The effects of DL- -methyltyrosine and L-DOPA on the hyperthermic and behavioral actions of LSD in rabbits

Lysergic acid diethylamide (LSD) in relatively small doses produces in rabbits a dose-related hyperthermia and behavioral excitation.After a 24 hr pretreatment with $\text{dl}\text{-α-}\text{methyl}\text{-p-}\text{tyrosine}$ (α-MT), the LSD hyperthermia is no longer dose related. With lower doses of LSD it is potentiated, and with higher doses attenuated. The behavioral actions of LSD are attenuated at all dose levels.The administration of l-dihydroxyphenylalanine (l-DOPA) restores the behavioral action of LSD in α-MT-pretreated rabbits. Prior administration of the dopamine-β-hydroxylase inhibitor, sodium diethyldithiocarbamate (DEDC) was ineffective in blocking the restorative action of l-DOPA.Analyses of brainstem catecholamines indicate that under the conditions of this study α-MT markedly depletes brain norepinephrine (NE) and dopamine (DA). l-DOPA restores DA and partially restores NE levels to control values. In animals pretreated with DEDC the effect of l-DOPA treatment on brainstem DA is enhanced with only slight increases in NE levels.     

The role of biogenic amines in the reserpine-induced alteration of minimal electroshock seizure thresholds in the mouse

A single injection of reserpine (1 $\text{mg}\text{kg}$ i.p.) produced an increased susceptibility to minimal electroshock seizures, as well as a decrease in whole brain levels of norepinephrine (NE), dopamine (DA), and serotonin (5-HT). The return to normal seizure susceptibility correlated well with the return of the ability of whole brain tissue to synthesize and retain ³H-amine formed from either ³H-3,5-l-tyrosine or ³H-5-hydroxy-dl-tryptophan. Selective inhibition of catecholamine synthesis with α-methyl-p-tyrosine, following reserpine administration, prevented the return to normal both of seizure susceptibility and NE and DA levels. The combination of disulfiram and reserpine also prevented the return to normal seizure susceptibility. After the latter treatment, levels of DA were elevated while NE remained depressed. Selective inhibition of 5-HT synthesis following reserpine similarly prevented the return of normal seizure susceptibility. Our study suggests that NE and 5-HT, but not DA, are important in regulating minimal electroshock seizure susceptibility.     

The distribution of beta-phenylethylamine in discrete regions of the rat brain and its effect on brain noradrenaline, dopamine and 5-hydroxytryptamine levels

β-Phenylethylamine (100 $\text{mg}\text{kg}$) injected interperitoneally into rats 1 hr before death, caused a significant depletion of whole brain levels of noradrenaline and dopamine, but not of 5-hydroxytryptamine. An investigation of discrete regions of the brain showed that the same dose of phenylethylamine caused significant depletion of dopamine in the cerebellum, corpus striatum, midbrain, and cortex, but not in the hypothalamus or medulla oblongata-pons region. All regions were depleted of noradrenaline, while only the midbrain and cortex were significantly depleted of 5-hydroxytryptamine. Administration of [4-T]-β-phenylethylamine, 100 $\text{mg}\text{kg}$, showed that the distribution of labelled phenylethylamine in various regions of the brain was significantly correlated with the distribution of dopamine (both in controls and after 100 mg $\text{β-phenylethylamine}\text{kg}$). These results and their significance are discussed.     

Dopamine and norepinephrine turnover in various regions of the rat brain after chronic manganese chloride administration

Rats were treated with MnCl₂ · 4H₂O (1 mg/100 g/day, i.p.) for a period of 4 months. The turnover of dopamine (DA) and norepinephrine (NE) was measured in several brain regions (brain stem, hypothalamus, corpus striatum and “rest of the brain”) by the decay in endogenous DA and NE after inhibition of tyrosine hydroxylase by α-methylparatyrosine. Monoamine oxidase (MAO) activity and manganese levels were also estimated. Manganese treatment produced a decrease in DA level and turnover in the corpus striatum but not in the rest of the brain. An increase in contents of NE was observed both in the brain stem and hypothalamus. NE turnover was found to be increased in the brain stem, decreased in the hypothalamus and unaltered in the rest of the brain. MAO activity was not significantly altered in all the brain regions studied. These results which show that chronic administration of manganese may cause regionally different changes in catecholamine turnover were discussed in relation to the accumulation of manganese in the brain regions and to other metabolic changes associated with manganese toxicity.     

