DOPA Accumulation Research Articles

NSD 1034: an amino acid decarboxylase inhibitor with a stimulatory action on dopamine synthesis not mediated by classical dopamine receptors.

The accumulation rates of 3,4'-dihydroxyphenylalanine (DOPA) and 5-hydroxytryptophan (5-HTP) after inhibition of aromatic amino acid decarboxylase (AADC) by 3-hydroxybenzylhydrazine (NSD 1015) or 1-(DL-seryl)-2- (2,3,4-trihydroxybenzyl)hydrazine (Ro 4-4602) have widely been used as measurements of the in vivo synthesis rates of monoamines. However, the values of dopamine (DA) turnover in rat striatum obtained using these drugs are much lower than values obtained by other methods. This discrepancy prompted us to further investigate the AADC inhibitor 1-(3-hydroxybenzyl)-1-methylhydrazine (NSD 1034) which earlier has been shown to give a DOPA accumulation rate in the striatum of the same magnitude as other measures of DA turnover. NSD 1034 was found to give a more than twofold higher DOPA accumulation rate than NSD 1015, NSD 1024, NSD 1039, NSD 1055 and Ro 4-4602 in the striatum. Also, in the limbic region and the hemispheres, but not in the substantia nigra, the DOPA accumulation was higher after NSD 1034 than after NSD 1015, but the difference was less pronounced. There was, however, no difference in 5-HTP accumulation between the drugs in any of the brain parts investigated. Although the DOPA accumulation rates are higher after NSD 1034 than after NSD 1015, the NSD 1015-induced DOPA accumulation seems to be more sensitive to changes in dopamine receptor occupancy. The different DOPA accumulation rates obtained with NSD 1015 and NSD 1034 are not due to differences in MAO inhibition, to interference with classical DA receptors, or to different degrees of AADC inhibition, but to an ability of NSD 1034 to stimulate DA synthesis. In addition, under certain conditions NSD 1034 also has a DA releasing action, like amphetamine. It is proposed that NSD 1034 and amphetamine stimulate DA synthesis and release by a common mechanism. The low value of DA synthesis rate, obtained when measured as DOPA accumulation after NSD 1015, is due to a substantial efflux of DOPA from the brain. The efflux of DOPA is equally large after NSD 1034 but the loss is compensated for by an increase in DOPA synthesis.

Decrease in tetrahydrobiopterin content and neurotransmitter amine biosynthesis in rat brain by an inhibitor of guanosine triphosphate cyclohydrolase

To investigate the regulatory role of tetrahydrobiopterin in neurotransmitter amine biosynthesis, 2,4-diamino-6-hdyroxypyrimidine, a potent inhibitor of guanosine triphosphate cyclohydrolase which is a rate-limiting enzyme of tetrahydrobiopterin biosynthesis, was administered intraperitoneally to weanling rats. Four h after 4 injections at 4-h intervals, the biopterin contents in plasma and liver were reduced to the level of 9 and 3.5%, respectively, of those in the control group injected with saline; while the contents in the whole brain, neocortex + striatum, diencephalon, and brainstem were 34, 50, 33 and 28%, respectively, of the control level. When in vivo tyrosine and tryptophan hydroxylase activities were measured over a 30-min period after the inhibition of aromatic amino acid decarboxylase, the accumulation of dihydroxyphenylalanine was reduced to 74, 77, 67 and 69% of the control in the whole brain, neocortex + striatum, diencephalon, and brainstem, respectively; and the accumulation of 5-hydroxytryptophan, to 71, 74, 66 and 65% of the control, respectively. On the other hand, 5-hydroxytryptamine and 5-hydroxyindole acetic acid contents were not altered in any brain regions, although norepinephrine and dopamine contents were reduced to approximately 70% of the control in the brainstem and the contents of dopamine metabolites were significantly decreased in the diencephalon and brainstem. Plasma phenylalanine level was significantly elevated, while the plasma tyrosine level was reduced, compared with the control level of these amino acids. These results indicate that the drug-treated rats could be an animal model for tetrahydrobiopterin-deficient disease involving neurological disorder.

