Showing papers in "Journal of Neural Transmission in 1983"

Dopamine receptor agonists: intrinsic activity vs. state of receptor.

Abstract: Based on observations with the novel dopamine-receptor agonist 3-(3-hydroxyphenyl-)-N-n-propylpiperidine, 3-PPP, especially its levorotatory enantiomer, it is proposed that the intrinsic activity of a receptor agonist depends in part on the responsiveness of the receptor; this in turn is determined by the degree of previous agonist occupancy on the receptor. A change in occupancy will induce a slow conformational change, influencing the responsiveness. This may constitute an important aspect of receptor adaptation and may help to explain otherwise puzzling phenomena,e.g. that compounds such as (−)-3-PPP or transdihydrolisuride can act as strong dopamine-receptor agonists in some locations and as antagonists in others. The observations discussed in the present paper may be interpreted to indicate that the dopamine receptors in different locations are, in fact, derived from a homogeneous receptor population, though in a varying state of adaptation. Thus it may prove worth-while to reconsider the various subclassifications of DA receptors proposed so far.

Three-dimensional computer reconstruction of midbrain dopaminergic neuronal populations: from mouse to man.

Abstract: A technique is described which has been used to quantitate the 3-dimensional configuration of the midbrain dopamine (DA) nuclei (cell groups A8, A9, and A10). This technique provides cell counting information, for example, the BALB/c mouse has approximately 25,000 midbrain DA neurons, the albino rat has about 40,000 neurons, and man (33 year old) has approximately 450,000 neurons. Furthermore, cell density topography maps were constructed which enable quantitation of the 3-dimensional cellular distribution. These topography maps revealed both similarities and differences across the three species examined. The number of midbrain DA neurons is known to be genetically determined and to decrease with aging. DA cell number is also related to motoric behavior and neurologic and perhaps psychiatric disease. The ability to quantitate DA regional cell densities represents a new technique which can be used to study the neurobiology of DA neurons and relate DA cell number to both normal and abnormal behaviors.

Muscarinic receptor compensation in hippocampus of Alzheimer patients.

Abstract: The activity of the acetylcholine synthesizing enzyme choline acetyltransferase (ChAT) (presynaptic marker) and number of muscarine-like receptor binding sites have been measured in the hippocampus from eight individuals with senile dementia of Alzheimer type (SDAT) and ten controls. A negative correlation (r = 0.80; p less than 0.05) was found between the ChAT activity and the number of muscarine-like receptors in the SDAT group but not in the controls. The findings might indicate an ongoing compensatory receptor mechanism as a response to changes in presynaptic cholinergic activity.

Comparative neuropharmacology of buspirone and MJ-13805, a potential anti-anxiety drug.

Abstract: Buspirone is a clinically efficacious anti-anxiety drug without any other benzodiazepine-like activity. Although buspirone can displace ligands for dopamine (DA) receptors, its equipotent analog, MJ-13805, cannot. Buspirone can potently increase dopaminergic impulse flow and metabolism, primarily due to inhibition of DA autoreceptors. However, MJ-13805 does not block striatal nerve ending DA autoreceptors and slightly increases striatal DA metabolism. Both drugs potently reverse catalepsy due to either DA receptor blockade or DA depletion which indicates an effect within the extrapyramidal system efferent from the DA neuron. Amantadine is at least ten fold less potent than these drugs for reversal of catalepsy. These data indicate that altered dopaminergic neurotransmission may not be important for the anti-anxiety effect of buspirone and that buspirone should be tested for efficacy in various models of movement disorders. The site and mechanism of action for buspirone and MJ-13805 remains obscure. A metabolite of buspirone, 1-piperazinylpyrimidine, does not reverse catalepsy although this drug is known to be active in anti-anxiety screening tests. Thus, buspirone may have separate mechanisms of action for reduction of anxiety and reversal of catalepsy.

The effects of benzodiazepine and non-benzodiazepine anxiolytics on locus coeruleus unit activity.

