5HT Turnover Research Articles

Twenty-four-Hour Rhythms of Serum Acth, Prolactin, Growth Hormone, and Thyroid-Stimulating Hormone, and of Median-Eminence Norepinephrine, Dopamine, and Serotonin, in Rats Injected with Freund's Adjuvant

The effect of Freund's adjuvant injection on 24-h variation of circulating ACTH, prolactin, growth hormone (GH), and thyroid-stimulating hormone (TSH) levels, and of norepinephrine (NE) content, and dopamine (DA) and serotonin (5HT) turnover in median eminence, was examined in adult rats kept under light between 0800 and 2000 h daily. Groups of 6–10 animals Freund's complete adjuvant or its vehicle at 1 lOOh 3 days before sacrifice and were killed by decapitation at six different time intervals throughout a 24-h cycle. In rats injected with adjuvant's vehicle, serum ACTH and prolactin exhibited peak values around the light-dark transition (p < 0.0001 and < 0.04, respectively), while the maximum in TSH was found in the late afternoon (p < 0.0001, one-way ANOVA). GH levels did not vary on a 24-h basis. In Freund's adjuvant-injected rats, 24-h variations of TSH levels became blunted, while 24-h variations of prolactin and ACTH persisted. Freund's adjuvant augmented serum ACTH and prolactin levels, and decreased GH and TSH levels (p < 0.0007, factorial ANOVA). Median-eminence NE content, and turnover of DA, assessed by measuring dihydroxyphenylacetic acid, DOPAC/DA ratio, and of 5HT, assessed by measuring 5-hydroxyindoleacetic acid, HIAA/5HT ratio, varied on a 24-h basis in rats receiving adjuvant's vehicle (p < 0.02). Median-eminence NE content attained its maximum at 1600–2000 h, while maxima in DOPA/DA and HIAA/5HT ratios occurred at 0400 h. Injection with Freund's adjuvant reduced the amplitude of the daily variation of NE content, shifted the maximum of DOPAC/DA ratio toward the light-dark transition, and blunted the daily variation in HIAA/5HT ratio in median eminence. The administration at 1200 of the immunosuppressant drug cyclosporine (5 mg/kg, 5 days) restored the augmented ACTH and prolactin levels (p < 0.0001, factorial ANOVA) and depressed GH and TSH levels (p < 0.02) found in Freund's adjuvant-injected rats. Cyclosporine was also effective in restoring 24-h rhythmicity of serum ACTH and TSH, but not of prolactin, levels. Cyclosporine did not modify the effect of Freund's adjuvant on time-of-day changes of median-eminence NE content, but it was effective in counteracting the changes of DA and 5HT turnover found after immunization. The results are compatible with a significant effect of immune-mediated inflammatory response at an early phase after Freund's adjuvant injection on ACTH, GH, prolactin, and TSH release, which is partially sensitive to immunosuppression by cyclosporine. (Chronobiology International, 14(3), 253–265, 1997)

Serotonergic neurotransmission in the spinal cord and motor cortex of patients with motor neuron disease and controls: quantitative autoradiography for 5-HT 1a and 5-HT 2 receptors

Serotonin 5-HT is a potent modulator of motor neuron excitability in the spinal cord. Serotonergic neurotransmission, because of its effects on glutamatergic excitation, may be relevant to the pathogenesis and therapy of motor neuron disease (MND). The human motor system was studied at two levels, spinal cord and motor cortex, by autoradiography for the 5-HT 1A and 5-HT 2 receptor subclasses. In addition, biochemical estimations of indole metabolites were performed in the spinal cord. Post mortem tissue from control cases and MND patients showed a reduction in 5-HT 1A receptor binding in the cervical ( p < 0.01) but not lumbar ventral horn in MND. 5-HT 2 receptors were preserved in the ventral horn at both levels and were focally abundant around motor neuron somata. Tissue levels of 5-HT were unchanged in the spinal cord in MND. The metabolite 5-HIAA was increased in the cervical spinal cord in MND as was the molar ratio of 5HIAA:5-HT, implying that there may be an increased turnover of 5HT. In the motor cortex and premotor cortex the 5-HT 1A receptor remained unchanged in MND. There was a 20% reduction in 5-HT 2 receptor binding sites ( p < 0.05) across all the cortical laminae with preservation of the normal pattern of laminar binding. These changes in two levels of the motor system in MND most likely represent physiological adaptations in the spinal cord and motor cortex rather than primary involvement of the serotonergic system in the pathogenesis of the disease.