Behavioral and neurochemical effects of repeated administration of delta 9-tetrahydrocannabinol in rats

The effects of repeated administrations of Δ⁹-tetrahydrocannabinol (THC, 10 mg/kg i.p. twice daily at 8-hr interval) were investigated on spontaneous motor activity (SMA) in 2.5 hr daily sessions and on the levels of various neurotransmitters (e.g. norepinephrine, NE; dopamine, DA; serotonin, 5-HT) in different brain areas such as caudate nucleus (CN), pons-medulla (PM) and diencephalon-midbrain (DM) in rats. After a single dose of the drug, the SMA of rats decreased during the first hour postdrug along with a decrease of DA levels in the CN and DM and NE levels in the DM and PM, and increase of 5-HT levels in the DM and PM. Following repeated daily administration, the SMA gradually decreased during the first hour postdrug to a minimum on day 5, and then increased beyond the normal level on day 8 reaching its peak on day 10. The SMA then decreased again and remained close to the normal level on day 15 onwards. Concomitantly, DA and NE levels decreased to their minimum, and 5-HT levels increased to their maximum in the respective brain areas on day 5; the levels of neurotransmitters then gradually approached their normal up to day 15. Thus, during the first hour after repeated administration of THC, the changes in behavioral depression can be correlated to the changes in the brain neurotransmitter levels. During the second hour of THC action, SMA was enhanced. On its repeated administration, this increase was gradually reduced up to day 6 after which SMA was again increased to its peak between day 8 and day 10 and then decreased. These behavioral changes could also be correlated with the changes in DA and 5-HT levels in the brain areas during the second hour postdrug after repeated administration.     

Effects of Panax ginseng root on the vertical and horizontal motor activities and on brain monoamine-related substances in mice

Effects of the Panax ginseng root (PGR) on spontaneous motor activity (vertical and horizontal motor activities), and on monoamine-related substances (tyrosine, DA, DOPAC, 3-MT, HVA, NE, MHPG, tryptophan, 5-HT, and 5-HIAA) in discrete brain areas (cerebral cortex, hippocampus, hypothalamus, corpus striatum, limbic lobe, midbrain, cerebellum, and medulla oblongata) of ddY male mice (weighing 18-22 g) were examined using an infrared photo-cell counter and HPLC with electrochemical detection. PGR (100 mg/kg) was orally administered, twice a day, for 2 successive weeks (2W-group) or 7 successive weeks (7W-group). Vertical and horizontal motor activities increased significantly in the 7W-group but not in the 2W-group when compared to those of the control group. As to brain monoamine-related substances, the metabolism of DA and NE in the cerebral cortex and of 5-HT in the corpus striatum and cerebellum in the 2W-group were facilitated, while metabolism of DA in the corpus striatum and of 5-HT in the hypothalamus and midbrain were inhibited. In the 7W-group, except for a facilitated metabolism of 5-HT in the cerebellum, metabolism of DA, NE and 5-HT in all discrete brain areas were inhibited. These results show that PGR exerts an influence on the CNS.     