Abstract: Two theories have been put forth concerning the anxiolytic actions of the anti-anxiety drugs. One theory maintains that these drugs decrease locus coeruleus output, and the other maintains that they facilitate gammaaminobutyric acid (GABA) neurotransmission at benzodiazepine (BZ)-linked GABA receptors. The BZ-anxiolytic diazepam does decrease locus coeruleus neuronal impulse flow. However, this decrease is not due to effects on BZ-linked GABA receptors in the locus coeruleus. Furthermore, the non-BZ anxiolytic buspirone, its metabolite and its analog all slightly increase locus coeruleus neuronal impulse flow. This increase, in the case of the metabolite, appears to be due, in part, to blockade ofα 2-adrenoceptors. Finally, buspirone, unlike diazepam, did not potentiate GABA inhibition at BZ-linked GABA receptor sites (i.e. cerebellar Purkinje cells). These data suggest that the non-BZ anxiolytic buspirone produces its anti-anxiety effects by unconventional mechanisms.

Differential epileptogenic potentials of selective mu and delta opiate receptor agonists.

Abstract: By using electroencephalographic (EEG) and electromyographic recordings in anaesthetized and free-moving rats, two opioid peptides, known as selective agonists forμ andδ opiate receptors, respectively, were examined for their epileptogenic properties

Effect of a stereospecific D2-dopamine agonist on acetylcholine concentration in corpus striatum of rat brain

Abstract: The enantiomers of LY141865, trans-(±)-4,4a,5,6,7,8a,9-octahydro-5-propyl-2H-pyrazolo [3,4-g]quinoline, were compared as dopamine D2 agonists by determining their abilities to elevate acetylcholine concentrations in rat corpus striatum. The levorotatory isomer, LY156258, increased striatal acetlycholine concentration at doses of 0.1–1 mg/kg i.p., whereas the dextrorotatory isomer had no effect even at doses as high as 30 mg/kg. The levorotatory isomer also decreased striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, but did not significantly alter dopamine or 5-hydroxyindoleacetic acid concentration. The dextrorotatory isomer had no effect on any of these substances alone and did not alter the effects of the levorotatory isomer. The elevation of striatal acetylcholine levels by LY156258 was mimicked by pergolide, a dopamine agonist, and was totally prevented by pretreatment with haloperidol, a dopamine antagonist. The elevation of striatal acetylcholine concentration by LY157258 was maximal at 0.5 hour and declined thereafter, following a time course similar to that of pergolide. Neither LY141865 nor LY156258 shared with peroglide and dopamine the ability to activate striatal adenylate cyclasein vitro, an effect mediated by D1 receptors. LY141865 and LY156258 (but not the dextrorotatory isomer) inhibited the binding of tritiated apomorphine and spiperone to striatal membrane receptors, but were not as potent as pergolide, they also had less effect, or no effect, on the binding of other tritiated ligands (dopamine, WB4101, clonidine, dihydroalprenolol, pyrilamine or quinuclidinyl benzilate) to their membrane receptors. These results indicate that LY156258 stereospecifically activates dopamine D2 receptors and the studies are the first evidence of stereospecificity of dopamine receptors mediating an increase in striatal acetylcholine concentration.

Deficient natural killer cell (NK) activity and macrophage functioning in schizophrenic patients

Abstract: The cytotoxic potential of mononuclear blood cells from 27 chronic schizophrenic patients was evaluated using quantitative measures of natural killer cell activity and macrophage inhibition of tumor cell growth. 44% of the patients had some evidence of deficient in vitro mononuclear cell function which was not correlated with a qualitative or quantitative alteration in the histologic appearance of these peripheral blood cells.

Various mental behavioral disorders in Parkinson's disease, primary degenerative senile dementia, and multiple infarction dementia.

Abstract: Following 2-4 years of hospitalization, the mental and physical ability of 21 patients with typical idiopathic PD, 10 patients with atypical Parkinson's syndrome and signs of cerebral arteriosclerosis, 29 patients with MID. and 14 patients with senile dementia of the Alzheimer type were evaluated according to various rating scales. All idiopathic parkinsonian patients had suffered from the disease for over 8 years. All patients were over 70 years of age and continuously subjected to the same environment. EEG and CT was performed. A rating scale consisting of 18 items for evaluation of the mental and physical capacity and ability to cope with daily psychosocial demands was used for each patient. Statistically highly significant differences resulted between the relative good mental ability of patients with idiopathic Parkinson's syndrome, with the exception of some brief pharmacotoxic psychoses, and the lower rating scores of patients with senile dementia of Alzheimer type and multiple infarction dementia. A smaller subgroup of patients with Parkinson's syndrome and additional focal signs in the neurological status and EEG showed moderate mental functional loss and a more frequent incidence of pharmacotoxic psychoses than the patients with idiopathic PD. Just as few congruencies of mental ability were found between patients with idiopathic, typical PD and patients with senile dementia of the Alzheimer type as between idiopathic PD and MID. Permanent dementia is not characteristic of patients with typical idiopathic PD even in advanced age. It is, however, for patients with MID and SDAT.

