Increased Dopamine Metabolism Research Articles

Changes of serotonin and dopamine metabolism in various forebrain areas of rats injected with morphine either systemically or in the raphe nuclei dorsalis and medianus

The regional brain metabolism of serotonin (5-HT) and dopamine (DA) was studied in rats injected with morphine either systemically or in the nuclei raphe medianus (MR) or dorsalis (DR). A subcutaneous injection of 10 mg/kg morphine significantly raised the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the diencephalon, striatum, nucleus accumbens and cortex with no effect in the hippocampus. Similar changes in 5-HT metabolism were found in animals injected with 5 μg/0.5 μl in the DR whereas morphine injected in the MR raised 5-HIAA levels only in the nucleus accumbens. A subcutaneous or direct injection of morphine in the DR significantly raised the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens, but injection in the MR was ineffective. All the effects of morphine were blocked by naloxone, injected either intraperitoneally (1 mg/kg) or directly in the raphe nuclei (2 μg/0.5 μl). Pretreatment with parachlorophenylalanine, an inhibitor of serotonin synthesis, significantly reduced the effect of morphine injected in the DR on dopamine metabolism in the striatum and nucleus accumbens. The data suggest that a major mechanism by which morphine increases 5-HT metabolism in the rat forebrain is activation of 5-HT cells in the nucleus raphe dorsalis, and this action may contribute to the increased DA metabolism found in the animal injected with morphine in this brain area.

Effect of acute ether stress on monoamine metabolism in median eminence and discrete hypothalamic nuclei of the rat brain and on anterior pituitary hormone secretion.

This study was designed to correlate the endocrine responses elicited by acute ether stress with the changes in metabolism of several monoamines in discrete nuclei of the rat brain. Concentrations of norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) and also of the specific metabolites of NE, DA, and 5-HT, 3-methoxy-4-hydroxyphenylethylene glycol, 3,4-dihydroxyphenylacetic acid, and 5-hydroxyindole-3-acetic acid, respectively, were concurrently measured in microdissected nuclei using high-performance liquid chromatography with electrochemical detection. The ratio of the metabolites to their respective amines was used as an estimate of the metabolism of NE, DA, and 5-HT. Acute exposure to ether vapors induced, within 5-15 min, large increments in plasma levels of adrenocorticotropic hormone (ACTH), beta-endorphin, and prolactin (PRL), and decrements in the levels of plasma growth hormone (GH). Significant increases in NE metabolism were observed in the rostral (ANr) and caudal (ANc) divisions of the arcuate nucleus, as well as in the paraventricular (PVN) and dorsomedial nuclei, 15 min after ether stress. A significant decrease in 5-HT metabolism was observed in the PVN, supraoptic nucleus, and ANc, whereas significant increases in 5-HT metabolism were detected in the suprachiasmatic nucleus and ANr. DA metabolism selectively increased in the ANr. The present results indicate that the acute changes in ACTH, beta-endorphin, PRL, and GH release induced by ether exposure are temporally correlated with increases in NE metabolism in many hypothalamic nuclei; a selective increase in DA metabolism restricted to the ANr, and differential effects on 5-HT metabolism, probably reflecting selective activation or inhibition of different populations of 5-HT neurons.

Effect of Middle Cerebral Artery Occlusion on Catecholamine Metabolism in Rat Brain