Increased turnover of serotonin in children with pulmonary hypertension secondary to congenital heart disease.

Serotonin (5HT) is a potent vasoconstrictor of the pulmonary vascular bed and may be involved in the pathophysiology of secondary pulmonary hypertension in children with a left-to-right shunt due to a congenital heart defect. To test this hypothesis we measured the total and free 5HT concentration in blood as well as the urinary excretion of its main metabolite 5-hydroxyindoleacetic acid (HIAA) in children showing a left-to-right shunt with (n = 10) and without (n = 18) pulmonary hypertension. 5HT and HIAA were also measured in children after corrective cardiac surgery using cardiopulmonary bypass (n = 14) and in controls without congenital heart disease (n = 18). The concentrations of total and free 5HT were not significantly different between controls and patients with a left-to-right shunt. After cardiac surgery total 5HT concentration was significantly reduced by about 65% owing to a postoperatively reduced platelet count. In patients with a left-to-right shunt the total 5HT content was similar in the right atrium (204.0 +/- 17.3 ng/ml), pulmonary artery (189.0 +/- 19.1 ng/ml), and aorta (195.0 +/- 19.3 ng/ml), as was the free 5HT concentration. Therefore no net release of 5HT from platelets occurred between these sampling sites. In patients with pulmonary hypertension, the urinary excretion of HIAA was significantly increased when compared with controls and patients without pulmonary hypertension. It is concluded that turbulent blood flow in children with a left-to-right shunt does not lead to a significant release of 5HT from platelets. However, the increased urinary excretion of HIAA in patients with pulmonary hypertension indicates an increased turnover of 5HT, probably due to an increased number of intrapulmonary neuroepithelial cells or a higher metabolic rate of 5HT within those cells.

Inhibition of MAO-B by (-)-deprenyl alters dopamine metabolism in the macaque (Macaca facicularis) brain.

The present study has examined whether MAO-B has a role in DA metabolism in the primate CNS in situ. Eleven macaques (macaca facicularis) were used in this study to examine the effects of (-)-deprenyl (1 mg/kg, i.v., 2 and 24 hours). (-)-Deprenyl administration completely and selectively blocked MAO-B activity and blocked DA metabolism in the caudate nucleus and frontal cortex. DA metabolism in the substantia nigra was not affected by MAO-B inhibition. Changes in DA metabolism were accompanied by changes in 5-hydroxytryptamine (5HT) turnover: 5-hydroxyindole acetic acid (5HIAA) levels increased in the caudate and decreased in the frontal cortex. Levels of 2-phenylethylamine (PE), a putative modulator of dopaminergic transmission, were increased by MAO-B inhibition in all three brain regions examined. It is concluded that in some regions of the primate brain, in contrast to the rat, MAO-B has an important role in DA metabolism.

Effect of probenecid on 5-hydroxyindoleacetic acid in cisternal cerebrospinal fluid of rats with portacaval anastomosis

Portal-systemic encephalopathy (PSE) is characterized by a neuropsychiatric disorder progressing through personality changes, to stupor and coma. Previous studies have revealed alterations of serotonin and of its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in brain tissue and CSF in experimental (rat) and human PSE. Increased brain 5-HIAA concentrations could result from its decreased removal rather than to increased serotonin metabolism. In order to evaluate this possibility, CSF 5-HIAA concentrations were measured using an indwelling cisterna magna catheter technique at various times following end-to-side portacaval anastomosis in rats (the most widely used animal model of PSE) treated with probenecid, a competitive inhibitor that blocks the active transport of acid metabolites out of the brain and CSF. Following portacaval anastomosis and probenecid treatment, CSF concentrations of 5-HIAA were increased to a greater extent than in sham-operated controls. When data were expressed as per-cent baseline values, the relative increase of CSF 5-HIAA in portacaval shunted rats following probenecid treatment was not significantly different from sham-operated controls. These findings confirm that increased 5-HIAA in the CNS in experimental PSE results from increased 5HT metabolism or turnover and that the probenecidsensitive acid metabolite carrier is intact in PSE.

