of importance to the regulatin of hypothalamically mediated endocrine function due to their neuroanatomical placement in the medical basal hypothalamus.

Participation of serotonin in the phasic release of luteinizing hormone. II. Effects of lesions of serotonin-containing pathways in the central nervous system.

Abstract: Circadian LH variations were measured in castrated, estradiol-implanted female rats bearing lesions of the raphe nuclei, in which most serotonin (5-HT) containing ascending projections originate, or mediopontine transections interrupting such projections before they enter the hypothalamus. Previous data indicated that pharmacological blockade of 5-HT biosynthesis abolishes the rhythmic pattern of LH secretion; the present study was intended to check whether surgical depletion of hypothalamic 5-HT had a similar effect and whether such abolition could be correlated with hypothalamic or forebrain endogenous concentrations of the amine and of its metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Maximal inhibition of hypothalamic 5-HT and 5-HIAA concentrations were obtained after complete basal mediopontine transections and after lesions of the medial and the dorsal raphe nuclei; under these conditions, the daily variations in plasma LH were reduced by more than 70%. Smaller lesions, even when they completely destroyed the medial raphe, were much less effective. A good correlation was observed between the amplitude of the LH cycle and the extent of hypothalamic, but not of forebrain, 5-HT and 5-HIAA depletion. However, and in contrast to the results of pharmacological 5-HT inhibition, the cyclic pattern of LH secretion could not be totally abolished by any of these surgical procedures. It is concluded that the dorsal raphe contributes to the regulation of rhythmic LH secretion in castrated female rats bearing estradiol implants by modulating the amplitude of this circadian cycle rather than by generating the rhythmic pattern itself.

Evidence for the role of serotonin in the inhibition of specific motor responses.

Abstract: Two behavioural paradigms were used to test the effects of serotonin depletion on a specific form of response inhibition. Treatment with both p-chlorophenylalanine (p-CPA) at 200 mg/kg and lesions of the medial raphe nucleus impaired the acquisition of a step-off passive-avoidance response. The experimental design allowed the elimination of alternative interpretations in terms of increased sensitivity to shock and increased responsiveness to stimuli. p-CPA also impaired response inhibition during an omission-training schedule. The results of the three studies support a general role of serotonin in withholding specific instrumental (reinforced) motor actions. The results contrast with those of studies supporting a role of noradrenaline in response inhibition. A tentative conclusion supports Konorski's (1967) suggestion for differentiation of various types of response inhibition that are mediated by different neurochemical systems.