Increased Serotonin Turnover Research Articles

Reboxetine attenuates forced swim test-induced behavioural and neurochemical alterations in the rat

The forced swim test is a behavioural paradigm that is predicative of antidepressant activity in rodents. Until recently, research has focused on the ability of antidepressant drugs to decrease immobility in the forced swim test paradigm, but the neurochemical sequelae induced by swim stress, or the neurochemical basis of antidepressant-induced behavioural changes have received little attention. In this regard, we have recently demonstrated that forced swim test exposure increases serotonergic activity in the amygdala, frontal cortex and hippocampus and dopamine turnover in the striatum. In addition, forced swim test-exposure activates the hypothalamic pituitary adrenal axis. The purpose of the present study was to examine the effect of treatment with the selective noradrenaline reuptake inhibitor reboxetine (3, 10 and 30 mg/kg; i.p.) on immobility and defaecation scores in the forced swim test, and on forced swim test-induced neurochemical and hypothalamic pituitary adrenal axis changes in the rat. Reboxetine treatment (10 and 30 mg/kg) significantly decreased immobility and defaecation in the forced swim test in dose dependent manner. Furthermore, reboxetine produced a dose dependent attenuation of forced swim test-induced increases in serotonin turnover in the amygdala and frontal cortex and dopamine turnover in the striatum. Reboxetine (30 mg/kg) produced a modest, but non-significant, attenuation of forced swim test-induced increases in serum corticosterone concentrations. These data demonstrate that, in addition to the behavioural activity of reboxetine in the rat forced swim test paradigm, a dose-dependent attenuation of swim stress-induced increases in serotonergic and dopaminergic activity occurred in a region specific manner. These are the first data to demonstrate that treatment with the selective noradrenaline reuptake inhibitor, reboxetine can impact on the activity of other neurotransmitter systems in response to stress. Moreover, these data further demonstrate that this paradigm is a valuable tool in studying the effect of antidepressants, on both behaviour and swim stress-related alterations in central neurotransmitter function and hypothalamic pituitary adrenal axis activity in the rat.

Adrenocortical suppression blocks the enhancement of memory storage produced by exposure to psychological stress in rats

Several reports have indicated that various stress stimuli modulate learning and memory processes. In the present study, the effects of adrenocortical suppression with the 11β-hydroxylase inhibitor metyrapone on the psychological stress-induced changes in memory storage in inhibitory avoidance training and in serotonin turnover in various brain regions were investigated in rats. Retention of one-trial inhibitory avoidance and the plasma corticosterone level were significantly enhanced by post-training exposure to psychological stress for 1 h. Pretreatment with metyrapone (12.5 or 25 mg/kg, s.c.) 90 min beforehand dose-dependently blocked the enhancement of memory storage and of the plasma corticosterone level produced by psychological stress. These results suggest that the adrenocortical system may contribute to the memory-enhancing effect of psychological stress. In a neurochemical study, a significant increase in serotonin turnover in the hippocampus and limbic forebrain, including the nucleus accumbens, were observed in rats that were exposed to psychological stress. In contrast to the behavioral experiments, these changes in serotonin turnover produced by exposure to psychological stress were not antagonized by pretreatment with metyrapone; instead, a further increase in serotonin turnover was observed only in the hippocampus. These results suggest that the serotonergic system in the hippocampus might be selectively regulated by adrenal steroids in response to stress, and imply the existence of negative feedback mechanisms via a hippocampal serotonergic system in the memory enhancement associated with corticosterone and psychological stress.

Morphine tolerance in arthritic rats and serotonergic system

To understand whether chronic inflammation alters the development of morphine tolerance, the tail-flick test was used to evaluate the analgesic effect of morphine (75 mg tablet, s.c.) in the arthritic rats at the day 9–12 after the inoculation with Freund's adjuvant. Spinal cord monoamines and amino acid neurotransmitters were concomitantly measured. Chronic inflammation attenuated the antinociceptive effect of morphine as tolerance developed faster in the arthritic rats compared to the vehicle-treated controls. In addition, ratio of 5-hydroxyindole-3-acetic acid/5-hydroxytryptamine (5-HIAA/5-HT) increased in the lumbar spinal cord of arthritic rats without any change in the concentrations of norepinephrine, glutamate, aspartate or GABA. Interestingly, increased serotonin turnover in the spinal cord was observed in both control and arthritic rats 24 hours after morphine treatment. Overall, the results suggest a significant role of serotonin up-regulation in the spinal cord during chronic pain and the development of morphine tolerance.

