Dopaminergic Neuronal Systems Research Articles

Ionic, neuronal and endocrine influences on the proopiomelanocortin system of the hypothalamus

Increasing evidence supports a neurotransmitter or a neuromodulator action for peptides derived from proopiomelanocortin in the hypothalamus. Peptide release involves sodium, potassium and calcium ion channels and is dependent on the presence of extracellular calcium ions at the time of depolarisation of neuronal membranes. Dopaminergic and ξ-aminobutyric acid-containing neuronal systems inhibit POMC-derived peptide release from the hypothalamus through D2-dopamine and GABA A receptors, respectively. Serotoninergic mechanisms exert a biphasic effect on peptide release being directly stimulatory at low concentrations of serotonin and indirectly inhibitory at higher concentrations via interactions with the endogenous dopaminergic system. Cholinergic and glutamergic drugs stimulate peptide release through nicotinic and N-methyl-D-aspartate receptors, respectively. Finally, circulating steroids regulate the hypothalamic POMC system with testosterone stimulating POMC gene expression whilst oestradiol and glucocorticoids induce an inhibitory control.

Ultrastructural correlates of functional relationships between nigral dopaminergic or cortical afferent fibers and neuropeptide Y-containing neurons in the rat striatum

This study examines the ultrastructural relationships established by the nigrostriatal dopaminergic and the corticostriatal afferent fibers with neuropeptide Y (NPY)-containing neurons in the rat striatum. By means of dual immunolabeling procedures using peroxidase conjugated F(ab) fragments and 125I-labeled protein A, direct appositions and morphologically defined synaptic contacts of the symmetrical type were visualized between tyrosine hydroxylase-labeled nerve terminals and NPY-labeled neurons. After deafferentation of the striatum from its cortical input direct appositions and asymmetrical synaptic contacts were evidenced between characteristic degenerative boutons and NPY-positive neurons in the striatum. These results suggest that striatal NPY interneurons undergo direct influence from both nigrostriatal dopaminergic and corticostriatal neuronal systems.

L-7 - Regulation of different dopaminergic neuronal systems in the mammalian brain

L-7 - Regulation of different dopaminergic neuronal systems in the mammalian brain

Distribution of retrogradely primulene-labeled dopamine-containing neurons forming spinal projections

The distribution of primuline-labeled dopamine-containing neurons in the rat forebrain was investigated by combining catecholamine fluorescence and retrograde neuronal labeling techniques following injection of fluorochrome into the upper thoracic spinal cord. It was found that only diencephalic neurons of catecholamine-containing group All, located in the dorsal hypothalamus and the caudal thalamus send out direct projections to the spinal cord. Cells of nonidentified transmitter category were also primuline-labeled in this area. An average of 173±4 catecholamine-containing neurons were revealed in group All, of which 86 were retrogradely labeled with primuline. Numbers of labeled dopamine-containing neurons increased, traveling in a rostro-caudal direction. The functional role which may be played by the dopaminergic diencephalo-spinal neuronal system described is discussed.

Formula omitted][formula omitted]electrochemical determination of extracellular dopamine in the caudate of freely-moving rats after a low dose of ethanol

Low doses of ethanol (i.e. < 1 g/kg) elicit behavioral stimulation, control discriminative performance and mediate reinforcement in rats. These effects are thought to be mediated through central dopaminergic neuronal systems. In the present study, dopamine and serotonin/ uric acid release from caudate was measured by in vivo voltammetry in freely-moving, unanesthetized rats after administration of a low dose of ethanol (600 mg/kg, IP). Within 15 min after a single ethanol administration, extracellular dopamine levels significantly increased in caudate, peaking at 35 min, and returning to baseline by 75 min. In addition, ethanol caused an attenuation of a second voltammetric signal that correlates with extracellular serotonln/uric acid concentrations, and this effect persisted through the course of the experiments. These neurochemical changes may underlie behavioral responses found after low doses of ethanol.

Is dopamine a transmitter in the periphery?

There is now substantial experimental evidence supporting the hypothesis that a dopaminergic neuronal system is present in peripheral tissues. This evidence includes identified and characterized dopaminergic receptors, the presence of relatively large concentrations of dopamine and DOPAC in some neurons and organ systems, and the differential loss of norepinephrine or dopamine following treatment with catecholaminergic neurotoxins. There are still many studies that remain to be completed, however, existing evidence is consistent with a peripheral dopaminergic neuronal system.