Acute and chronic effects of fluoxetine and haloperidol on mouse brain serotonin and norepinephrine turnover

Evidence from clinical studies suggests that the noradrenergic system may play a role in the pathophysiology of antidepressant- and neuroleptic-induced akathisia. In limited previous neurochemical research, acute treatment with selective serotonin reuptake inhibitors (SSRIs) has been reported to increase rat brain norepinephrine (NE) turnover or release We have examined the neurochemical effects of 2 hr, 4 day, and 20 day treatment with the SSRI fluoxetine, and the neuroleptic haloperidol, on regional brain monoamine metabolism. Short and long-term fluoxetine treatment produced substantial decreases (to 65–79% of control) in serotonin (5HT) turnover However no effects of fluoxetine on mouse brain NE turnover - as assessed by forebrain, hypothalamus, and hindbrain 3-methoxy-4-hydroxvphenylglycol (MHPG) levels or MHPG/NE ratios - were observed. Acute (2 hr) fluoxetine also did not alter regional NE turnover in rat brain. In contrast, haloperidol tended to increase MHPG levels and MHPG/NE ratios in the mouse brain regions studied The persistence of decreased 5HT turnover during fluoxetine treatment, the lack of an effect of fluoxetine on NE turnover, and the increased NE turnover seen after haloperidol may have important implications regarding drug responsivity and the mechanism of akathisia induction

Dopaminergic modulation of serotonin metabolism in rat striatum: A study with dopamine uptake inhibitor GBR-12909

The dopamine (DA) uptake inhibitor, GBR 12909 (GBR) and a neonatal dopaminergic denervated rat model were used as tools to study the influence of DA on the serotonin (5HT) system in the striatum. The striatal levels of the amines and their acid metabolites (dihydroxyphenylacetic acid, DOPAC; 5-hydroxyindoleacetic acid, 5HIAA) were determined by HPLC. The administration of a single dose (20 mg/kg) of GBR failed to affect the steady-state levels of the amines or metabolites. Repeated administration of GBR (20 mg/kg/day) for 2 or 4 days decreased DA and DOPAC; only the 4-day regimen decreased 5HT and increased 5HIAA levels. The neonatal dopaminergic lesion with 6-hydroxydopamine (6OHDA) depleted (> 95%) DA and DOPAC and increased 5HT and 5HIAA levels in the striatum. Administration of GBR (20 mg/kg/day for 4 days) to lesioned animals failed to influence the lesion-induced increases in 5HT and 5HIAA levels. The results suggest GBR decreases the steady-state levels of DA, resulting in a compensatory increase in the turnover of 5HT that is dependent on the presence of intact dopaminergic terminals. Thus, the effect of GBR on 5HT turnover is indirect. The studies provide further support for a prominent dopaminergic influence on striatal 5HT metabolism.

Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC). BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D1 agonist SKF38393. Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT). In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection. In vitro binding studies showed that BRC exhibited high (Ki values in low nanomolar range) affinities for DA D2A, D2B, D3, alpha 1 and alpha 2 adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT1A receptors. The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D1 receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D1 receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.