Post-mortem degradation kinetics of brain norepinephrine

The post-mortem degradation kinetics of norepinephrine (NE) from brain stored at 25°, 15°, 0°, ?5° and ?10° have been determined. The first 20 per cent of NE was lost by zero-order kinetics, while degradation of the major part of the remaining NE followed two consecutive first-order processes. Both the zero- and first-order constants showed a temperature dependency and were used to construct Arrhenius temperature plots. The zero- and first-order rate constants yielded energies of activation of 17.2 and 16.3 $\text{kcal}\text{mole}$ respectively. When stored at 25°, approximately 25 per cent of total NE remained in mouse brain 144 hr after death. The amount of NE remaining 144 hr postmortem increased as the storage temperature decreased. Post-mortem NE degradation kinetics also were studied in rats. The NE degradation kinetics in rat brain were similar to those observed in mice. Although the zero-order degradation rate constant for rats was about one-third that found for mice, no difference was found in the first-order rate constants. Oxidative metabolism of NE in rat brain stopped shortly after death and metabolism proceeded non-oxidatively via normetanephrine. Monoamine oxidase (MAO) activity in mouse brain post-mortem also was found to be temperature dependent. Approximately 75 per cent of MAO activity remained in mouse brain when stored for 144 hr at 25°, while approximately 90 per cent remained when stored at ?10°.     

Excitatory amino acid analogues: Neurotoxicity and seizures

The neurotoxic and convulsant properties of conformationally restricted and synthetic analogues of excitatory acidic amino acids were examined after stereotaxic injection into the striatum and the dentate gyrus of the hippocampal formation. In the striatum, neurotoxicity was quantified by the reduction in the activity of choline acetyltransferase and glutamate decarboxylase, markers for striatal intrinsic neurons. The following sequence of neurotoxic potencies was defined; kainic acid ～- domoic $\text{acid}\text{? α-}\text{keto kainic acid}\text{>}\text{ibotenic acid}\text{～- cis-}\text{cyclopentyl glutamic acid}\text{>}\text{quisqualic acid}\text{～- N-}\text{methyl}\text{-}\text{d}\text{-}\text{aspartic acid}$. When normalized for neurotoxic potencies, a wide variation in the convulsant effects of the agents was observed after hippocampal injection. $\text{N-}\text{Methyl}\text{-}\text{d}\text{-}\text{aspartate}$ produced nearly continuous electroencephalographic seizures for 2 hr after injection, where α-ketokainate and quisqualate caused seizure activity for 64 and 45% respectively of this period; kainate, α-allo kainate and domoate caused intermittent seizure activity during approximately 30% of the recording period; ibotenate and cyclopentylglutamate had minimal convulsant effects. Seizures were associated with a significant reduction in the levels of norepinephrine and with increases in the levels of 5-hydroxy-indoleacetic acid in the cortex and hippocampal formation and increases in the levels of γ-aminobutyric acid in the hippocampal formation. Kainate, domoate, keto-kainate and α-allo-kainate caused extensive lesions of the hippocampal formation that also involved the pyriform cortex; ibotenate and cyclopentylglutamate caused uniform but substantial lesions limited to the dentate gyrus, whereas quisqualate and $\text{N-}\text{methyl}\text{-}\text{d}\text{-}\text{aspartate}$ produced small and restricted lesions. The results demonstrate a poor correlation between the neurotoxic and convulsant potencies of these excitatory amino acid analogues and suggest that receptor-specific interactions may account for these disparities.     

Effect of intraventricular injections of 6-hydroxydopamine in neonatal rats on the catecholamine levels and tyrosine hydroxylase activity in brain regions at maturity.

Intraventricular injections of 6-hydroxydopamine (6-OHDA, 25 μg) on days 1 and 2 after birth produced a marked change in tyrosine hydroxylase activity in only one rat brain region, the corpus striatum, whereas the ability of brain tissue to synthesise catecholamines, as measured by the rate of tyrosine hydroxylation in brain homogenates, was significantly reduced in amygdala, cortex, hippocampus, hypothalamus, septum and thalamus, and greatly increased in both dorsal and ventral pons. Both increases and decreases in the rate of tyrosine hydroxylation in all brain regions with the exception of the corpus striatum and septum were blocked by pretreatment of the newborn rats with desmethylimipramine (DMI) 45 min before the 6-OHDA. Similarly, norepinephrine (NE) levels were reduced in amygdala, cortex, hippocampus, hypothalamus, septum and thalamus, and increased in cerebellum, medulla, midbrain and pons. These 6-OHDA-induced changes in NE were also blocked by DMI pretreatment. The NE and dopamine (DA) levels and the rate of tyrosine hydroxylation were markedly reduced in striatum, and DMI again blocked the depletion of NE but potentiated both the decrease in DA and the decreased rate of tyrosine hydroxylation. It is suggested that the pattern of decreased NE levels in forebrain regions and increased NE levels in hindbrain after neonatal 6-OHDA treatment does not depend on degeneration of forebrain terminals, since at suitably low 6-OHDA levels the NE changes can be shown to occur in the absence of changes in the tyrosine hydroxylase activity.     