Development of tolerance and supersensitivity to phencyclidine in rats after repeated administration of phencyclidine

In rats treated with phenyclidine (PCP) repeatedly (PCP 10 mg/kg per day for 14 days), the back-pedalling, head-weaving and turning induced by PCP were attenuated (tolerance), while PCP-induced sniffing, rearing and ambulation were potentiated (supersensitivity). The behavior induced by the direct and indirect serotonin (5-HT) agonists, 5-methoxy-N,N-dimethyltryptamine and p-chloroamphetamine, was attenuated, while the sniffing, rearing or licking induced by the direct and indirect dopamine (DA) agonists, apomorphine and methamphetamine, were potentiated in the chronic PCP-treated rats. The DA and 5-HT contents in the nucleus accumbens and the ratio of HVA to DA in the striatum increased following the repeated PCP administration. Pentobarbital-induced sleep time did not change in the chronic PCP-treated rats as compared with the control rats. In addition, there was no significant difference between the disappearance rate of PCP in the brain of the rats treated with PCP repeatedly and the rate in the control rats. These results suggest that functional changes in the dopaminergic and serotonergic neuronal systems develop on repeated administration of PCP but that such changes do not develop in the hepatic drug-metabolizing system. In addition, tolerance develops in the serotonergic neuronal system while supersensitivity develops in the dopaminergic neuronal system. Biochemical findings suggest that increased mesolimbic dopaminergic neuronal function plays an important role in the development of the supersensitivity.

Dopamine and cognitive disturbance in depression CSF HVA to 5HIAA ratio higher in patients with subjective memory disturbance

Subjective memory disturbance during the course of an episode of major depression was positively and highly significantly correlated with the homovanillic acid to 5-hydroxyindoleacetic acid (HVA/5HIAA) ratio in cerebrospinal fluid (CSF) of 206 patients with RDC major depressiva disorders. Cognitive impairment in affective disorders is suggested to be related to an altered functional interaction between serotonergic and dopaminergic neuronal systems.

Pharmacological properties of SM-3997: a new anxioselective anxiolytic candidate.

Pharmacological properties of SM-3997 (3a alpha,4 beta,7 beta,7a alpha-hexahydro-2-(4-(4-(2-pyrimidinyl)-1- piperazinyl)-butyl)-4,7-methano-1H-isoindole-1,3(2H)-dione dihydrogen citrate) have been examined in rats and mice. SM-3997 showed a dose-related anticonflict activity in rats in a water lick conflict paradigm, and it had no effect on water consumption in a spontaneous water drinking test. The potency of SM-3997 appeared to be equal to that of buspirone and about one-half that of diazepam. No tolerance to the anticonflict activity of SM-3997 was observed following 5 and 10 consecutive days of treatment. Unlike diazepam, SM-3997 had no anticonvulsant effect and had very weak muscle relaxant and hypnotic effects. On the other hand, SM-3997 and buspirone exhibited dopamine antagonistic action, although the potency of SM-3997 was less than one fourth that of buspirone. These results show that SM-3997 is a new anxioselective anxiolytic agent which is weaker than buspirone in the dopaminergic neuron system.

Pharmacological Properties of SM-3997: A New Anxioselective Anxiolytic Candidate

Pharmacological properties of SM-3997 (3aα,4β,7β,7aα-hexahydro-2-(4-(4-(2-pyrimidinyl)-1 -piperazinyl)-butyl)-4,7-methano-1 H-isoindole-1,3(2H)-dione dihydrogen citrate) have been examined in rats and mice. SM-3997 showed a dose-related anticonflict activity in rats in a water lick conflict paradigm, and it had no effect on water consumption in a spontaneous water drinking test. The potency of SM-3997 appeared to be equal to that of buspirone and about one-half that of diazepam. No tolerance to the anticonflict activity of SM-3997 was observed following 5 and 10 consecutive days of treatment. Unlike diazepam, SM-3997 had no anticonvulsant effect and had very weak muscle relaxant and hypnotic effects. On the other hand, SM-3997 and buspirone exhibited dopamine antagonistic action, although the potency of SM-3997 was less than one fourth that of buspirone. These results show that SM-3997 is a new anxioselective anxiolytic agent which is weaker than buspirone in the dopaminergic neuron system.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment decreases dopamine and increases lipofuscin in mouse retina

The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a relatively selective neurotoxin that destroys dopamine (DA)-containing nigrostriatal neurons. We have now studied the effects of MPTP on retinal dopaminergic neurons. Acute treatment resulted in the accumulation of DA when evaluated by direct chemical analysis or histofluorescence. Chronic treatment resulted in a decrease of DA, an apparent loss of fluorescent cells, and a striking increase of lipofuscin in the retina. Thus, MPTP may be a useful drug for studying the dopaminergic neuronal system of retina and the possible link between neurons and the accumulation of lipofuscin.