The authors previously reported on local cerebral glucose utilization (LCGU) and local cerebral blood flow (LCBF) in rats 1 hour after the occlusion of the left middle cerebral artery. It was found that LCGU was decreased in the ipsilateral cerebral cortex and the lateral striatum, where the LCBF was also reduced. On the other hand, LCGU was increased in the ipsilateral medial striatum, olfactory tubercle, globus pallidus, subthalamic nucleus, and lateral habenula, which are the “non-ischemic” regions and closely connected with the dopaminergic neurons. In the present work, catecholamines and their metabolites were measured using the same ischemic model rats. The results were compared with the changes in LCGU and LCBF in the various cerebral regions. Noradrenaline concentration was reduced mainly in the “ischemic” regions, such as the ipsilateral cerebral cortex and lateral striatum, and there was an increase in the “non-ischemic” lateral thalamic nucleus. On the other hand, dopamine (DA) was increased bilaterally in the regions closely connected with dopaminergic neurons. However, 3, 4-dihydroxyphenylacetic acid and homovanillic acid were increased only in the ipsilateral regions and a small decrease was found in the contralateral striatum. These changes in DA and its metabolites indicate that DA metabolism was increased ipsilaterally in both the “ischemic” and “non-ischemic” regions but it was probably inhibited on the contralateral side. Since DA agonist, apomorphine, has been reported to increase energy metabolism (LCGU) mainly in the regions closely connected with the dopaminergic neurons, the results of the present work suggest that the ischemia in the ipsilateral cortex and lateral striatum caused an increase in DA neuron activity, which may be the cause of the increased LCGU in the ipsilateral “non-ischemic” dopamine rich regions, whereas the decrease in LCGU, inspite of the increased DA metabolism in the ipsilateral cortex and lateral striatum, were probably due to the direct effects of ischemia (the depletion of glucose supply). The contralateral change in DA was thought to be a biochemical diaschisis, which was mediated neuronally via a crossed nigrostriatal pathway.

Effects of neonatal monosodium glutamate (MSG) treatment on the hormonal and central monoaminergic dynamics associated with acute ether stress in the male rat

Neonatal treatment with monosodium glutamate (MSG) induces severe neurochemical damage to several brain regions, and these lesions are expressed in adult life by a variety of endocrine and behavioral abnormalities. The present study analyzes the extent of the neurochemical damage to several monoaminergic systems by evaluating the changes in norepinephrine (NE), dopamine (DA), and 5-hydroxytryptamine (5-HT) metabolism induced by the neurotoxin in several discrete hypothalamic loci. Moreover, the study also evaluated the ability of MSG-treated rats to respond to acute ether stress, by measuring the release of ACTH and prolactin induced by ether and correlating those changes with the alterations in monoamine metabolism in the arcuate (AN), dorsomedial (DMN), and suprachiasmatic (SCN) nuclei and in the median eminence (ME). The results indicate that MSG treatment induces marked changes in monoamine metabolism in several of the regions examined. The metabolite of DA, dihydroxyphenylacetic acid, was markedly depressed in the AN, SCN, and DMN. NE metabolism was also significantly lower in the AN of MSG-treated animals. 5-HT metabolism was also altered by MSG treatment, with significant decrements recorded in the SCN, DMN, and AN. Both control and MSG-treated rats showed highly significant increments in ACTH and PRL release 5 and 15 min after exposure to ether vapors. The only quantitative difference between the two groups was a smaller increment in ACTH levels 5 min after ether in the MSG group. Ether stress increased DA metabolism in the AN, NE metabolism in the AN and DMN, and 5-HT metabolism in the SCN in control animals. With the exception of the latter, all these changes in amine metabolism were also observed in the MSG rats. In addition, increased NE and DA metabolism was recorded in the SCN and DMN of MSG-treated rats. The results indicate that although MSG treatment causes severe changes in amine metabolism in discrete brain regions, neither the neurochemical nor the hormone response to ether stress appears to be greatly affected. The additional changes in monoamine metabolism observed in MSG rats after ether may represent part of a compensatory mechanism evoked by the central nervous system in adaptation to the neonatally-induced neurochemical deficits.

Spontaneous recovery from motor asymmetry in adult rats with 6-hydroxydopamine-induced partial lesions of the substantia nigra

Animals with 6-hydroxydopamine-induced partial unilateral lesions of the substantia nigra exhibit spontaneous recovery from motor asymmetry, a transitory increase in dopamine turnover and an increase in tyrosine hydroxylase activity in the denervated striatum. The recovery of function in these animals seems to be due to the compensatory increase in dopamine metabolism as well as due to the time-dependent increase in tyrosine hydroxylase resulting from either enzyme activation or following reinnervation of the denervated striatum by nigral efferents spared by the partial lesions.