Choline acetyltransferase activity and mass fragmentographic measurement of acetylcholine in specific nuclei and tracts of rat brain.

The mass fragmentographic assay of acetylcholine (ACh) is the only available method to measure the acetylcholine content of rat brain nuclei. The ACh concentration and the choline acetyltransferase activity (ChA) of specific rat brain nuclei and tracts are reported. The highest ACh concentration (1.2 $\text{nmol}\text{mg}$ protein) and ChA activity (576 $\text{nmol}\text{mg}$ protein per hr) was in the nucleus interpeduncularis, which possessed twice as much ACh and ChA as the nucleus accumbens and nucleus caudatus. The midbrain nuclei: dorsalis raphes and linearis pars caudalis contained as much ACh as the nuclei accumbens and caudatus but the ChA activity was only a fraction of that of the accumbens and caudatus. The three pontine nuclei: locus eoeruleus, tegmenti dorsalis and dorsalis vagi contained slightly less ACh than the nuclei accumbens and caudatus but the ChA varied. It was low in the locus coeruleus but 10- fold higher in the dorsalis vagi. It is proposed that the ratio of ACh content to ChA activity may have some predictive value to determine whether most of the ACh measured in various brain nuclei is located in cell bodies or axon terminals. The data presented are compared with histochemical data on the location of acetylcholinesterase (Palkovits and Jacobowitz, 1974). This comparison suggests that when the ratio ACh/ChA × 100 is greater than 0.7 and the ACh content is 0.30 $\text{nmol}\text{mg}$ protein or greater, the transmitter may be located in nerve terminals. When this ratio is smaller than 0.4 and the ChA activity is greater than 5.0 $\text{nmol}\text{mg}$ protein per hr, the ACh measured may be located in cholinergic cell bodies or small cholinergic interneurones. This suggestion is supported by measurement of the ACh concentration and ChA activity in brain nuclei which are known to contain cholinergic cell bodies (e.g. motor nucleus of the vagus), small cholinergic interneurones (n. caudatus and n. accumbens) and cholinergic nerve terminals (n. locus coeruleus, dorsalis raphes).     

Methyl bromide alters catecholamine and metabolite concentrations in rat brain

The effects of inhalation exposure of rats methyl bromide (MB) on dopamine (DA), homovanillic acid (HVA), norepinephrine (NE), 3-methoxy-4-hydroxyphenylglycol (MHPG), serotonin (5HT), and 5-hydroxyindoleacetic acid (5HIAA) concentrations of various brain regions (striatum, hypothalamus, frontal cortex, midbrain, and medulla oblongata) were investigated. Rats received a single 8 hr exposure to MB, and amines and metabolites were separated by a reverse-phase HPLC, and were quantified via native fluorescence. An exposure to 100 ppm MB decreased tissue levels of DA and NE in all brain areas at 0 or 2 hr following exposure. HVA and MHPG contents were significantly increased in almost all brain regions. In a second study, rats were exposed to four concentrations of MB ranging from 31-250 ppm, and monoamine and metabolite levels in brain regions measured immediately after the exposure. Again, there were dose-dependent decreases of DA and NE, and increases in HVA and MHPG. Less clear changes in 5 HT and 5HIAA contents were observed. These data suggest that alterations of catecholamine metabolism may be a factor in MB-induced neurotoxicity.     