The activity of monoamine oxidase -A and -B in brains from chronic alcoholics.

Abstract: The activity of monoamine oxidase-A was found to be lower in homogenates of hypothalamus and caudate nucleus, but not in cortex of the gyrus cinguli and hippocampus, from chronic alcoholics with respect to homogenates from autopsy cases without histories of alcohol abuse. The activity of monoamine oxidase -B was also lower in the alcoholics, but this could be due to the selective effect of age upon this enzyme form, since the alcoholics were younger than controls. No difference was found for either monoamine oxidase -A or -B activities in brain homogenates from an alcohol preferring (AA) strain of rats, with respect to those from a water preferring (ANA) strain.

Bidirectional effects of benzodiazepine receptor ligands against picrotoxin- and pentylenetetrazol-induced seizures

Abstract: The dose response curves of picrotoxin-induced seizures and pentylenetetrazol-induced seizures were shifted to the right by the benzodiazepine (BZ) receptor agonist lorazepam, and to the left by the inverse agonists, DMCM, ZK 90886, FG 7142 and CGS 8216. The BZ receptor antagonists ZK 93426 and Ro 15-1788 had no effect on the dose response curves. The anticonvulsive action of lorazepam and the proconvulsive action of DMCM against picrotoxin-induced seizures and against pentylenetetrazol-induced seizures was inhibited by low doses of ZK 93426 and Ro 15-1788. These results indicate that the bidirectional effects of benzodiazepine receptor ligands on picrotoxin and pentylenetetrazol induced seizures is actually mediated through benzodiazepine receptors.

Regional GABA concentration and [3H]-diazepam binding in rat brain following repeated electroconvulsive shock.

Abstract: It has been confirmed that 24 hours following a series of electroconvulsive shocks (ECS) given once daily for 10 days (ECS×10) to rats there is an increase in GABA concentration in the corpus striatum. A similar change was seen after the ECS had been given to rats anaesthetised with halothane, or when 5 ECS were given spread out over 10 days, the rats being anaesthetised during the ECS. A daily convulsion for 10 days elicited by flurothyl exposure resulted in an increased striatal GABA concentration, but also increased the GABA concentration in the hypothalamus, hippocampus and cortex. The increase in striatal GABA concentration was present 24 hours after ECS daily for 5 days or 3 days after ECS daily for 10 days. No change in [3H]-diazepam binding was seen in hippocampus, cortex or corpus striatum 24 hours after the last of 10 once daily ECS. The increase in striatal GABA concentration was therefore seen at all times when enhanced monoaminemediated behaviours have been demonstrated following seizures.

Demonstration of autoreceptors on dopamine neurons in different brain regions of rats treated with gammabutyrolactone.

Abstract: Following interruption of the nerve impulse flow in the dopamine neurons by treatment with gammabutyrolactone, the selective dopamine autoreceptor agonist B-HT 920 reduced the DOPA accumulation after DOPA decarboxylase inhibition and the 3,4-dihydroxyphenylacetic acid concentration in the corpus striatum, the nucleus accumbens, the olfactory tubercle, the limbic cortex and the rostral part of the cerebral cortex of rats. The effects were completely inhibited by the dopamine receptor antagonist haloperidol, indicating that they were caused by stimulation of dopamine autoreceptors. In the caudal part of the cerebral cortex and the cerebellum, B-HT 920 somewhat reduced the concentration of dihydroxyphenylacetic acid via a haloperidol-sensitive mechanism, suggesting that there are a few dopamine neurons with autoreceptors in these regions. No evidence was obtained for the presence of autoreceptors on the dopamine neurons in the hypothalamus. The gammabutyrolactone-induced elevation of the dopamine concentration was not reduced by B-HT 920 in any region, suggesting that this effect of gammabutyrolactone was caused by decreased release rather than increased synthesis of dopamine under our experimental circumstances.