Effect of Tryptophan Treatment on Self-Biting and Central Nervous System Serotonin Metabolism in Rhesus Monkeys (Macaca mulatta)

Two studies were conducted to examine the effects of oral L-tryptophan (TRP) supplementation as a treatment for self-injurious behavior (SIB) and to investigate behavior and central serotonin turnover of male rhesus monkeys. In Study One, TRP was administered to seven individually housed rhesus monkeys with a recent history of spontaneous SIB. While the monkeys were on TRP treatment (100 mg/kg twice a day), cisternal cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid increased markedly (p=.0013) above baseline (baseline mean=207.6 pmol/ml ± 39; TRP mean=320.3 pmol/ml ± 83.4) , and the duration of self-biting behavior decreased below baseline (p=.03) . In Study Two, 14 individually housed rhesus monkeys without a history of SIB were placed on three different doses of TRP in random order (50, 100, and 200 mg/kg twice a day). TRP had no effect on any behavioral or biochemical variables in the normal monkeys. Conclusions: Supplemental tryptophan in well-tolerated doses reduced self-biting and increases serotonin turnover rate in male monkeys with a recent history of SIB. The same doses of TRP do not affect behavior or serotonin metabolism in male monkeys without a history of SIB.

Age-related decline in emotional adaptability to short-term stressful situation: The participation of the monoaminergic nervous systems in the cerebral limbic system

The relationship between emotional stress adaptability and amine dynamics in serotonergic, noradrenergic or dopaminergic nervous systems in the cerebral limbic system was investigated in young (10 weeks old) and aged (110 weeks old) rats. The appearance of emotional stress responses such as struggling behavior and vocalization in both young and aged rats was caused by exposure to acute restraint stress. During exposure to acute restraint stress for 1 h, the appearance of these responses in young rats decreased time-dependently, but the struggling behavior of aged rats was constant throughout the exposure. After exposure to acute restraint stress, the serum corticosterone concentration in young and aged rats was significantly increased. Also, a significant increase in serotonin turnover (5-hydroxyindole-3-acetic acid/serotonin) was observed in the amygdala (AM), hippocampus (HC) and septum (SE) of the young rat brain, but this neurochemical change was not observed in these regions of the aged rat brain. Furthermore, in the AM, HC and SE of young rats, norepinephrine turnover (4-hydroxy-3-methoxyphenylglycol/norepinephrine) was significantly increased by exposure to acute restraint stress. Norepinephrine turnover in the AM and SE of aged rats was increased, but was unaltered in the HC. On the other hand, acute restraint stress had no effect on dopamine turnover (3,4-dihydroxyphenyl acetic acid/dopamine) in the AM, HC or SE of either young or aged rats. These findings suggest that emotional adaptability to acute restraint stress declines age-dependently. Also, the decreases in serotonergic nervous activities in the cerebral limbic system and noradrenergic activities in the HC may be related to the decline of emotional stress adaptability.

Antagonism of central CRF systems mediates stress-induced changes in noradrenaline and serotonin turnover in rat brain regions.

The present study was conducted to test the hypothesis that central corticotropin-releasing factor (CRF) systems mediate the changes in the dynamics of brain noradrenergic and serotonergic systems induced by electric footshock stress. Serum corticosterone concentrations were determined fluorometrically and brain monoamine contents (noradrenaline, serotonin and their metabolites) in five brain regions in rats were measured by high-performance liquid chromatography with electrochemical detection 10 and 40 min after exposure to electric footshock stress for 1 hour. Intracerebroventricular administration of a CRF antagonist, alpha-helical CRF (100 micrograms), had no effect on serum corticosterone concentrations in either normal or stressed animals. However, electric footshock stress-induced increases in noradrenaline turnover were significantly reduced by the administration of alpha-helical CRF9-41, in the amygdala and septum at both time points after exposure to electric footshock stress. In contrast, electric footshock stress-induced increases in serotonin turnover in all of the brain regions were further elevated by the administration of alpha-helical CRF 9-41, in almost all of the brain regions examined. These results suggest that central CRF neuronal systems are involved in mediating the electric footshock stress-induced changes in the dynamics of brain noradrenergic and serotonergic systems in rats.