Unilateral Destruction of Dopamine Pathways Increases Ipsilateral Striatal Serotonin Turnover in Rats

In order to evaluate the influence of dopaminergic transmission on regional brain utilization of serotonin (5HT), the effects of the destruction of the ascending dopamine (DA) pathways on regional brain 5HT metabolism in the rat were examined. Complete unilateral lesions of the nigrostriatal DA pathways (>90% DA loss) were made by infusing the neurotoxin 6-hydroxydopamine into either the left medial forebrain bundle (MFB) or the left substantia nigra (SN). At 6 weeks after the lesions, levels of 5HT and its major metabolite, 5-hydroxyindoleacetic acid (5HIAA), were determined bilaterally in the striatum, frontal cortex, and hypothalamus. In the striatum of the lesioned hemisphere, the 5HT level decreased by more than 50%, while the ratio of 5HIAA:5HT (an index of 5HT turnover) increased by more than 90%. In the same rats, cortical and hypothalamic 5HT, 5HIAA, and 5HT turnover were not changed as a result of the MFB or SN lesions. These results suggest that the loss of DA innervation in the striatum triggers an increase in 5HT turnover and a net depletion of 5HT in the striatum. To verify that the loss of DA was responsible for the observed striatal 5HT changes, we examined the effect of intracerebral implantation of DA-containing pellets into one group of MFB-lesioned rats, The lesioned rats with placebo pellets did not differ from lesioned rats without pellets, whereas the implantation of DA pellets reversed the lesion-induced changes in the 5HT levels and 5HIAA:5HT ratios. It appears that DA normally acts to inhibit 5HT release in the striatum. Accordingly, the loss of DA innervation results in overactive 5HT transmission, which leads to a net depletion of 5HT stores. As striatal 5HT levels and turnover can be restored to normal by sustained infusion of DA in the lesioned rats, the presence of DA in the striatum appears crucial for the maintenance of normal 5HT function.

Function of the peripheral serotoninergic pathways in migraine: a proposal for an experimental model.

We propose a model for assessing the function of 5HT receptors in migraine by evaluating their expression on monocytes by means of double-labeling fluorocytometry (CD14-positive cells FITC-labeled). This model demonstrates that during headache induced in migraine without aura sufferers given isosorbide dinitrate followed by sumatriptan treatment 5HT expression on monocytes progressively increases. This increase may be due to the activation of 5HT turnover and to the increased availability of 5HT displaced by sumatriptan from cerebrovascular receptors during head pain.

The serotoninergic bulbospinal system and brainstem-spinal cord content of serotonin-, TRH-, and substance P-like immunoreactivity in the aged rat with special reference to the spinal cord motor nucleus.

The 5-hydroxytryptamine (5HT) containing bulbospinal pathway was studied with immunohistochemical (IF) and chemical techniques in 2-3 and 30 months old male Sprague-Dawley rats. The coexisting neuropeptides substance P (SP), thyrotropin-releasing hormone (TRH) and galanin were also analysed. Furthermore, the expression of mRNA encoding aromatic L-amino acid decarboxylase (AADC), prepro-TRH, and preprotachykinin (prepro-SP) was analysed with in situ hybridization (ISH) in the midline raphé nuclei inthe lower brainstem. The results showed a decreased number of axonal 5HT fibers with a normal morphology in the ventral horn of the aged rat lumbosacral spinal cord, and several 5HT immunoreactive (IR) fibers with an aberrant morphology, suggestive of axonal degeneration, were intermingled. This was evident in both the dorsal and ventral horn of the spinal cord. The 5HT-IR fibers with an aberrant morphology usually also contained TRH-and/or SP- and/or galanin-like immunoreactivity (LI) in the ventral horn. These signs of degeneration were clearly less evident in the thoracic and cervical spinal cord segments. Moreover, these changes varied between aged litter-mates. This was in agreement with behavioural signs of motor disturbances, present in about 40% of the aged rats and which in all cases were confined to the hindlimbs. Chemical analyses disclosed significantly lower levels of TRH-LI and, in particular, SP-LI in both the ventral and dorsal quandrants of the spinal cord in the aged rat compared to young adults. The differences were largest in the lumbar regions of the spinal cord. Corresponding analysis of 5HT and 5-hydroxyindoleacetic acid (5HIAA) in the same tissue specimens revealed largely unaltered levels of 5HT and a slight increase in 5HIAA, indicating the possibility of an increased 5HT turnover in the aged rat spinal cord. Neurons in nucleus raphé obscurus and nucleus raphé pallidus were immunoreactive to 5HT, and after pretreatment with colchicine to TRH-, SP-, and galanin-LI as well. There was no obvious difference in number of labeled cells, or labeling intensity, between colchicine-treated young adult and aged rats, although, in the corresponding region of medulla oblongata, chemical analysis disclosed significantly lower levels of 5HT, TRH, and, in particular, SP in untreated aged rats. In contrast, in situ hybridization analysis revealed increased mRNA levels encoding prepro-TRH and prepro-SP in old rats, while mRNA content encoding AADC mRNA was similar in young adult and aged rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Modulation of 5HT 1A receptors in the hippocampus and the raphe area of rats treated with clonazepam