Effect of neuroleptic drugs on striatal dopamine release and metabolism in the awake rat studied by intracerebral dialysis

This study investigated the effect of three neuroleptic drugs, (±)-sulpride, haloperidol and cis-flupenthixol, on dopamine release and metabolism in the striatum of the awake rat. Endogenous extracellular dopamine and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HHA), as well as the 5-hydroxytryptamine (5HT) metabolite 5-hydroxyindoleacetic acid (5HIAA), were determined in striatal perfusates in awake rats by using intracerebral dialysis together with high performance liquid chromatography with electrochemical detection. Sulpride (10, 50 and 250 mg/kg), cis-flupenthixol (0.5 and 2 mg/kg) and haloperidol (2 mg/kg) all increased the levels of dopamine in striatal perfusates. However, the time course and magnitude of these effects differed markedly depending upon the neuroleptic used. Sulpiride (10, 50 and 250 mg/kg), cis-flupenthixol (0.05, 05 and 2 mg/kg) and haloperidol (0.05, 0.5 and 2 mg/kg) increased extracellular levels of DOPAC and HVA while having little effect on 5HIAA. In contrast to the effect on dopamine levels the changes in DOPAC and HVA followed similar time courses and were of similar magnitude independent of the neuroleptic used. The response of the dopamine metabolites seemed to occur at lower doses of the neuroleptics than the response of dopamine release itself. Furthermore, there was no close relationship between changes in dopamine as compared to changes in DOPAC and HVA. Finally, there was no correlation between any of the neurochemical changes measured and the occurrence of catalepsy. These data suggest that neuroleptic drugs have two separate actions on the dopamine neuron in vivo, one causing an increase in dopamine release and another producing an increase in dopamine metabolism, which is probably a consequence of increased dopamine synthesis. Furthermore neither of these effects are related to catalepsy.

Effects of agents increasing serotonin transmission on the increase of dopamine metabolism caused by morphine in the rat nucleus accumbens

The effect of subcutaneous injection of 10 mg/kg morphine on homovanillic acid (HVA) concentrations in the nucleus accumbens was studied in rats which had received d-fenfluramine, a serotonin releaser, or m-chlorophenylpiperazine, a serotonin agonist, before morphine. 2.5 mg/kg d-fenfluramine or m-chlorophenylpiperazine had no effect on HVA in the nucleus accumbens but significantly reduced the rise in HVA induced by morphine. None of the drugs modified the levels of morphine in the rat brain. The results suggest that agents increasing serotonin transmission inhibit the effect of morphine on dopamine neurons innervating the nucleus accumbens.

Lithium does not interact with haloperidol in the dopaminergic pathways of the rat brain.

Prophylactic treatment with lithium has been reported to prevent haloperidol-induced dopamine (DA) receptor supersensitivity. If such an effect exists, then lithium may be useful in the prevention of tardive dyskinesia, which is related to the neuroleptic-induced DA hyperfunction. In the experiments reported here chronic lithium administration had no effect on DA synthesis or utilization in the nigrostriatal, mesolimbic, or mesocortical DA pathways in the rat brain. Similarly, lithium had no effect on the increase in DA metabolism induced by the acute administration of haloperidol. Also, chronic lithium treatment failed to modify the biochemical tolerance which developed after prolonged administration of the neuroleptic drug. Supersensitivity of the presynaptic DA receptors, which was induced by prolonged exposure to haloperidol, likewise was unaffected by prophylactic lithium treatment. We conclude that lithium does not affect changes in DA metabolism or receptor supersensitivity induced by haloperidol. These results do not support the use of lithium in neurological disorders that may be related to neuroleptic-induced DA receptor supersensitivity.