Effects of postpuberal castration on dopamine receptor sensitivity in the male rat brain.

In order to study the effects of castration of brain dopamine (DA) receptor sensitivity, the effects of apomorphine on locomotor activity and striatal DA synthesis, as assessed by the dihydroxyphenylalanine (DOPA) accumulation after NSD-1015 treatment, were examined in normal and castrated male Sprague-Dawley rats pretreated with reserpine (5 mg/kg-18 hrs). There was an enhanced locomotor response to apomorphine (0.05-0.1 mg/kg) in castrated animals, as compared to sham operated controls. Furthermore, the increase in DOPA accumulation produced by the reserpine treatment was antagonized to a greater extent by apomorphine in the castrated animals. These results indicate an enhanced DA receptor sensitivity at both pre- and post-synaptic sites.

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC-4392), a presynaptic dopamine autoreceptor agonist and postsynaptic D2 receptor antagonist

7-[3-(4-[2,3-dimethylphenyl]piperazinyl)propoxy]-2(1H)-quinolinone (OPC- 4392), was synthesized in our laboratories and compared with apomorphine, 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) and dopamine antagonists in a series of tests designed to characterize dopamine receptor activation and inhibition. The assertion that OPC-4392 acts as an agonist at presynaptic dopamine autoreceptors is supported by the following behavioral and biochemical observations: OPC-4392, 3-PPP and apomorphine inhibited the reserpine-induced increase in DOPA accumulation in the forebrain of mice and in the frontal cortex, limbic forebrain and striatum of rats. In addition, the gamma-butyrolactone (GBL)-induced increase in DOPA accumulation in the mouse forebrain was also inhibited by OPC-4392. 3-PPP and apomorphine. Haloperidol antagonized the inhibitory effect of OPC-4392 in both instances. The inhibitory effect of OPC-4392 on GBL-induced DOPA accumulation lasted for at least 8 hours after oral administration to mice, while that of 3-PPP and apomorphine disappeared in 4 hours after subcutaneous injection. OPC-4392 failed to increase spontaneous motor activity in reserpinized mice, enhance spontaneous ipsilateral rotation in rats with unilateral striatal kainic acid (KA) lesions, induce contralateral rotation in rats with unilateral striatal 6-hydroxydopamine (6-OHDA) lesions and inhibit 14C-acetylcholine (Ach) release stimulated by 20 mM KCl in rat striatal slices. In addition, OPC-4392 appears to block postsynaptic D2 receptors since OPC-4392, as well as dopamine antagonists, was able to inhibit stereotyped behavior and climbing behavior induced by apomorphine in mice, displace the 3H-spiroperidol binding to rat synaptosomal membranes in vitro and reverse the inhibitory effect of apomorphine on Ach release in rat striatal slices. These results suggest that OPC-4392 acts as a dopamine agonist at presynaptic autoreceptors related to dopamine synthesis and acts as dopamine antagonist at postsynaptic D2 receptors.

A nonisotopic method for determination of the in vivo activities of tyrosine hydroxylase in the rat adrenal gland

A rapid and reliable method for determination of in vivo activities of tyrosine hydroxylase in the rat adrenal gland is presented. This method involves determining the rate of accumulation of 3,4-dihydroxyphenylalanine (Dopa) in the adrenal gland after decarboxylase inhibition by NSD 1015, using HPLC with electrochemical detection after purification of the acid-deproteinized tissue extract with Bio-Rex 70 columns followed by alumina batch method. Purification of the sample with alumina adsorption alone, a method usually used for purification of catecholamines and Dopa, was ineffective: epinephrine and norepinephrine, which are present in high concentrations, interfered with an accurate determination of Dopa, and dopamine, which is retained strongly on the reverse-phase column, interfered with a rapid analysis. Purification with Sephadex G-10 columns followed by alumina adsorption was also ineffective. After purification with columns of weak cation-exchange resins such as Bio-Rex 70 or Amberlite CG-50 followed by alumina adsorption, most of the epinephrine and norepinephrine was removed and dopamine was eliminated. Thus a rapid and accurate determination of Dopa could be made. Of the two cation exchangers, Bio-Rex 70 was more effective. Accumulation of Dopa in the adrenal gland was linear up to 30 min after administration of NSD 1015 and a plateau was reached with doses over 10 mg/kg. Using this method, we investigated the effects of immobilization stress, reserpine, and hypoxia on in vivo activities of tyrosine hydroxylase in the adrenal gland.