Species differences in behavioural effects of rolipram and other adenosine cyclic 3h, 5h-monophosphate phosphodiesterase inhibitors

Abstract: The effect of the phosphodiesterase (PDE) inhibitors rolipram, Ro 20-1724 and isobutylmethylxanthine (IBMX) on motor behaviour and rectal temperature was studied in mice, rats and guinea pigs following intraperitoneal administration (0.39 to 25 mg/kg). The selective adenosine cyclic 3′, 5′-monophosphate (cAMP) PDE inhibitors rolipram and Ro 20-1724 in each species caused a dissimilar pattern of neurotropic effects: Hypothermia andhypokinesia in mice, hypothermia,hypokinesia and head twitches in rats, hypothermia,hyperkinesia and head twitches in guinea pigs. The head twitches were associated with forepaw shaking and increased grooming. Rolipram was the most potent compound in the three species. In guinea pigs it was less active than in rats or mice. Ro 20-1724 was approx. 15 to 30 times less potent in inducing the characteristic alterations in the various species. The alkylxanthine PDE inhibitor IBMX, 0.39 to 6.25 mg/kg, slightly stimulated the locomotor activity of mice and rats, most probably due to antagonism of central adenosine actions. IBMX, 6.25 to 25 mg/kg, caused a pattern of neurotropic effects identical to that produced by the selective cAMP PDE inhibitors, indicating the prevalence of the cAMP PDE inhibitory action over the adenosine antagonistic action at higher dosages. IBMX was approx. as potent as Ro 20-1724 in this respect. The species differences in the neurotropic responses to cAMP PDE inhibitionin vivo presumably reflect similar differences in the extent of cAMP accumulation in brain tissue of the three speciesin vitro. Enhanced availability of brain cAMPin vivo in the various rodent species seems to be correlated with diverse patterns of more or less complex motor behavioural symptoms.

Action of apomorphine, bromocriptine and lergotrile on gamma-aminobutyric acid and acetylcholine release in nucleus accumbens and corpus striatum.

Abstract: The effect of three dopamine agonists, apomorphine, bromocriptine and lergotrile, was tested on the release ofγ-aminobutyric acid, (GABA) and acetylcholine (ACh) from tissue slices of rat nucleus accumbens and striatum. All three agentsin vitro caused a dose dependent depression of the K+-evoked release of [14C]-GABA in corpus striatum. This effect was also obtained followingin vivo drug application and when endogenous GABA release was determined. A similar depression of GABA release was obtained in the nucleus accumbens. Both dopamine and dibutyryl adenosine-3′∶5′-cyclic monophosphoric acid inhibited the K+-evoked release of [14C]-GABA in corpus striatum. This inhibitory effect was not reversed by sulpiride. Bromocriptine and lergotrile also depressed the K+-evoked release of [3H]-acetylcholine from tissue slices of corpus striatum but not nucleus accumbens, as has previously been demonstrated for dopamine and apomorphine. In contrast, sulpiride enhanced the release of [3H]-acetylcholine and molindone reversed the apomorphine inhibition of [3H]-acetylcholine release. These results indicate that dopaminergic agents may influence the release of both GABA and ACh in the corpus striatum but only GABA in the nucleus accumbens.

Some effects of chronic antidepressant treatments on rat brain monoaminergic systems.

Abstract: A range of established and putative antidepressant therapies were studied for the effect of their long-term administration on two facets of presynaptic monoaminergic functioning in rat brain, namely NE, DA, and 5-HT turnover and alpha 2-adrenoceptor sensitivity. Unless stated otherwise drugs (10 mg/kg) were injected i.p. twice daily for 14 days. ECT (100 mA for 1 s) was applied once daily for 10 days. Changes in turnover were indirectly assessed by measuring levels of metabolites. Brain levels of MHPG-SO4 were unchanged by chronic amitriptyline, imipramine, nisoxetine (20 mg/kg), nortriptyline, salbutamol (5 mg/kg), and ECT. Amitriptyline elicited a slight, but significant, increase in brain DOPAC content. Brain levels of 5-HIAA were increased by amitriptyline, imipramine, salbutamol, and ECT. An overall view of the results indicates that no common pattern of change was elicited by the range of antidepressant therapies studied. Central alpha 2-adrenoceptor sensitivity was assessed by investigating the effect of various therapies on the ability of clonidine (25 mg/kg i.p.) to decrease rat brain MHPG-SO4 content. The clonidine-induced fall was attenuated by desipramine, imipramine, and ECT. Amitriptyline, iprindole, mianserin, nisoxetine, nortriptyline, Org 6582 (10 mg/kg once daily), pargyline (25 mg/kg once daily), salbutamol, and trazodone were ineffective. The following chronic antidepressant therapies were investigated for their effect on rat frontal cortex 3H-clonidine binding: amitriptyline, desipramine, imipramine, iprindole, mianserin, nisoxetine, nortriptyline, pargyline, salbutamol, and ECT. CHronic, but not acute, pargyline decreased 3H-clonidine binding and this was due to a diminished number of binding sites. The induction of subsensitive presynaptic alpha 2-adrenoceptors in rat brain is not a property common to all forms of antidepressant therapies. Hence it cannot be the fundamental mode of action of antidepressants. No correlation exists between the changes in rat cortical 3H-clonidine binding and the observed changes in the sensitivity of central presynaptic alpha 2-adrenoceptors.