Phencyclidine Increases Forebrain Monoamine Metabolism in Rats and Monkeys: Modulation by the Isomers of HA966

The noncompetitive NMDA receptor antagonist phencyclidine (PCP) has psychotomimetic properties in humans and activates the frontal cortical dopamine innervation in rats, findings that have contributed to a hyperdopaminergic hypothesis of schizophrenia. In the present studies, the effects of the enantiomers of 3-amino-1-hydroxypyrrolid-2-one (HA966) on PCP-induced changes in monoamine metabolism in the forebrain of rats and monkeys were examined, because HA966 has been shown previously to attenuate stress- or drug-induced activation of dopamine systems. In rats, PCP (10 mg/kg, i.p.) potently activated dopamine (DA) turnover in the medial prefrontal cortex (PFC) and nucleus accumbens. Serotonin utilization was also increased in PFC. Pretreatment with either R-(+)HA966 (15 mg/kg, i.p.) or S-(-)HA966 (3 mg/kg, i.p.) partially blocked PCP-induced increases in PFC DA turnover, whereas neither enantiomer altered the effect of PCP on DA turnover in the nucleus accumbens or the PCP-induced increases in serotonin turnover in PFC. PCP (0.3 mg/kg, i.m.) exerted regionally selective effects on the dopaminergic and serotonergic innervation of the monkey frontal cortex, effects blocked by pretreatment with S-(-)HA966 (3 mg/kg, i. m.). Importantly, these data demonstrate that in the primate, PCP has potent effects on dopamine transmission in the frontal cortex, a brain region thought to be dysfunctional in schizophrenia. In addition, a role for S-(-)HA966 as a modulator of cortical monoamine transmission in primates is posited.

Cell Body Infusions of Brain-Derived Neurotrophic Factor Increase Forebrain Dopamine Release and Serotonin Metabolism Determined with in Vivo Microdialysis

Publisher Summary The survival and phenotypic expression of a variety of cultured central nervous system neurons, including dopaminergic and serotonergic neurons are promoted by brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). Chronic infusions of BDNF or NT-3 above the rat pars compacta elevate spontaneous or amphetamine-stimulated locomotor behaviors and increase neostriatal dopamine and serotonin metabolism. BDNF or NT-3 infusions to the rat dorsal raphe nucleus also increase serotonin turnover in the nucleus accumbens, caudate-putamen, and other forebrain regions. Nigral infusions of BDNF produce a 42% increase in the spontaneous release of dopamine above that of PBS-infused animals and smaller (16-22%), nonsignificant elevations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Nigral NT-3 infusions produce a 22%, nonsignificant elevation in dopamine release and 17-18%, nonsignificant increases in DOPAC and HVA compared with animals infused with phosphate-buffered saline (PBS). Raphe infusions of BDNF produce a 13% nonsignificant increase in nucleus accumbens serotonin dialysis and a doubling of 5-HIAA. As nigral infusions of NT-3 do not augment striatal dopamine release, and because BDNF augments basal but not amphetamine-stimulated dopamine release, the effects of these nigral infusions on spontaneous and amphetaminestimulated behaviors cannot be explained solely by actions on nigrostriatal dopamine neurons. Midbrain infusions of BDNF have little effect on serotonin release, even though they doubled serotonin metabolism before and after amphetamine challenge. BDNF infusions produce a somewhat greater elevation in serotonin release during p-chloramphetamine (PCA). In the basal state, these increases may be masked by efficient serotonin reuptake and intracellular degradative mechanisms, that would explain the large increase in 5-HIAA produced by BDNF.

Dopamine, serotonin and tachykinin in self-injurious behavior

The neurobiologic basis of self-injurious behavior (SIB) in Lesch-Nyhan syndrome and in other neuropsychiatric conditions remains unclear. The purpose of this review is to summarize recent data concerning SIB induced by the dopamine (DA) uptake inhibitor, GBR-12909 (GBR) and to compare the neurochemical data that have accumulated over the years on SIB in neonatal 6-hydroxydopamine (6OHDA) lesioned rats. The DA uptake inhibitor, GBR, upon repeated administration to adult rats elicits SIB that is temporally associated with a reduction of striatal DA (3̃0%), increased turnover of serotonin and a robust induction of tachykinin transcription resulting in enhanced biosynthesis and presumably release of tachykinins (substance P and neurokinin A). GBR-induced SIB could be blocked by dopaminergic lesions or by D1 or D2 antagonists. Neonatal dopaminergic lesions resuit in a high degree of DA loss (>90%) and elevated levels of serotonin. In this model, SIB is precipitated by DA agonists via activation of Dl DA receptors which are in turn linked to an induction of tachykinin biosynthesis and release. The data taken together suggest that (a) a substantial reduction of DA accompanied by an increase in serotonin turnover may be essential conditions that are conducive to the occurrence of SIB, and (b) this phase is either superimposed with, or followed by a D1 and/or D2 DA receptor-linked activation of striatonigral tachykinin neurons resulting in enhanced tachykinin biosynthesis and release that may sustain the SIB. Thus, a dynamic interplay between DA, serotonin and tachykinin neuronal Systems of the basal ganglia appear to influence the genesis and/or expression of SIB.