Opiate-induced turning in rats after injection into the ventral tegmental area

Morphine and ethylketazocine caused ipsilateral circling when injected unilaterally into the ventral tegmental area (VTA) of rats. Systematic naloxone only slightly inhibited this effect while systemic diprenorphine completely prevented circling. Systemic haloperidol and alpha-methyl-p-tyrosine also blocked circling. Rats made tolerant to morphine still turned after morphine injection into the VTA. Levorphanol, dextrorphan, methadone, DADLE, dynorphin(1–13), SKF 10,047 and phencyclidine were inactive when injected unilaterally into the VTA of naive rats; naloxone and naltrexone alone also were inactive. The opiate-induced circling appears to involve a non-mu opiate receptor as well as a dopaminergic neuronal system.

Dopaminergic mediation of a behavioral effect of l-cathinone

Ten male rats were trained to discriminate between the stimulus properties of 0.6 mg/kg l-cathione and saline in a two-lever food-motivated operant task. Once trained, rats showed a dose-dependent increase in discrimination over a dosage range of 0.15–1.2 mg/kg l-cathinone. Analysis of this dose-response relationship indicated an ED50 of 0.27 mg/kg. Pretreatment with 0.2 mg/kg of the specific dopamine blocking drug haloperidol increased this ED50 to 0.47 mg/kg and significantly decreased discriminative performance when co-administered with either 0.15, 0.3, or 0.6 mg/kg l-cathinone. Since the dose-effect curves for cathinone with and without haloperidol pre-treatment were parallel, it is suggested that l-cathinone, the active constituent in khat, produces its discriminative properties, in part, by mediation of dopaminergic neuronal systems.

Role of dopaminergic and serotonergic neuronal systems in the prefrontal cortex of rats in phencyclidine-induced behaviors.

This study was designed to determine the action sites of phencyclidine (PCP) involved in the development of behaviors such as head-weaving, immobility, turning and backpedalling in relation to dopaminergic and serotonergic neuronal functions. Injection of PCP into the caudate nucleus or prefrontal cortex dose-dependently produced head-weaving, although the injection of PCP into the nucleus accumbens failed to produce head-weaving. The intensity of head-weaving induced by injection of PCP into the prefrontal cortex was relatively high when compared to that induced by injection of PCP into the caudate nucleus or lateral ventricle. Pretreatment with p-chlorophenylalanine (300 mg/kg), a serotonin (5-HT) synthesis inhibitor, attenuated head-weaving induced by injection of PCP into the prefrontal cortex. Injection of PCP (50-100 micrograms) into the prefrontal cortex also produced immobility for 5 min post-injection. Rats pretreated with pimozide (1 mg/kg), a dopamine (DA) antagonist, also produced immobility after the injection of PCP into the prefrontal cortex and this effect was attenuated by pretreatment with ritanserin, a 5-HT2 receptor antagonist. On the other hand, pretreatment with methamphetamine attenuated PCP (5 and 7.5 mg/kg)-induced turning and backpedalling but not head-weaving. Pretreatment with large doses of apomorphine, a DA agonist, also greatly attenuated PCP (7.5 mg/kg)-induced behaviors, i.e. head-weaving, turning and backpedalling. These effects of DA agonists were prevented by haloperidol (0.25 mg/kg), a DA antagonist. These results suggest that PCP-induced turning and backpedalling may be mediated by reducing dopaminergic transmission, although PCP-induced head-weaving and immobility may be produced by increasing serotonergic transmission in the prefrontal cortex.

Methamphetamine-lnduced Behavioral Alterations Following Repeated Administration of Methamphetamine

AbstractRepeated administration of a large dose of methamphetamine (MA) (25 mg/kg, i.p. twice daily for 4 days) to mice enhanced locomotor activity and decreased stereotyped behavior following a subsequent injection of MA. Simultaneous determinations of catecholamines revealed a depletion of brain dopamine. The moderate doses of haloperidol significantly enhanced MA-induced locomotor activity in mice. A significant enhancement of MA-induced locomotor activity was observed in the rats pretreated with 6-hydroxydopamtne into the striatum, and this effect correlated negatively with the striatal dopamine level. These results suggest that hypofunction of striatal dopaminergic neuron systems induced by repeated administration of MA may be one of possible mechanisms of the enhancement of MA-induced locomotor activity due to the decrease of stereotyped behavior.