Basal ganglia outflow pathways and circling behaviour in the rat

Abstract: The role of efferents in substantia nigra pars reticulata in the mediation of circling behaviour in the rat has been studied by means of lesions designed to interrupt these pathways or to damage nigral projection areas. The behavioural model used was the circling rodent with a prior 6-hydroxydopamine lesion of the left nigro-striatal pathway in which amphetamine induced ipsiversive rotation and apomorphine induced contraversive rotation. Removal of the left fronto-parietal cortex caused only a transient decrease in drug-induced rotation. An electrolytic lesion of the left, right or both parafascicular thalamic nuclei did not alter circling behaviour. Electrolytic lesioning of the left ventromedial thalamus decreased apomorphineinduced contraversive circling whereas a lesion of the right ventromedial thalamus decreased amphetamine-induced ipsiversive rotation. Bilateral electrolytic lesions of the ventromedial thalamus did not alter drug-induced circling. Unilateral or bilateral electrolytic lesioning of the medial superior colliculus did not alter the rotational response to apomorphine or amphetamine. However, an electrolytic lesion interrupting the dorsal tegmental decussation reduced apomorphine-induced circling but not amphetamine-induced circling. That a critical role for the nigro-thalamic and nigro-tectal pathways is not involved in the mediation of circling behaviour was confirmed by placing knife cuts so as to separate these structures from the substantia nigra; such lesions failed to alter the contraversive rotation induced by the ipsilateral injection of muscimol into substantia nigra pars reticulata. Electrolytic lesions of the ipsilateral nucleus reticularis gigantocellu laris or kainic acid lesions of the ipsilateral nucleus tegmenti pedunculopontinus did not alter drug-induced circling in animals with a prior 6-hydroxydopamine nigral lesion. In contrast, an ipsilateral lesion of the midbrain periaqueductal grey matter and adjacent midbrain reticular formation (the angular complex) decreased apomorphine-induced contraversive rotation in such animals, while bilateral lesions reduced both apomorphine-and amphetamine-induced circling; in each case the postural component of rotation was abolished. Unilateral kainic acid lesions of the angular complex in naive animals caused ipsiversive rotation which was enhanced by apomorphine. Unilateral kainic acid lesions of the angular complex with an ipsilateral 6-hydroxydopamine nigral lesion caused reversal of the previous contraversive rotation to apomorphine, and enhanced amphetamine-induced ipsiversive rotation. A nigro-reticular pathway to the midbrain reticular formation adjacent to the periaqueductal grey matter (the angular complex) appears critical in the mediation of the postural component of drug-induced rotation in animals with a prior unilateral 6-hydroxydopamine lesion of the dopaminergic nigro-striatal system. Nigro-thalamic pathways and pathways from nigra to the superficial and medial superior colliculus do not seem to be involved, although we cannot exclude a role for the deep lateral superior colliculus which, in any case, is anatomically and functionally closely related to the midbrain tegmental reticular formation.

Day/night rhythmicity in the methylating capacities for different 5-hydroxyindoles in the pineal, the retina and the Harderian gland of the golden hamster (Mesocricetus auratus) during the annual seasons.

Abstract: In the pineal, the Harderian gland and the retina of the golden hamster the day/night capacity for the synthesis of different methoxyindoles is investigated under natural conditions for one 24-hour period in the months of December, March and June. The amounts of the methoxyindoles and the diurnal rhythms in the synthesis are different in the various months during which the tests were performed. There is a striking increase in the synthesis of melatonin and methoxytryptophol in all three organs in June as compared with December. Equally striking is the high synthesis of methoxytryptamine in the pineal in June, whereas this compound was not formed in the Harderian gland and the retina in this month. Methoxytryptophan synthesis was not observed in June in any of the three organs. Methoxyindoleacetic acid rhythmicity shows a pattern more or less identical to that of melatonin and methoxytryptophol. A high synthesis exists at the end of the June day, but greater fluctuations during the days of the two other months. Acetylmethoxytryptophol is synthesized in the pineal during the night in March, but in the late afternoon in June. The largest quantity of this compound is found in the Harderian gland in December, in the pineal in March and in the retina in June. The largest amounts of melatonin and methoxytryptophol are synthesized when gonadal weight is largest. The possible correlation between the amounts synthesized, the rhythmicities in synthesis and the reproductive system is discussed.