1. Clonazepam is one of the most potent benzodiazepines known to decrease the activity of the central serotonergic systems. The acute and subchronic administration of clonazepam reduced serotonin (5HT) turnover rate in the hippocampus of the rat, as determined by the ratio of the monoamine and its metabolite, 5-hydroxyindoleacetic acid. 2. The modulation of 5HT binding sites and 5HT 1A receptors by the administration of clonazepam for various periods of time were studied in the hippocampus and the raphe area by experiments with radialigands. 3. The density of [ 3H]5HT recognition sites increased in the hippocampus of clonazapam-treated rats in a dose- and time-dependent manner. This increase was impaired by the simultaneous administration of the 5HT agonist 5-methoxy- N, N-dimethyltryptamine. The affinity of this binding did not significantly change. This observation might indicate an increase in some of the SHT receptors or an increase of the uptake site. 4. The binding parameters for [ 3H]DPAT, B max and K d, decreased in the hippocampus but not in the raphe area of clonazepam-treated rats. It seems that the presynaptic reduction in 5HT function, resulting in the decrease of its availability at the synaptic space, modifies the corresponding 5HT recognition sites. 5. These changes could be related to the anxyolitic activity or the withdrawal symptoms of benzodiazepines.

Changes induced by sodium cromoglycate on brain serotonin turnover in morphine dependent and abstinent mice.

This study was designed to explain the action of sodium cromoglycate (CRO) on the brain serotonergic system in control, morphine tolerant (by SC implantation of a 75 mg morphine pellet), and also in morphine dependent mice just before naloxone-precipitated withdrawal. After SC injections of CRO in control mice, morphine tolerant mice (day 4 of addiction), and 1 h before abstinence (withdrawal was induced by SC injection of 1 mg/kg naloxone on day 4 of addiction), animals were decapitated and various brain areas were rapidly removed. 5HT (Serotonin) and 5HIAA (5-hydroxyindole-3-acetic acid) were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD). The ratio 5HIAA/5HT provided one index by which the turnover of the indoleamine was measured. CRO increased the turnover of 5HT in most of the brain areas studied in both control and morphine dependent mice. Furthermore, previous administration of CRO prior to naloxone challenge induced a significant increase in the 5HIAA/5HT ratio in the hypothalamus and striatum. These results are discussed as the reason for the preventive effect of CRO on jumping behaviour in morphine abstinent mice.

Exercise training: Significance of regional alterations in serotonin metabolism of rat brain in relation to antidepressant effect of exercise

Alterations of 5HT and its chief metabolite 5HIAA were studied in four regions of the rat brain following acute 1-h swim exercise and 4 week chronic swim exercise (30 min/day, 6 days per week). Acute exercise significantly increased the synthesis and metabolism of 5HT in brain stem. Hypothalamus also showed increased levels of 5HT. However, no changes were observed in the cerebral cortex and hippocampus. Chronic exercise activated not only the synthesis but also the metabolism of 5HT in the cerebral cortex; this neuronal adaptation was sustained even 1 week after the termination of training. In brain stem, increased 5HT turnover was observed immediately after training. In hypothalamus, decrease in 5HT and 5HIAA levels occurred immediately after training, followed by a rebound increase in their levels after 1 week posttraining rest. In hippocampus, a delayed effect was observed, because 5HT level was unaltered immediately after the training, but its turnover decreased after 1 week rest. These findings have been discussed in an attempt to explain the antidepressant effect of exercise based on the 5HT deficiency theory of endogenous depression.