Differential response to immobilization stress of striatal dopaminergic and hippocampal noradrenergic systems in aged rats

The effect of restraint stress on synthesis of central norepinephrine (NE) and dopamine (DA) was studied in adult and old rats. The rate of in vivo synthesis of the two catecholamines was determined in hippocampus (a prevalently noradrenergic area) and in striatum (a prevalently dopaminergic area) by measuring the accumulation of DOPA for 60 min after decarboxylase inhibition. NE synthesis was stimulated by stress in the first 30 min, after which the accumulation of DOPA declined. The stimulation was much greater in old rats. In striatum, endogenous DOPA concentration was significantly lower in old rats. Stress significantly enhanced DOPA accumulation in the first 30 min in both age groups but after this interval accumulation continued linearly only in young rats. These results indicate that in aged rats the response to stress of some noradrenergic and dopaminergic systems may be altered in opposite directions.

Activity of tuberoinfundibular dopaminergic neurons and concentrations of serum prolactin in the rat following lithium administration.

Maintenance of rats on a lithium-containing diet for 3-21 days resulted in a suppression of prolactin (PRL) secretion in vivo and in vitro. Lithium treatment also resulted in an increase in the activity of tuberoinfundibular dopaminergic neurons, as evidenced by an increased accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after inhibition of DOPA decarboxylase and an increased concentration of dopamine in the anterior pituitary gland. The accumulation of DOPA in the neurointermediate lobe of the pituitary gland, the prefrontal cortex, the striatum and the nucleus accumbens was also enhanced by lithium treatment. It is concluded that lithium treatment enhances the synthesis of dopamine in many brain regions and that an increased activity of tuberoinfundibular dopaminergic neurons results in an enhanced inhibitory control of PRL secretion.

Effect of electrical stimulation of the ventromedial nucleus and the dorsomedial nucleus on the activity of tuberoinfundibular dopaminergic neurons.

Perikarya and terminals of tuberoinfundibular dopaminergic (TIDA) neurons are located in the arcuate nucleus (ARN) and in the median eminence (ME), respectively. Dopamine (DA) released from TIDA terminals in the ME inhibits prolactin secretion from the anterior pituitary. Anatomical studies have described the sources of afferents to ARN and ME, but not to TIDA neurons per se. The ventromedial nucleus (VMN) and the dorsomedial nucleus (DMN) of the hypothalamus project to ARN and ME and have a role in prolactin regulation. In the present study, VMN and DMN were investigated as possible sources of TIDA afferents. Alterations in the activity of TIDA neurons were estimated by measuring plasma concentrations of prolactin and the rates of DA synthesis (3,4-dihydroxyphenylalanine - DOPA - accumulation after administration of the decarboxylase inhibitor NSD 1015) and metabolism (concentrations of the DA metabolite 3,4-dihydroxyphenylacetic acid - DOPAC) in the ME following electrical stimulation of ARN, VMN, and DMN in ovariectomized female rats. Thirty minutes of bilateral stimulation of ARN or DMN increased DOPA accumulation in the ME; stimulation of the VMN had no effect. 5-Hydroxytryptamine synthesis in the ME was unaffected by stimulation of any region. Plasma prolactin levels declined during DMN stimulation, varying with the frequency and duration of the electrical stimulus. DA metabolism within TIDA neurons increased with DMN stimulation, as evidenced by increased DOPAC concentrations in the ME. In females whose basal TIDA activity has been increased by haloperidol treatment or decreased by bromocriptine treatment, DMN stimulation was still able to increase DOPA accumulation in the ME. The present data suggest the presence of stimulatory TIDA afferents originating from or passing through the DMN.