Increased dopamine metabolism in the rat neostriatum after toxic doses of d-methylamphetamine

Rats were given repeated large doses of d-methylamphetamine ( d-MA which have been shown to destroy a fraction of nigrostriatal dopamine (DA) nerve terminals. Two to three weeks later, the synthesis of DA in the remaining neostriatal DA terminals was examined by measuring the rate of accumulation of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of L-aromatic amino acid decarboxylase by 3-dihydroxybenzylhydrazine (NSD 1015). The release of DA from surviving DA terminals was also examined by measuring the steady-state level of 3,4-dihydroxyphenylacetic acid (DOPAC). Both the rate constant of the synthesis of DA and the DOPAC/DA ratio were increased in the neostriatum of rats with large depletions of neostriatal DA. These findings suggest that both synthesis and release of neostriatal DA are enhanced in rats in which d-methylamphetamine destroyed a large number of nigrostriatal DA terminals.

The effect of opiate treatment on the postdecapitation reflex and monoamine metabolism in the rat spinal cord

Postdecapitation seizures (PDR) are a spinal reflex which seems regulated by some monoaminergic neurons present in the spinal cord (S.C.). In order to better characterize the role of dopaminergic neurons in PDR, we studied the effect of treatment with opiates, which are known to increase dopamine (DA) and serotonin (5HT) metabolism in the brain, on the duration of PDR and on the metabolism of DA and 5HT in S.C. Morphine, given either IP or ICV, reduced the duration of PDR and increased DA metabolism. Both effects were more evident after systematic administration. [D-Ala 2]Met 5 enkephalin amide acted similarly to ICV administered morphine. Biochemical and behavioral effects were significantly correlated.

Serotonin and dopamine afferents to the rat locus coeruleus: a biochemical study after lesioning of the ventral mesencephalic tegmental-A10 region and the raphe´dorsalis

The monoamine levels in the locus coeruleus (LC) were determined by HPLC following specific lesions of the ventral mesencephalic tegmental-A-10 regions (VMT-A10) and raphe´dorsalis (RD). Only lesions in the VMT-A10 area decreased the dopamine (DA) content, which strongly suggests that the projection from this region to the LC is of dopaminergic nature. Lesions of the RD increased DA metabolism in the LC and provoked significant decreases in the serotonin (5-HT) levels.

Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons

1. 1. The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum. 2. 2. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release. 3. 3. At high doses, sulpiride increases both dopamine metabolism and release. 4. 4. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent.

Evidence that the purported dopaminergic agonist (3,4-dihydroxyphenylimino)-2-imidazolidine (DPI) may reduce rat striatal dopamine turnover by an α 2-adrenergic mechanism

The potent α-adrenergic agonist DPI, which has also been claimed to be a selective dopaminergic agonist, was shown to reduce rat striatal dopamine (DA) synthesis, DA utilization and DA metabolism following intraperitoneal administration (25 μ mol/kg). An analytical procedure for the determination of DPI was developed and its application showed that DPI did not penetrate into the brain in substantial amounts. The possibility of a direct stimulatory action upon striatal presynaptic DA receptors was excluded by the demonstration that DPI lacked effectiveness both in the γ-butyrolactone model and following intrastriatal administration. The selective α-adrenergic agonists phenylephrine ( α 1) and tramazoline ( α 2) also appeared to reduce striatal DA metabolism. The selective α-adrenergic antagonists prazosin ( α 1) and yohimbine ( α 2) decreased and increased DA metabolism, respectively, the yohimbine-induced increase being antagonized by DPI. The carbon-bridge analogue (3,4-dihydroxybenzyl)-2-imidazoline (DHBI) had about the same activity as DPI, whereas the potential DPI metabolite (4-hydroxy-3-methoxyphenylimino)-2-imidazolidine (HMPI) was without effect upon striatal DA metabolism. The results are discussed in relation to the remarkable resemblance with the literature data concerning clonidine. It is concluded that the DPI-elicited attenuation of striatal DA turnover is, in all likelihood, the result of a stimulation of α 2-adrenoceptors possibly located within the central nervous system. The results cast some doubt on the designation of DPI as a selective DA-inhibitory receptor agonist.