Behavioral depression and its neurochemical correlates at high doses of d-amphetamine in rats

D-Amphetamine at low doses (0.5–1.0 mg/kg; base i.p.) increased spontaneous motor activity (SMA) and induced stereotypy (ST) in rats with the peak effects occurring during the 2nd hr. Dopamine (DA) levels in the caudate nucleus (CN) and diencephalon-midbrain (DM) as well as the noreptnephrtne (NE) level in the DM were markedly elevated at 60 min postdrug. However, at high doses (2 mg/kg or more) the peak effect on SMA occurred during the 1st hr and was decreased, whereas ST was further enhanced; neurochemically, DA level in the DM and serotonin (5-HT) level in the pons-medulla (PM) showed most marked elevation. Decrease in SMA at high doses appears to be partly due to DA-related increase in ST and partly due to an enhanced inhibitory 5-HT mechanism.     

Naloxone-precipitated changes in biogenic amines and their metabolites in various brain regions of butorphanol-dependent rats

Influence of a naloxone (an opioid receptor antagonist) challenge (5 mg/kg, IP) on levels of biogenic amines and their metabolites in various brain regions of rats infused continuously with butorphanol (a μ/δ/κ mixed opioid receptor agonist; 26 nmol/μl/h) or morphine (a μ-opioid receptor agonist; 26 nmol/μl/h) was investigated using highperformance liquid chromatography with electrochemical detection (HPLC-ED). Naloxone precipitated a withdrawal syndrome and decreased the levels of: dopamine (DA) in the cortex and striatum, 3,4-dihydroxyphenylacetic acid (DOPAC) in the striatum, homovanilic acid (HVA) in the striatum, limbic, midbrain, and pons/medulla regions in butorphanol-dependent rats. However, the levels of norepinephrine (NE), serotonin (5-hydroxytryptamine; 5-HT), and 5-hydroxyindoleacetic acid (5-HIAA) in the regions studied were not affected by naloxone-precipitated withdrawal. In addition, naloxone increased the HVA/DA ratio in the cortex, while this ratio was reduced in the limbic, midbrain, and pons/medulla. The reduction of 5-HIAA/5-HT ratio was also detected in the limbic area. In the animals rendered dependent on morphine, the results obtained were similar to those of butorphanol-dependent rats except for changes of 5-HIAA levels in some brain regions. These results suggest that an alteration of dopaminergic neuron activity following a reduction of DA and its metabolites in specific brain regions (e.g., striatum, limbic, midbrain, and pons/medulla) play an important role in the expression of the opioid withdrawal syndrome.     

Action in vitro and in vivo of chlorpromazine and haloperidol on cyclic nucleotide systems in mouse cerebral cortex and cerebellum.

Three different procedures were utilized to study the action of chlorpromazine (CPZ) and haloperidol on adenylate cyclase-cyclic nucleotide systems in the mouse cerebral cortex and cerebellum. Using incubated tissue slices which in both tissues demonstrate an activation of adenylate cyclase by norepinephrine (NE), CPZ was found to be more effective than haloperidol in reducing this response. With the second method it was shown that adenylate cyclase in homogenates was stimulated in both tissues by NE while dopamine (DA) was active in only the cerebral cortex. With this broken cellular preparation, CPZ exerted greater antagonism than haloperidol on both the NE- and DA-sensitive enzymes. Moreover, the DA-responsive enzymes were blocked by both agents to a greater extent than was observed with the NE-induced stimulation. In the third experiment haloperidol and three doses of CPZ were injected into mice in vivo, at specified intervals; thereafter the tissues were rapidly inactivated by focused microwave irradiation (0.5 sec), and cyclic AMP and cyclic GMP levels were subsequently determined. In general, the acute injections ($\text{1}\text{2}$–8 hr) of CPZ and haloperidol diminished the steady-state levels of the two nucleotides. Subchronic administration (24–48 hr) usually resulted in elevated cyclic AMP amounts. The data indicate that under both in vitro and in vivo conditions, neuroleptics inhibit neurohumorally-induced activation of adenylate cyclase. Subchronic injections, however, suggest other factors become prominent i.e. inhibition of phosphodiesterase or enhanced receptor sensitivity.     