Brain Monoaminergic, Neuroendocrine, and Immune Responses to an Immune Challenge in Relation to Brain and Behavioral Lateralization

Host responses to immune challenges involve central neurotransmission, the hypothalamo-pituitary adrenal axis, and the immune system. In the present work, we investigated the possibility of an asymmetry in the modification of brain monoamine metabolism induced by a systemic injection of lipopolysaccharide (LPS) in adult female mice. We also studied the possible influence of behavioral lateralization, as assessed by a paw preference test, on the reactivity of the nervous, neuroendocrine, and immune systems to a LPS challenge. The results showed that LPS administration induced an enhanced brain activity as demonstrated by an increase in noradrenergic, serotoninergic, and dopaminergic metabolism. Increased serotonin metabolism, observed in the hypothalamus and hippocampus, only occurred on the left side. Furthermore, the increase in serotonin turnover in the medial hypothalamus, the elevation of plasma adrenocorticotropin levels, and the decrease in T lymphocyte proliferation were observed in right-handed and ambidextrous mice but not in left-handed animals. Taken together, the results demonstrate that an immune challenge could induce neurochemical, neuroendocrine, and immune responses similar to those of stress, suggesting that LPS may be a stress inducer. Interestingly, these responses that may be asymmetrically expressed appear to depend on behavioral lateralization.

Amylin increases transport of tyrosine and tryptophan into the brain

Injection of amylin (diabetes-associated peptide) into the hypothalamus induces anorexia, increases brain metabolism of dopamine and serotonin and elevates brain level of tryptophan. When male Sprague-Dawley rats were treated with 50 mg/kg l-tryptophan and l-tyrosine ethyl ester 30 min prior to the intrahypothalamic injection of 2 μg amylin, brain tryptophan and tyrosine levels were selectively increased as compared to rats treated with amylin alone. Hypothalamic and striatal serotonin metabolism also appeared to be increased following the amino acid-amylin treatment combination. These results suggest that amylin may increase transport of tyrosine and tryptophan into the brain, and that the increased availability of tryptophan may contribute to increased serotonin turnover observed following intrahypothalamic amylin treatment.

Effect of PCPA or tryptophan on brain serotonin and on consumption of a high protein or high carbohydrate diet by rainbow trout, Oncorhynchus mykiss

The effect of increased or decreased brain serotonin on consumption of a high protein or a high carbohydrate diet by rainbow trout, Oncorhynchus mykiss, was evaluated. Groups of rainbow trout were acclimated to either a high protein or a high carbohydrate diet for 6 weeks. Fish then received a dietary pretreatment meal containing 5% p-chlorophenylalanine, which decreased brain 5-HT and 5-HIAA, or 7% crystalline tryptophan, which increased brain 5-HIAA and 5-HIAA/5-HT. Intake of a challenge meal (high protein or high carbohydrate, consistent with the diet to which they had been acclimated) was then determined. Food consumption by fish fed the high protein diet was unaffected by either dietary pretreatment meal. Conversely, both p-chlorophenylalanine and tryptophan pretreatment decreased food consumption by fish fed the high carbohydrate diet. These results suggest that changes in brain serotonin turnover in rainbow trout are not important in controlling intake of a high protein diet. Furthermore, because consumption of the high carbohydrate diet was decreased both by p-chlorophenylalanine, which decreased serotonin turnover, and by tryptophan, which increased serotonin turnover, this also suggests that serotonin turnover may not be an important signal controlling consumption of high carbohydrate diets by rainbow trout.