Hypothalamic monoamine turnover in ring doves ( streptopelia risoria), courting, incubating and brooding young

1. The turnovers of hypothalamic 5-hydroxytryptamine (5HT), dopamine (DA) and noradrenaline (NE) were measured in male and female ring doves ( Streptopelia risoria) at three stages of the breeding cycle: courtship, 3 days after pairing; early incubation, 1–2 days after egg laying; and brooding, 1–3 days after the squabs had hatched. 2. In both sexes plasma LH decreased progressively from courtship through incubation to brooding young. Crop sacs were fully developed in doves brooding young but not at other stages of the reproductive cycle, indicating increased concentrations of plasma prolactin. 3. The turnovers of 5HT and DA in both sexes were significantly higher ( P<0.001) in doves brooding young than in birds incubating eggs or nest building. The turnover of DA was higher in females than in males at the onset of incubation. The turnover of NE was lower ( P > 0.01) in females at the onset of incubation than during courtship or brooding. 4. Increased turnover of hypothalamic DA may be more closely related to brooding behaviour than to changes in prolactin or LH secretion. 5. Increased hypothalamic 5HT turnover in brooding doves appears to be more directly related to crop sac development, and by inference increased prolactin secretion, than to depressed plasma LH concentrations.

Serotonin and dopamine turnover in the female rainbow trout ( Oncorhynchus mykiss) brain and pituitary: Changes during the annual reproductive cycle

Brain serotonin (5HT) and dopamine (DA) turnover were studied at various stages of the reproductive cycle of the female rainbow trout by simultaneous determination by HPLC of neurotransmitters and major related metabolites. An increase of 5HT turnover in telencephalon and hypothalamus and a decrease of DA turnover in pituitary and hypothalamus were observed during the periovulatory period. Some changes also occurred during vitellogenesis: decreased 5HT metabolite in telencephalon and preoptic area and increased DA content in preoptic area. These data suggest that physiological fluctuations of biogenic amines could be involved in both ovarian recrudescence and ovulation, with major effects on the hypothalamo-hypophysial complex during the periovulatory period.

Region-selective reduction of brain serotonin turnover rate and serotonin agonist-induced behavior in mice treated with clonazepam

Evidence supports a complex interaction between benzodiazepines and the central serotonergic system. This study attempts to correlate biochemical changes in the serotonin (5HT) system induced by clonazepam (CLON) with the behavioural response to a 5HT agonist. The acute administration of CLON to mice produced a time-dependent decrease in 5HT turnover rate in the raphe area (dorsal and medial raphe nuclei) and modified the serotonergic syndrome induced by 5-methoxy-N,N,-dimethyltryptamine (DMT). One hour after CLON administration, a dose-dependent increase in 5HT concentration was found in the raphe area, while 5-hydroxyindoleacetic acid (5HIAA) levels remained stable, leading to an increase in 5HT/5HIAA ratio, indicative of reduced 5HT turnover rate. No significant changes were detected in the frontal cortex of CLON-treated mice. After 4 days of CLON treatment, the 5HT turnover rate was still decreased in the raphe area and unchanged in the frontal cortex. Acute CLON administration produced dose-dependent alterations in locomotor activity, not observed after subchronic administration. Lateral head weaving, a motor manifestation of the serotonergic syndrome produced by DMT, was less intense in CLON-treated animals. The modifications in the 5HT system induced by CLON are region selective, suggesting differences in the receptors implicated in the interaction. Altered synaptic availability of 5HT as a result of CLON administration may be responsible for the differential response to DMT in control and CLON-treated mice.