Tyrosine administration enhances dopamine synthesis and release in light-activated rat retina.

Abstract: Exposure of dark-adapted albino rats to light (350 lux) significantly elevated retinal levels of the dopamine metabolite dihydroxyphenyl acetic acid during the next hour; their return to a dark environment caused dihydroxyphenyl acetic acid levels to fall. Retinal dopamine levels were increased slightly by light exposure, suggesting that the increase in dihydroxyphenyl acetic acid reflected accelerated dopamine synthesis. Administration of tyrosine (100 mg/kg, i. p.) further elevated retinal dihydroxyphenyl acetic acid among light-exposed animals, but failed to affect dopamine release among animals in the dark. These observations show that a physiological stimulus-light exposure-can cause catecholaminergic neurons to become tyrosine-dependent; they also suggest that food consumption may affect neurotransmitter release within the retina.

The autonomic innervation of the vasa nervorum.

Abstract: Using catecholamine fluorescence and histochemical cholinesterase staining combined with quantitative image analysis a direct autonomic innervation of arteries, arterioles, venules, veins and artero-venous anastomoses within peripheral nerves was demonstrated in normal as well as in chemically sympathectomized rats.

Involvement of adrenergic receptor mechanisms within hypothalamus in the fever induced by amphetamine and thyrotropin-releasing hormone in the rat

Abstract: The mechanisms underlying the thermal effects induced by intrahypothalamic administration of either d-amphetamine or thyrotropin-releasing hormone (TRH) has been investigated in conscious rats. Direct administration of d-amphetamine (1–10μg in 1μl) or TRH (1–4μg in 1μl) into the preoptic anterior hypothalamus caused hyperthermia or fever at the ambient temperature (Ta∶ 8, 22 and 30 °C) studied. The fever induced by d-amphetamine or TRH was due to increased metabolic heat production at Ta 8 °C, while at Ta 30 °C the fever was due to cutaneous vasoconstriction in the rat. At Ta 22 °C, the fever was due to both increased metabolism and cutaneous vasoconstriction. Furthermore, the fever induced by intrahypothalamic administration of TRH was greatly reduced by pretreatment with intrahypothalamic administration of either yohimbine (a blocking agent of alpha-adrenergic receptors), phentolamine (a blocking agent of alpha-adrenergic receptors) or DL-propranolol (a blocking agent of beta-adrenergic receptors) in the rat. However, the fever induced by d-amphetamine was antagonized by pretreatment with yohimbine or phentolamine, but not with DL-propranolol in the rat. These observations indicate that the adrenergic receptor mechanisms within the hypothalamus are involved in the fever induced by both d-amphetamine and TRH.

Probenecid Sensitive Pathway of Elimination of Dopamine and Serotonin Metabolites in CSF of the Rat

Abstract: CSF was removed at a constant flow rate of 1μl/min from the third ventricle of anesthetized rats. Fiveμl CSF samples were directly injected every 15 min into a liquid Chromatographic system coupled with an amperometric detector. Mean CSF values for free dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) were 1.4, 0.9, and 2.6×10−6M respectively. High doses of probenecid resulted in a linear increase of acidic metabolite concentrations which gave an index of the fractional turnover rates related to the resorption by the weak organic acid carrier. Accumulation rates were 0.24, 0.87, and 1.58μmol/l/h for DOPAC, HVA and 5-HIAA respectively. This route of elimination was predominant for 5-HIAA while it represented only a small part of total turnover for DOPAC. A high elimination rate constant for HVA validates the use of control levels of this metabolite as an indication of fractional HVA turnover dependent upon probenecid-sensitive carrier.

24-hour-variation of pineal gland volume, pinealocyte nuclear volume and mitotic activity in male Sprague-Dawley rats.