Differences in the Effects of Morphine on the α-Methyl-p-tyrosine-induced Depletion of Dopamine and Noradrenaline in Various Areas of the Mouse Brain

Abstract: The effect of morphine on the α-methyl-p-tyrosine (αMT)-induced depletion of dopamine (DA) and noradrenaline (NA) was studied in various brain areas of male NMRI mice, whose locomotor activity is clearly stimulated by morphine. Morphine (10 mg/kg) accelerated the αMT-induced DA depletion in the striatum and in the area “rest of forebrain + midbrain”, which contains the limbic dopaminergic neurons, but did not clearly alter it in the hypothalamus. The effects were blocked by naloxone. The enhancement of the striatal DA depletion was attenuated when morphine was given after αMT or when morphine dose was increased to 30 mg/kg. The smallest dose of morphine to enhance the αMT-induced NA depletion in the forebrain + midbrain area was 3 mg/kg, and in the hypothalamus and the lower brain stem 10 mg/kg. The enhancement of the NA depletion was dose-dependent, occurred whether morphine was given before or after αMT, and was blocked by naloxone. Our findings suggest that morphine alters the αMT-induced depletion of cerebral DA in mice similarly to what has been reported to occur in rats. In contrast its effects on cerebral NA depletion in mice are clearly different from its effects in rats. The substantial activation of cerebral noradrenergic systems, especially of those in the forebrain + midbrain area, in mice could underly the fact that morphine's predominant behavioural effect in mice is stimulation of motor activity.     

Effects of diisopropyl phosphorofluoridate on acetylcholine, cholinesterase and catecholamines of several parts of rabbit brain

Diisopropyl phosphorofluoridate (DFP) was administered to rabbits in which the pretreatment with a monoamine oxidase inhibitor, JB835, and DOPA caused an elevation in nore-pinephrine (NE) and, to a lesser extent, in dopamine (DA) levels in the thalamus, hypothalamus, midbrain and hippocampus.Pretreatment with JB835-DOPA combination and/or elevation of NE and of DA caused no significant effect upon either cholinesterase activity or acetylcholine (ACh) levels in the caudate nucleus, midbrain, thalamus or hypothalamus. Diisopropyl phosphorofluoridate caused nearly complete inhibition of cholinesterase activity in all these brain parts whether or not the animals were pretreated with JB835 and DOPA, and with atropine. Diisopropyl phosphorofluoridate induced elevation of levels of ACh was somewhat lowered by JB835-DOPA pretreatment in the case of the thalamus and hypothalamus but not in that of the caudate nucleus or midbrain; atropine but not atropine methyl nitrate further lowered ACh levels in all brain parts.Diisopropyl phosphorofluoridate caused a decrease of NE levels and elevation of DA levels in all 4 brain parts of the pretreated rabbits. In identically pretreated animals atropine methyl nitrate given prior to DFP prevented the DA increase but was without effect upon the NE decrease in these brain parts.Dopamine was affected maximally in the hypothalamus, midbrain and thalamus concomitantly with major increments in ACh at these sites. Maximal decreases in NE occurred in the caudate, thalamus and midbrain; the extent of these changes did not parallel that of the changes in ACh.These findings confirm our earlier results (Glisson, Karczmar and Barnes, 1972) and expand them to additional brain parts. They are discussed with respect to brain localization of ACh and catecholamine systems.     

Receptor involvement in the central noradrenergic inhibition of ACTH secretion in the rat

In male rats the α-blocking agent phentolamine, 1.0 and 2.0 $\text{mg}\text{kg}$ i.p., increased plasma corticosterone 1 hr later. The β-blocking agent propranolol was ineffective in this order. The administration into the third ventricle of the brain of a systemically ineffective dose of phentolamine increased plasma corticosterone when examined 1 hr later. Phentolamine, 2.0 $\text{mg}\text{kg}$ i.p. given 1 hr before laparatomy stress, reduces the dexamethasone plus ipro-niazid-induced block of the adrenocortical activation. Propranolol was not effective in removing this block. These data support the hypothesis of an a receptor mediation of the tonic noradrenergic inhibition of CRF-ACTH secretion.     