Pre-weaning non-handling of rats disrupts latent inhibition in males, and results in persisting sex-and area-dependent increases in dopamine and serotonin turnover

Pre-weaning "handling" of rat pups (1-21 days) is reported to result in a number of behavioural differences from "nonhandled" pups, persisting into adult life. In general, these are associated with altered emotional reactivity. We now report the results of a replication of a previous finding that handling also affects performance on a latent inhibition (LI) task, which involves learning in the absence of motivation. The effect of 30 pre-exposures to a tone stimulus on the formation of an association from two pairings between that stimulus and footshock was determined. The association was indexed by the suppression of licking resulting from tone presentation during licking for water reward. In adult female rats, pre-exposure prevented the formation of this association (i.e. LI was present) whether they had been handled or nonhandled pre-weaning. However in adult males, pre-exposure was effective only in handled rats, and not in nonhandled. This confirms the striking pattern of results reported previously by another group (Weiner et al., 1987). The turnover of dopamine (DA) and serotonin was subsequently determined post mortem from the ratios of metabolites to amines in DA-innervated brain areas of the rats used in the present study. Pre-weaning nonhandling and female sex, were independently associated with increased dopamine turnover, and to a lesser extent with increased serotonin turnover. While these increases were not sex-specific, nonhandled males did show a pattern of increased DA turnover relative to serotonin turnover in limbic areas; previous pharmacological and physiological studies support the idea that this pattern may be associated with impairment of LI. It is concluded that preweaning nonhandling is indeed associated with an impairment of LI restricted to males, and is associated with enduring changes in DA and 5HT turnover in both sexes. Further studies are indicated to determine the precise role of these changes in the behavioural effects of pre-weaning nonhandling.

Regional serotonin and dopamine activity: Sensitivity to amphetamine and aggressive behavior in mice

We were interested in comparing the effect of distinctive attack and defeat experience on regional monoamine turnover and on d-amphetamine (AMPH) sensitivity. Male mice were randomly assigned to groups that received zero, one, or ten defeat experiences or that attacked an intruder zero, one, or ten times. Twenty-four hours after the last attack or defeat, mice were administered one of four AMPH doses (0, 0.1, 1.0, or 10.0 mg/kg i.p.) and tested in a resident-intruder confrontation. A separate group of mice were sacrificed immediately after the last attack or defeat. Using the high-performance liquid chromatography (HPLC) technique, dihydroxyphenylacetic acid (DOPAC):dopamine (DA) and 5-hydroxyindolacetic acid (5HIAA):serotonin (5HT) were measured in micropunched sections of the corpus striatum, amygdala, and nucleus accumbens. A single defeat decreased DA turnover in the amygdala, whereas one attack experience increased DA and 5HT turnover in the n. accumbens and amygdala, respectively. AMPH sensitivity was enhanced following acute defeat. In animals that had repeated agonistic experience, acute attack or defeat did not alter DOPAC:DA or 5HIAA:5HT ratios. Mice with attack experience were more sensitive to AMPH following multiple rather than a single aggressive encounter. The distinct effects of defeat and attack experience on mesolimbic DA activity and on AMPH sensitivity suggest that monaminergic fibers terminating in the n. accumbens can be functionally dissociated from fibers terminating in the amygdala.

Diabetes mellitus: Stress, neurochemistry and behavior

Neurochemical alterations in several rodent models of insulin-dependent diabetes are compared and their relevance to behavioral and physiological pathology in the clinical disorder is discussed. In the majority of rodent models, reductions in metabolism of norepinephrine (NE), dopamine (DA) and serotonin (5HT) in the central nervous system (CNS) have been reported. While there are two reports of increased 5HT turnover in CSF or post-mortem brains of diabetic humans experiencing severe ketoacidosis, these patients were receiving insulin therapy. Insulin appears to have effects on monoamines opposite to that of chronic hyperglycemia. Both in rodent models and in clinical populations, there is widespread evidence of enhanced hormonal and behavioral responsiveness to stress. There are findings in rodent models indicating that hormonal responses to stress are related to CNS monoamine activity. The mechanisms responsible for both hormonal and CNS alterations in diabetes, as well as their involvement in behavioral pathology, can best be investigated further using animal models.