Abstract: In two experiments carried out on two alternate days, the 24-hrhythmicity of pineal gland volume, pinealocyte nuclear size in cortex and medulla and mitotic actty were studied in male Sprague-Dawley rats, to assess to what extent morphological parameters reflect the pronounced day/night differences in pineal melatonin formation. Pineal volume exhibited statistically significant changes in the second experiment only, with a distinct trough at 6 p.m. Karyometry revealed highly variable patterns. In the first experiment, pinealocyte nuclear changes lacked parallelism in cortex and medulla. The cortex exhibited a bimodal curve with peaks at noon of the first day and at 6 a.m. of the second day, and two troughs at 6 a.m. and midnight respectively of the first day. The medulla showed no clear-cut rhythmicity. In the second experiment, cortex and medulla reacted similarly, nuclear size decreasing from 6 a.m. to 6 p.m., remaining low thereafter. Mitotic activity of pinealocytes is low (on average 23 mitotic figures/gland). In both experiments statistically significant differences existed between certain times, pointing in the direction of 24-hrhythmicity, but whereas the curve exhibited a peak at midnight in the first experiment, mitotic activity in the second experiment showed a trough at midnight. It is concluded that for as yet unexplained reasons morphological parameters do not appear to accurately reflect circadian rhythmicity of pineal melatonin formation.

DL-3,4-threo-DOPS in Parkinson's disease: Effects on orthostatic hypotension and dizziness

Abstract: Parkinsonian patients with orthostatic hypotension and dizziness due to usual antiparkinson therapy have been treated with the precursor ammoacid of noradrenaline, DL-3,4-threo-dihydroxyphenylserine (DL-3,4-threo-DOPS). Oral and intravenous administration improved these side effects significantly. A combined treatment of L-dopa, peripheral decarboxylase inhibitor and DL-3,4-threo-DOPS seems to be of benefit with respect to akinesia and orthostatic hypotension.

Diazepam potentiates the effect of neuroleptics on behavioural activity as well as dopamine and norepinephrine turnover: Do benzodiazepines have antipsychotic potency?

Abstract: A single injection of diazepam (10 mg/kg, s. c.), haloperidol (2 mg/kg, i. p.) or chlorpromazine (10 mg/kg, i. p.) decreased the ambulatory as well as sniffing behaviour of rats. These behavioural responses were further decreased when diazepam was administered concurrently with the neuroleptic. Acute haloperidol or chlorpromazine treatment increased striatal dopamine as well as cerebro-cortical norepinephrine turnover. In contrast, diazepam diminished the release of both of these catecholamines. When diazepam was administered together with haloperidol or chlorpromazine, a further decrease particularly in dopamine release was seen in striatum. This effect of diazepam on norepinephrine and dopamine turnover persisted even after 21 days of daily treatment. Similarly, the sedative effect of diazepam elicited in the form of depressed locomotor activity was also apparent after long-term administration of this benzodiazepine. However, chronic administration of neuroleptics enhanced the spontaneous locomotor activity and sniffing behaviour by about 25% Furthermore, repeated neuroleptic treatment decreased the synthesis and turnover of dopamine and norepinephrine. This was reflected in decreased tyrosine hydroxylase and homovanillic acid level in striatum as well as by low concentration of 3-methoxy-4-hydroxyphenylethylene glycol in the cerebral cortex. When diazepam was administered together with haloperidol or chlorpromazine for 21 days, behavioural activity remained elevated and was comparable to groups of rats receiving neuroleptics alone. The concommitant injection of diazepam and neuroleptics for 21 days elicited a synergistic effect on decreased synthesis and release of dopamine as well as norepinephrine. These data provide neurochemical evidence for potentiation of the neuroleptic effects by a benzodiazepine.

Glucuronide and sulfate catecholamine conjugates in rat and human plasma.

Abstract: We have developed a method to selectively estimate free, glucuronidated and sulfated catecholamines (epinephrine [E], norepinephrine [NE], dopamine [DA]) in a single plasma sample. The method incorporates the first step of the catecholamine radioenzymatic assay and the selective enzymatic hydrolysis of conjugates by glucuronidase or sulfatase preparations. The method has been applied to rat and human plasma with a view to determine the relative importance of either conjugate (sulfate or glucuronide) toward free catecholamines. No previous reports were available for the concentration of either conjugate in rat plasma or the level of glucuronide conjugate in human plasma. Both sulfate and glucuronide conjugates of the three catecholamines were found in rat and human plasma, at different levels. Sulfate conjugates predominated in man and glucuronides in rat. In human, hand immersion in ice water for three minutes which increased free catecholamine levels in the first minutes of the test, elicited too a delayed increase of glucuronide levels at the 30th minute (except for DA glucuronide which was already elevated at the third minute). As to the sulfates, only E sulfate was increased at the 10th minute. Our results suggest that glucuronidation may be an important pathway for catecholamine metabolism in man at rest or under sympathetic stimulation. In rat, our data point out the influence of blood sampling conditions (dietary, catheterization, decapitation) on the studied compounds and suggest that the nearest conditions from basal state may be fulfilled in sucrose-fed rats.The predominates of glucuronides in rat plasma agrees with previous metabolic reports.