A conditioned taste aversion induced by alpha-methyl-p-tyrosine

Rats treated with either four 50 $\text{mg}\text{kg}$ or 100 $\text{mg}\text{kg}$ injections of alpha methyl-p-tyrosine (α-MPT) spaced 12 hr apart acquired an aversion to a 0.1% saccharin solution in a two-bottle choice with water. Rats treated with either saline or four injections of 100 $\text{mg}\text{kg}$ of α-MPT without saccharin present exhibited a complete preference for the saccharin solution. In a subsequent experiment, the saccharin aversion induced by the four 100 $\text{mg}\text{kg}$ α-MPT injection procedure was found to persist after telencephalic norepinephrine had returned to normal levels. Thus, α-MPT was found to be a highly effective drug for inducing a taste aversion at dose levels which did not produce obvious signs of toxicity.     

Cholinergic mechanisms of analgesia produced by physostigmine,morphine and cold water swimming

This study concerns the cholinergic involvement in three experimental procedures which produce analgesia. Rats were given one of seven treatments: saline (1.0 $\text{ml}\text{kg}$, i.p.); morphine sulfate (3.5, 6.0 or 9.0 mg/kg, i.p.); physostigmine salicylate (0.65 mg/kg, i.p.); warm water swim (3.5 min at 28°C); and cold water swim (3.5 min at 2°C). Each rat was tested on a hot plate (59.1°C) once prior to and 30 min after treatment. Immediately after the last test the rats were killed with focussed microwave radiation. Levels of acetylcholine (ACh) and choline (Ch) in six brain areas (brain stem, cerebral cortex, hippocampus, midbrain, cerebellum and striatum) were analyzed by gas chromatograph-mass spectrometer. Morphine (9.0 mg/kg), physostigmine and cold water swimming caused significant analgesia.Morphine elevated the levels of ACh in the cerebellum and striatum, cold water swimming—in the cerebellum, striatum and cortex, and physostigmine—in the striatum and hippocampus. Levels of choline were elevated by morphine in the cerebellum, cortex and hippocampus, while cold water swimming elevated levels of choline in the cerebellum, cortex, striatum and hippocampus. Physostigmine did not change levels of choline in any of the brain areas studied. These data suggest that the analgetic effects of morphine or cold water swimming may be mediated by components of the cholinergic system that differ from those involved in the analgetic effects of physostigmine.     

Myriocin, a serine palmitoyltransferase inhibitor, alters regional brain neurotransmitter levels without concurrent inhibition of the brain sphingolipid biosynthesis in mice

Myriocin is a specific serine palmitoyltransferase (SPT) inhibitor whose effect on the brain is unknown. Brain amine metabolism and sphingolipid biosynthesis were studied in mice treated intraperitoneally with 0, 0.1, 0.3 or 1 mg/kg per day of myriocin for 5 days. Regional concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxytryptamine (5-HT, serotonin), 5-hydroxyindoleacetic acid (5-HIAA) and norepinephrine (NE), were determined. Sphinganine (Sa) and sphingosine (So) concentrations and SPT activity in brain and liver were used to evaluate the impact of myriocin on sphingolipid biosynthesis. Myriocin treatment increased DA in striatum and hippocampus and reduced it in cortex. NE concentration decreased in cerebellum and 5-HT levels were reduced in cortex and in medulla oblongata. Changes in ratios for DOPAC/DA and HVA/DA were observed in hippocampus, cortex and midbrain. Brain Sa, So and SPT activity remained unchanged, whereas Sa and SPT activity decreased in liver. Results showed that myriocin may alter the levels and metabolism of brain amines and this effect is not related with inhibition of sphingolipid biosynthesis in the nervous system.