Increases in dopamine metabolism are not a general feature of intracranial self-stimulation

Rats with electrodes implanted in the ventral tegmentum and posterior hypothalamus were trained to press a lever to obtain electrical stimulation through the electrodes. Stimulation in animals with ventral tegmental electrodes led to an increased concentration of homovanillic acid and dihydroxyphenylacetic acid in the forebrain of the animals. Stimulation in the posterior hypothalamus did not result in such raised concentrations in spite of the fact that the behaviour from the two sites was indistinguishable. Responding in the posterior hypothalamus was reduced by doses of neuroleptic drug similar to those reported to reduce responding in the ventral tegmental area.

Evidence that noradrenaline modulates the increase in striatal dopamine metabolism induced by muscarinic receptor stimulation

The effect of oxotremorine was studied on the concentration of homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylethylglycol (MHPG) in the corpus striatum of rats. At a dose of 1 mg/kg oxotremorine incresed HVA levels by 68% and MHPG, by 51%. MHPG was also increased in the nucl. accumbens (58%) and neocortex (42%). Pretreatment with clonidine 0.1 mg/kg, abolished the increased in MHPGin the striatum and significantly inhibited the rise in HVA. 1-Propanolol 2.5 mg/kg, but not d-propanolol, had an effect similar to that of clonidine. A lower dose of oxotremorine (0.5 mg/kg) increased striatal HVA by 36% but did not alter MHPG levels This increase in HVA was not reduced by 1-propranolol. Eight days after bilateral lesions of the locu coeruleus, there was a reduction in the basal concentrations of noradrenaline (41%) and MHPG (57%) in the striatum. The data suggest that a higher doses of oxotremorine (1 mg/kg), but not a lower dose (0.5 mg/kg), a noradrenergic pathway is stimulated to increase the rate of metabolism of noradrenaline in the striatum. Oxotrremorine also appears to increase dopamine metabolism in the striatum by at least two separate mechanisms, one of which involves the mediation of noradrenaline.

Feeding increases dopamine metabolism in the rat brain.

Feeding induced by food deprivation is accompanied by an increased production of the dopamine metabolite 3,4-dihydroxyphenylacetic acid in the brains of rats. This neurochemical change occurs in the nucleus accumbens, the posterior hypothalamus, and the amygdala but not in other dopaminergic nerve terminal fields such as the corpus striatum. These results indicate that the release of dopamine from particular groups of central neurons is increased during feeding and suggest that anatomically distinct subgroups of central dopaminergic neurons serve different roles in the regulation of food intake.

Choline administration: Central effect mediated by stimulation off acetylcholine synthesis

Oral administration of either choline or physostigmine to rats stimulated the metabolism of dopamine in brain. Treatment of rats with an acetylcholine receptor blocker (atropine) or an inhibitor of acetylcholine synthesis [4-(1-naphthylvinyl) pyridine] antagonized the choline-induced increase in dopamine metabolism. In contrast to its effect on the choline-induced increase in dopamine metabolism, 4-(1-naphthylvinyl) pryridine did not prevent the increase induced by physostigmine. These results indicate that oral administration of choline augments central cholinergic function, and suggest that the mechanism involves stimulation of the rate of synthesis and release of acetylcholine.

Increased dopamine metabolism in rat striatum after infusions of substance P into the substantia nigra

Increased dopamine metabolism in rat striatum after infusions of substance P into the substantia nigra

Conditioning of striatal dopamine metabolism with methadone, morphine or bulbocapnine as an unconditioned stimulus.

Psychotropic drugs such as methadone, morphine and bulbocapnine produce increments in dopamine metabolism as an unconditioned reflex. When a buzzer noise is used as a conditioned stimulus (CS) with these drugs as unconditioned stimuli, the buzzer CS acquires the properties of the drugs in increasing dopamine metabolism. These results suggest that the brain, like other visceral organs, can be conditioned in terms of neurotransmitter release or metabolism.