Changes in CSF neurotransmitters in infantile spasms

Cerebrospinal fluid (CSF) from 7 patients with infantile spasms (mean age: 6.7 months) was collected before and after treatment with adrenocorticotropic hormone (ACTH). The concentration of neurotransmitter metabolites was analyzed using high-performance liquid chromatography and compared to the metabolite concentration in the CSF from 7 age-matched controls (mean age: 6.1 months). Pretreatment levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid, 3-methoxy-4-hydroxyphenyl glycol (MHPG), and kynurenine were significantly lower in infantile spasm patients compared to controls. Following treatment, marked increases in 5-HIAA and decreases in kynurenine levels were observed in the CSF of the 5 infants whose seizures were eliminated or reduced by ACTH. In the 2 nonresponders 5-HIAA levels decreased. The level of MHPG was reduced slightly in 5 infants, including the 2 nonresponders, and was increased in 2 responders. CSF homovanillic acid levels increased in 4 infantile spasm infants and decreased in 3 following ACTH. These data demonstrate that the presence of seizures in infantile spasms is associated with a significant decrease in serotonergic activity and that elimination of seizures by ACTH is accompanied by increased serotonin turnover. The simultaneous increase of 5-HIAA and decrease of kynurenine, an alternate metabolite of tryptophan, suggests an underlying disturbance of tryptophan metabolism in infantile spasms. The possibility that elimination of seizures by ACTH may be related to decreased production of certain kynurenine metabolites, particularly quinolinic acid, is discussed.

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.

Hypothyroidism increases serotonin turnover and sympathetic activity in the adult rat

Adult, male Sprague-Dawley rats underwent surgical thyroidectomy (Tx) or sham surgery. In all three experiments from which data are reported, a 3-week recovery period was allowed. In experiments I and II, baseline measurements of colonic temperature (Tc) and urinary norepinephrine excretion (NE) were obtained, and both variables were monitored daily for the duration of the studies. After baseline measurements, half of each surgical group was given either triiodothyronine (T3) or vehicle injections subcutaneously; in experiment I replacements continued for 1.5 days, while in experiment II T3 replacement continued for 3.5 days. Rats were decapitated at the end of each experiment and serotonin (5-HT) turnover was measured in brainstem. Serotonin turnover in rostral and caudal brainstem was increased with Tx (p less than 0.05). Increased turnover in caudal brainstem was normalized by T3 only in experiment II. Similarly, decreased Tc and elevated NE with Tx were normalized in experiment II but not in experiment I. In experiment III, NE measurements normalized on a creatinine excretion basis indicated that increased NE is evident with Tx, irrespective of normalization procedure. Significant correlations between 5-HT in caudal brainstem and metabolic correlates of sympathetic function, concurrent normalization of NE and 5-HT in caudal brainstem, plus work from other laboratories describing sympathoexcitatory serotonergic neurons located in the caudal brainstem suggest that the central and peripheral changes in the hypothyroid rat are causally related.

Inhibition of phosphoenolpyruvate carboxykinase activity appears to be the key biochemical lesion in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in rats

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its acute toxicity by inducing a gradually increasing voluntary feed refusal. However, this seems not to be caused by a direct effect on the central nervous system, as far higher concentrations of TCDD were found in the brain after intracerebroventricular (i.c.v.) than after lethal intravenous (i.v.) injections, but were not accompanied by a wasting syndrome. TCDD causes inhibition of several key enzymes of gluconeogenesis, with phosphoenolpyruvate carboxykinase (PEPCK) responding earliest and strongest to the insult. Responses of pyruvate carboxylase (PC) and glucose-6-phosphatase (G-6-Pase) are less pronounced and begin at later time points. Blood and brain levels of tryptophan increase following TCDD treatment with a lag period of about three days, shortly after the decrease of PEPCK activity becomes apparent. Since thi samino acid is the precursor of the appetite suppressant neurotransmitter serotonin, and since it is normally degraded via gluconeogenesis, a series of events can be suggested to explain the TCDD-induced wasting syndrome. By an as yet unrevealed mechanism TCDD decreases the activity of PEPCK to about 40 percent of normal, leading to a back-up of gluconeogenic substrates, among them tryptophan, which in turn can further inhibit PEPCK activity in vivo. This causes an increase in serotonin turnover in brain and possibly in other tissues. Increased serotonergic activity in turn is likely to play an important role in the increasing feed refusal of TCDD-treated rats which eventually leads to death.