Absence of synthesis-modulating nerve terminal autoreceptors on mesoamygdaloid and other mesolimbic dopamine neuronal populations

The present study sought to map the distribution of dopamine (DA) synthesis-modulating autoreceptors on DA nerve terminals innervating the amygdala and other limbic structures of the rat brain at a level of anatomic resolution (i.e., discrete component nuclei) commensurate with the functional organization of such structures. The biochemically estimated response of mesoamygdaloid and other limbic DA neuronal populations to conditions of minimal (gammabutyrolactone administration or surgical axotomy) and maximal (low-dose apomorphine administration) activation of nerve terminal DA autoreceptors was examined and compared to the response of mesostriatal and mesocortical DA neurons. In contrast to the caudate nucleus, nucleus accumbens, and olfactory tubercle, neither gammabutyrolactone (GBL) nor axotomy increased biochemically estimated DA synthesis (DOPA accumulation) in any of the amygdaloid nuclei, the anterior amygdaloid area, septal nuclei, or subdivisions of the interstitial (bed) nucleus of the stria terminalis. These results indicate that, similar to the medial prefrontal cortex and median eminence, DA synthesis in mesoamygdaloid and other subcortical limbic DA neuronal populations is not under the regulatory influence of tonically active, nerve terminal-localized autoreceptors. Both GBL and axotomy increased DOPA accumulation in the anterior cingulate cortex, but not in allocortical projection fields. In contrast to the differential distribution of DA synthesis-modulating terminal autoreceptors, the end-product inhibition of tyrosine hydroxylase activity appears to be a ubiquitously expressed regulatory property of DA neurons. The decrease in DA metabolism produced by the administration of a low, presumably auto-receptor-selective, dose of apomorphine exhibited a DA neuronal population distribution distinctly unlike that of the aforementioned effects of GBL or axotomy on DOPA accumulation. These results reinforce the DA neuronal population-selective distribution of synthesis-modulating autoreceptors and indicate that nerve terminal-localized autoreceptors are operative in regulating DA synthesis in only a minority of DA-innervated brain structures. Further, the demonstration of such autoreceptors is dependent upon the preparation, pharmacological tools, and functional endpoints chosen for study.

Effects of the C3-methylated derivatives of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on central 5-hydroxytryptamine receptors

The effects of the four possible C3-methylated stereoisomers of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) ((−)-CM-11, (+)-CM-11, (−)-CM-12, (+)-CM-12) on brain 5-hydroxytryptamine (5-HT) receptor functions were studied in rats. (−)-CM-11 and (+)-CM-12 inhibited dose dependently in all brain parts the accumulation of 5-hydroxytryptophan following decarboxylase inhibition. Their antipodes were inactive. The disappearance of 5-HT induced by α-propyldopacetamide was retarded by (−)-CM-11 and (+)-CM-12. The biochemically active isomers produced a flat body posture and forepaw treading. The results indicate that (−)-CM-11 and (+)-CM-12 stimulate 5-HT receptors directly although not as potently as 8-OH-DPAT. The concentration of dopamine was lowered and that of homovanillic acid was elevated by (+)-CM-11 and by both enantiomers of CM-12 in the corpus striatum and in the limbic system of rats. The accumulation of DOPA following decarboxylase inhibition was not markedly changed by any of the compounds. Locomotor activity was enhanced by (+)-CM-11 but not by any of the other compounds, and the effect was haloperidol-resistant. (+)-CM-11 induced no asymmetry in rats in which the corpus striatum was inactivated on one side. Thus, none of the isomers of CM-11 or CM-12 appears to have any effect on the dopamine receptors.

Region-selective activation of brain monoamine synthesis by sexual activity in the male rat

In vivo catecholamine and 5-HT synthesis during sexual activity and treadmill locomotion was estimated in male rats by measuring the accumulation of DOPA and 5-HTP after inhibition of cerebral aromatic amino acid decarboxylase by means of NSD-1015 (100 mg · kg − i.p.). An increase in catecholamine as well as 5-HT synthesis during sexual activity was observed in both the neostriatum and the nucleus accumbens. An increase in catecholamine synthesis during treadmill locomotion was found in the neostriatum only. No significant changes in monoamine synthesis were found in the septal area or in the anterior hypothalamus.