Evidence of dopa in the nerves of sea anemones.

Abstract: An analysis of the presence of catechol-derivatives in the sea anemonesMetridium senile andTealia felina, made with the aid of high-pressure liquid chromatography (HPLC), established the presence of dopa, 5-OH-dopa, and 5-S-cysteinyldopa. In addition, 2-S-cysteinyldopa and 2.5-diSS-cysteinyldopa occurred inMetridium. Two unknown substances were found to be present in the tentacles ofMetridium and in the tentacles of some specimens ofTealia. Neither catecholamines nor serotonin could be traced in detectable amounts. No dopa-decarboxylase could be demonstrated by the assay performed in this investigation.

The effect of morphine on 5-hydroxytryptamine synthesis and metabolism in the striatum, and several discrete hypothalamic regions of the rat brain.

Abstract: The effects of morphine on 5-hydroxytryptamine (5-HT) synthesis (accumulation of 5-hydroxytryptophan following inhibition of aromatic L-amino acid decarboxylase) and metabolism (concentration of 5-HT and its primary metabolite, 5-hydroxyindole-3-acetic acid [5-HIAA]) were determined in discrete nuclei of the rat brain using high performance liquid chromatography coupled with electrochemical detection (LCEC) Morphine (10 mg/kg, sc) increased 5-HT synthesis in the medial preoptic (MPO), suprachiasmatic (SCN) and arcuate (AN) nuclei as well as the striatum (ST) 1 hour following its administration 5-HT synthesis in the median eminence (ME) was not affected at any time examined A lower dose of morphine (5 mg/kg) also stimulated 5-HT synthesis in the AN Although steady state concentrations of 5-HT were not greatly affected by morphine administration, the concentration of 5-HIAA in the AN, MPO, and ST increased following morphine (10 mg/kg, sc, 1 hour) The increase in 5-HT synthesis observed in the MPO, SCN, AN, and ST 1 hour following morphine involved the activation of opiate receptors as administration of an opiate receptor antagonist, naloxone, blocked this effect These results, indicate that morphine causes an increase in 5-HT synthesis and metabolism via an opiate receptor-mediated mechanism in the AN, MPO, SCN, and ST but not in the ME

The 5-hydroxytryptamine receptor of blood platelets.

Abstract: Blood platelets show specific, high affinity binding of 3H-5-hydroxytryptamine, 3H-ketanserin and 3H-D-lysergic acid diethylamide. 5-HT-antagonists are considerably more potent than agonists regarding both the displacement of specifically bound 3H-ketanserin and the shape change reaction mediated by the 5-HT-receptor. The latter depends on a rise of free intracellular Ca2+. The binding site for 3H-ketanserin and the site at which the 5-HT-induced shape change is triggered show the characteristics of a 5-HT2-receptor whose intracellular mediator seems to be Ca2+. The 5-HT2-receptor of platelets may be used as a partial model for that in neurons; however, it remains to be elucidated whether Ca2% is a mediator of the latter.

Effect of gammahydroxybutyric acid on serotonin synthesis, concentration and metabolism in the developing rat brain

Abstract: 5-HT synthesis, levels and degradation were investigated in the whole brain and regional brain areas in 4,14, and 28 days old rats after administration of gammahydroxybutyric acid (GHBA). 5-HT synthesis was investigated by means of 5-HTP accumulation after decarboxylase inhibition by NSD 1015. 5-HTP accumulation increased in the 14 and 28 days old rats but decreased in the 4 days old animals 90 min after GHBA, 750 mg/kg. In the 28 days old rats a corresponding increase was also noted in the precursor amino acid tryptophan. Regional and whole brain 5-HT levels were not altered by GHBA treatment. Regional as well as whole brain levels of 5-HIAA increased in the 14 and 28 days old rats after GHBA administration.