Elevation of dopamine D 2 but not D 1 receptors in adult rat neostriatum after neonatal 6-hydroxydopamine denervation

Monoamine levels and the binding properties of [ 3H]SCH23390, a D 1-specific ligand, and [ 3H]raclopride, a D 2-specific ligand, were measured in the rostral and caudal neostriatum to investigate the fate of dopamine receptors following bilateral cerebroventricular injection of 6-hydroxydopamine in 3-day-old rats. After survival times of 15, 30 or 90 days, measurement of monoamine levels and of [ 3H]SCH23390 binding were also obtained from the cerebral cortex. At all three survival times, dopamine content was reduced by more than 90% of control values in both the rostral and caudal neostriatum; in cerebral cortex, the dopamine depletion was less profound (80%) and noticeable only after 1 and 3 months. In the rostral but not the caudal neostriatum, serotonin and 5-hydroxyindoleacetic acid concentrations were markedly increased at 1 and 3 months; cortical serotonin also was augmented at 3 months. There were no changes in neostriatal [ 3H]SCH23390 binding at any of the survival times, but a transient elevation occurred in the cortex at 1 month. In the rostral but not the caudal neostriatum, [ 3H]raclopride binding showed a slight elevation at 1 month and a further, highly significant increase at 3 months. As measured in individual rats, this increase in [ 3H]raclopride binding was linearly correlated with the increase in serotonin turnover (ratio of 5-hydroxyindoleacetic acid/serotonin). Such an up-regulation of D 2 receptors, restricted to the rostral neostriatum which was also the site of a serotonin hyperinnervation, was probably indicative of a serotonin control on the expression of D 2 receptors after dopamine denervation.

Chronic exposure to low doses of MPTP. II. Neurochemical and pathological consequences in cognitively-impaired, motor asymptomatic monkeys

Chronic low-dose MPTP exposure was previously found to impair cognitive performance in monkeys. These monkeys developed deficits in performance of delayed response and delayed alternation tasks but maintained performance on visual pattern discrimination. This, along with other subtle behavioral changes, occured in the absence of gross parkinsonian motor symptoms. The present study reports the results of neurochemical and neuropathological examination of the brains of these animals. Chronic low-dose MPTP exposure resulted in profound decreases in caudate dopamine (DA) levels and slightly less severe depletions in the putamen. Increases in striatal HVA/DA ratios suggest an increase in DA turnover in these areas. In contrast to striatal DA depletions, we found significant increases in striatal serotonin levels without an associated increase in serotonin turnover. At the cortical level, we found inconsistent changes in frontal cortical DA levels and variable decreases in norepinephrine levels. Since the most profound and consistent deficits were in the nigrostriatal dopamine system. We also suggest that the most of the behavioral consequences of chronic low-dose MPTP exposure stem from the striatal dopamine depletion. We also suggest that the maintenance of motor function in the presence of massive striatal DA depletions may be due to less impairment of putamen DA vs. caudate DA, by an increase in striatal DA turnover, a compensatory increase in serotonin availability, or a combination of these and possibly other as yet undetermined compensatory mechanisms. Furthermore, we propose the present model utilizing chronic low-dose exposure to MPTP as a model for the early, compensated form of Parkinson's disease.

Effects of amitriptyline and nortriptyline on cerebral activity of the CDF-1 mouse strain

1. 1. Equal dose regimens of amitriptyline, a tertiary amine tricyclic antidepressant, were more potent than nortriptyline, a secondary amine derivative, in suppressing CDF-1 mouse locomotor activity. 2. 2. A suggestive increase in dopamine turnover rate in mouse cerebral cortex and striatal brain regions was apparent by amitriptyline but not nortriptyline. 3. 3. A suggestive increase in serotonin turnover in mouse cerebellum and striatum was determined for nortriptyline. 4. 4. Both antidepressants increased cerebral cortex, midbrain and cerebellum serotonin levels from saline control. 5. 5. Increases of regional brain dopamine by amitriptyline and serotonin by nortriptyline concurrent with reuptake blockade of the respective serotonin and dopamine may contribute to their differential extrapyramidal and sedating side effects.

Lesch‐nyhan syndrome: A study of motor behavior and cerebrospinal fluid neurotransmitters

We studied 5 boys, 2 to 10 years old, with marked or complete deficiency of hypoxanthine-guanine phosphoribosyltransferase and Lesch-Nyhan syndrome with varying degrees of mental retardation, dysarthria, chorea, dystonia, spasticity, and ataxia. Four patients had marked reduction of homovanillic acid in the cerebrospinal fluid (CSF) and all showed low CSF 3-methoxy-4-hydroxy phenylethylene glycol, indicating reduced dopamine and norepinephrine turnover. Three patients showed high CSF 5-hydroxyindoleacetic acid, suggesting increased serotonin turnover. Some patients improved with carbidopa-levodopa, but others benefited from tetrabenazine, a monoamine-depleting agent. This study provides support for the theory of abnormal central monoamine metabolism in Lesch-Nyhan syndrome.