Effect of electrical stimulation of the arcuate nucleus on neurochemical estimates of tuberoinfundibular and tuberohypophysical dopaminergic neuronal activities

The activity of nigrostriatal dopaminergic neurons has been estimated biochemically by measuring the rates of dopamine (DA) synthesis (accumulation of dihydroxyphenylalanine (DOPA) after NSD 1015) and turnover (decline of DA concentrations after α-methyltyrosine) in the striatum. It has been assumed that the activities of tuberinfundibular dompaminergic (TIDA) and tuberohypophysial dopaminergic (THDA) neurons can also be estimated by making the same measurements in the terminals of these neurons in the median eminence and the posterior pituitary, respectively. In the present study, this assumption was tested directly by measuring the rates of DA synthesis and turnover in the median eminence and posterior pituitary following electrical stimulation of TIDA and THDA cell bodies in the arcuate nucleus. Electrical stimulation of the arcuate nucleus increased the rate of DOPA accumulation and the α-methyltyrosine-induced decline of DA concentrations in the median eminence and in the neural and intermediate lobes of the posterior pituitary. γ-Butyrolactone (GBL), an anesthetic that selectivelly inhibits DA impusle flow, reduced by the rates of DA synthesis and turnover in the median eminence. GBL also increased prolactin secretion which is tonically inhibited by DA released from TIDA neurons. Serum prolactin levels were significantly decreased by arcuate nucleus stimulation in GBL-anesthetized rats. These results indicate that the rates of DA synthesis and turnover within the median eminence and posterior pituitary reflect the activities of TIDA and THDA neurons, respectively.

Differential effects of haloperidol, clozapine, and fluperlapine on tuberoinfundibular dopamine neurons and prolactin secretion in the rat.

Two atypical neuroleptic agents, clozapine and fluperlapine, produced rapid elevations in plasma PRL concentrations that were similar in magnitude to those produced by haloperidol. However, the PRL response to clozapine or fluperlapine was of much shorter duration than that elicited by haloperidol. Clozapine, but neither fluperlapine nor haloperidol, produced a rapid increase in the activity of tuberoinfundibular dopamine (TIDA) neurons, as evidenced by an enhanced accumulation of dihydroxyphenylalanine (DOPA) in the median eminence after the inhibition of DOPA decarboxylase. The clozapine-induced increase in DOPA accumulation was evident within 30 minutes after its administration and persisted for at least 4 hours. The clozapine-induced increase in the activity of TIDA neurons may account, in part, for the abbreviated PRL response to this neuroleptic. In addition, ability to produce a short-lived increase in PRL secretion in the rat appears to be common to the atypical neuroleptic drugs.

Lesions of dopamine neurons in the medial prefrontal cortex: effects on self-administration of amphetamine and dopamine synthesis in the brain of the rat.

It has been suggested that dopamine (DA)-containing neurons within the medial prefrontal cortex subserve a role in the positive reinforcing effects of psychomotor stimulants. Injections of 6-hydroxydopamine (6-OHDA) into this region, which destroyed a major portion of the DA innervation, but maintained the integrity of noradrenergic and serotonergic neurons, failed to alter either the acquisition or maintenance of the intravenous self-administration of d-amphetamine in rats. Compared to vehicle-injected controls (sham lesions), the animals treated with 6-OHDA acquired the drug-abuse behaviour and maintained comparable, stable rates of self-injection. The lesions increased concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the nucleus accumbens septi but not in the striatum. The increased synthesis of DA in the nucleus accumbens septi [demonstrated by increased accumulation of dihydroxyphenylalanine (DOPA)] was abolished by the intravenous administration of d-amphetamine, in patterns mimicking those of animals trained in self-administration.

Turnover of dopamine and dopamine metabolites in rat brain: comparison between striatum and substantia nigra.

Measurements of the turnover of dopamine (DA) and DA metabolites have been performed in the striatum and substantia nigra (SN) of the rat. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid have been assessed from the disappearance rates after blocking their formation by inhibition of monoamine oxidase by pargyline and of catechol-O-methyltransferase by tropolone. DA turnover has been measured as 3-methoxytyramine (3-MT) plus DA accumulation rate after MAO inhibition by pargyline and as accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD 1015 or NSD 1034. These measures of DA turnover have been compared with alpha-methyl-p-tyrosine (alpha-MT)-induced DA disappearance rate. In SN all the different measures of DA turnover are in the same range (55-62 nmol/g protein/h) whereas in striatum DOPA accumulation rate after NSD 1015 and alpha-MT-induced DA disappearance rate (16-23 nmol/g/h) are much lower than DOPAC disappearance rate after pargyline, 3-MT plus DA accumulation rate after pargyline, and DOPA accumulation rate after NSD 1034 (39-46 nmol/g/h). The data confirm our previous findings indicating that the fractional turnover rate of DA is more rapid in SN than in striatum and that O-methylation of DA is relatively more important in SN. In striatum at least two pools of DA with different turnover rates appear to exist, whereas in SN, DA behaves as if located in a single compartment.

Blockade of dopamine receptors explains the lack of 5-HT stereotypy on treatment with the putative 5-HT1A agonist LY165163.

The putative serotonin (5-HT)1A agonist 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluormethylphenyl) piperazine (LY165163, PAPP) induces hyperphagia and hypothermia in rats, but unlike other 5-HT agonists, does not induce 5-HT stereotypy even at high doses (10 mg/kg sc). LY165163 (1 mg/kg) increased striatal DOPA accumulation in animals treated with the aromatic amino acid decarboxylase inhibitor 3-hydroxy-benzylhydrazine (NSD 1015) (100 mg/kg ip). This increase was also found when the drug was given to animals pretreated with parachlorophenylalanine (pCPA) (150 mg/kg ip daily for 3 days). LY165163 (2 and 4 mg/kg sc) inhibited stereotyped behaviour induced by the dopamine (DA) agonist apomorphine (2 mg/kg sc). LY165163 (2, 4, 10 mg/kg sc) also inhibited stereotyped components of the 5-HT syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT; 5 mg/kg ip) which previous studies (e.g. Andrews et al. 1982) suggested to require DA (head weaving, reciprocal forepaw treading). Thus, while other 5-HT1A agonists such as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) cause stereotypy, this does not occur with LY165163, probably because the drug blocks DA receptors.

Direct inhibitory effect of long term estradiol treatment on dopamine synthesis in tuberoinfundibular dopaminergic neurons: in vitro studies using hypothalamic slices.

The mechanism of the inhibitory effect of long term treatment with estradiol on dopamine synthesis in tuberoinfundibular dopaminergic (TIDA) neurons was studied by using hypothalamic slices from ovariectomized rats. Treatment with 2 mg estradiol valerate (EV) at a 3-week interval increased the weight of the anterior pituitary gland and the concentration of serum PRL. In vivo and in vitro dopamine synthesis in TIDA neurons were estimated in EV-treated animals by 3,4-dihydroxyphenylalanine (DOPA) accumulation in the median eminence after injections of 3-hydroxybenzylhydrazine (NSD 1015), a DOPA decarboxylase inhibitor, and after incubation of hypothalamic slices with NSD 1015, respectively. In vivo DOPA accumulation in the median eminence was less in EV-treated rats than in control rats. The basal rate of in vitro DOPA accumulation in the median eminence of hypothalamic slices from EV-treated rats was lower than that in control rats. Ca2+-dependent DOPA accumulation in the median eminence, determined by incubation in medium containing depolarization agents such as 50 mM K+ and veratridine, was decreased in EV-treated rats. Furthermore, cAMP-dependent DOPA accumulation, determined by incubation with Bu2cAMP or forskolin, was also suppressed in EV-treated rats. The decreased depolarization-induced DOPA accumulation in the median eminence recovered after cessation of EV treatment. Hyperprolactinemia lasting for 6 weeks, achieved by transplantation of anterior pituitaries under the kidney capsule, increased the rate of depolarization-induced DOPA accumulation in the median eminence. On the other hand, EV treatment was effective in inhibiting depolarization-induced DOPA accumulation in hypophysectomized rats regardless of the presence of anterior pituitary transplants. These results suggest that chronically administered estradiol inhibits dopamine synthesis in TIDA neurons via a direct action on the hypothalamus and overcomes the facilitatory action of PRL on dopamine synthesis; and estradiol inhibits all three distinct systems that regulate basal, Ca2+-dependent, and cAMP-dependent dopamine synthesis in TIDA neurons.

Stress, prolactin and hypothalamic dopaminergic neurons

Most of what is known about dopamine (DA)-containing neurons in the brain has been learned from studies on the nigrostriatal system, although it is misleading to consider a neuron in this system as a “model” for other DA neurons in the brain. In this presentation the properties of nigrostriatal DA neurons are compared with those hypothalamic DA neurons that comprise the tuberoinfundibular system. These latter neurons, which have cell bodies in the arcuate nucleus and short axons which terminate in the median eminence, function to inhibit the release of prolactin from the anterior pituitary. The activities of the nigrostriatal and tuberoinfundibular DA neurons were estimated biochemically by measuring the rates of synthesis (accumulation of DOPA after the administration of a decarboxylase inhibitor, NSD 1015), turnover (decline of DA after the administration of a tyrosine hydroxylase inhibitor, α-methyltyrosine) and metabolism (concentrations of dihydroxyphenylacetic acid) of DA in regions of the brain that contain the terminals of these neurons (striatum and median eminence, respectively). Tuberoinfundibular DA neurons differ from nigrostriatal DA neurons in that the former neurons: (1) are not directly regulated by DA receptor-mediated mechanisms, (2) are stimulated by prolactin, (3) exhibit a sexual difference with activity being 2–3 times greater in females and (4) are inhibited by afferent neuronal circuits that are activated by suckling and restraint stress.

Brain monoamine metabolism is altered in rats following spontaneous, long-distance running.

Brain monoamine metabolism in rats was studied during spontaneous, long-term running in a microprocessor-controlled wheel cage. Immediately after heavy spontaneous exercise, DOPA accumulation was decreased in dopamine-rich brain regions such as the limbic forebrain and corpus striatum, indicating a decreased rate of synthesis of dopamine in brain. In contrast, DOPA accumulation was increased in the noradrenaline-predominated region of the brain stem, indicating an increased synthesis of noradrenaline in this region. Alterations in brain monoamine metabolism were normalized in exercising animals analysed 24 h after the last running period. Changes in brain monoamine metabolism may be involved in the mechanisms underlying the clinically observed psychological effects of physical exercise.

Neurochemical and behavioural evidence for an agonist action of 1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl) piperazine (LY 165163) at central 5-HT receptors

1-[2-(4-aminophenyl)ethyl]-4-(3-trifluoromethylphenyl)piperazine (LY 165163, PAPP) (1 mg/kg s.c.) significantly decreased 5-hydroxytryptophan (5-HTP) accumulation in cortex, hippocampus, striatum, septum, pons + medulla and midbrain and increased DOPA accumulation in the cortex and striatum following inhibition of aromatic amino acid decarboxylase with NSD 1015. LY 165163 increased food intake in non-food-deprived rats over 2, 4 and 24 h after administration. Depletion of brain 5-hydroxytryptamine (5-HT) by parachlorophenylalanine (pCPA) prevented the hyperphagic effect over 2 and 4 h after treatment with LY 165163 (1 mg/kg). Components of the postsynaptically mediated 5-HT behavioural syndrome were not detected at doses of LY 165163 between 1 and 10 mg/kg, although locomotion was increased at lower doses and the rats were inactive at the highest dose. Results in general indicate that LY 165163 is a centrally active agonist at 5-HT presynaptic receptors.