Non-benzodiazepine anxiolytics: Potential activity of phenylpiperazines without 3H-diazepam displacing action

Four phenylpiperazine derivatives exhibited an activity similar to benzodiazepines and meprobamate in the 4-plate test. One of these (compound IV) demonstrated anxiolytic like activity in a step-down avoidance technique, in electroshock induced aggression and in the staircase test. In contrast to benzodiazepines, compound IV was not anticonvulsant, myorelaxant or sedative. Confirmation of the anxiolytic activity of compound IV in animal models was obtained in 3 separate clinical trials in anxious patients. The mechanism of action of these phenylpiperazines appears to be different from the benzodiazepines as they do not displace 3H-diazepam binding nor do they interact with other elements of the GABA receptor macromolecular complex. Instead, compound IV interacts with both dopaminergic and serotoninergic neuron systems. Thus, from this data it would appear that an activity at the benzodiazepine recognition site is not obligatory for anxiolytic activity in man or in animals models.

Effects of phencyclidine in combination with morphine on the levels of met-enkephalin, dopamine, DOPAC and HVA in discrete brain areas of mice

The study investigated the interaction between phencyclidine (PCP) and morphine in affecting the levels of met-enkephalin, dopamine, DOPAC and HVA in mice. Morphine 5 mg/kg alone and PCP 10 mg/kg alone failed to change the levels of met-enkephalin in the midbrain and striatum. However, PCP in combination with morphine produced an increase in met-enkephalin levels and a decrease in HVA levels. In the midbrain, there was a direct relationship between the decrease in met-enkephalin levels and the increase in HVA levels. These results suggest that PCP may change the function in dopaminergic and enkephalinergic neuronal systems in the midbrain and/or striatum.

Alterations in the retinal dopaminergic neuronal system in rats with streptozotocin-induced diabetes.

Neurochemical alterations, which may be associated with the development of diabetic retinal dysfunction, were investigated using streptozotocin (STZ)-induced hyperglycemia in rats. Young male Wistar rats, weighing 100-150 g, were made diabetic with daily intraperitoneal injections of STZ (30 mg/kg) for 5 days. This treatment caused a continuous hyperglycemia (400-600 mg/dl) and suppressed gain in body weight. Nine weeks after the STZ treatment, a significant increment in retinal valine and a decline in phenylalanine were noted, while the concentrations of other neuroactive amino acids, such as gamma-aminobutyric acid and aspartic acid, in the retina remained unchanged. On the other hand, the concentration of retinal dopamine (DA) was found to decrease significantly from the third week of hyperglycemia, when [3H]spiperone binding showed a tendency to increase in the retinal particulate fraction. However, the activities of tyrosine hydroxylase and aromatic L-amino acid decarboxylase (AADC) and the uptake of [3H]tyrosine showed no alteration in the retina of diabetic rats. The accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) in vivo in the retina of diabetic rats, measured following the administration of the AADC inhibitor m-hydroxybenzyl-hydrazine (100 mg/kg i.p.), was also unchanged. Although [3H]DA uptake by retinal tissue was similar in control and diabetic animals, the spontaneous efflux of [3H]DA from the retina was found to be significantly accelerated in STZ-treated animals. In addition, the release of preloaded [3H]DA, elicited by repeated photic stimulation, was significantly attenuated in retina from diabetic rats. These results suggest that an accelerated efflux of DA, possibly leading to the depletion of DA from the retinal DA system, may account for early retinal dysfunctions known to occur in diabetic subjects.

Apomorphine increases ethanol discrimination

Rats were trained to discriminate between the stimulus properties of 600 mg/kg ethanol and saline in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower ethanol doses and analysis of the dose-response curve indicated an ED50 of 372 mg/kg. Pretreatment with 0.16 mg/kg apomorphine produced increased discriminative performance at each ethanol dose and the combination generated a dose-response curve parallel to ethanol administered alone with an ED50 of 232 mg/kg. This significant shift to the left of the ethanol dose-response curve after apomorphine administration is discussed in relation to dopaminergic neuronal systems and the clinical use of apomorphine in alcoholics.

Effects of behaviorally active doses of thyrotropin-releasing hormone and its analog MK-771 on dopaminergic neuronal systems in the brain of the rat

The effects of thyrotropin-releasing hormone (TRH) and an analog of this hormone, MK-771, were determined on body shaking behavior and on biochemical estimates of the activity of dopamine (DA) neurons in the rat. Both compounds elicited dose-related episodes of “wet-dog shakes”. A dose of TRH (20 mg/kg, i.p.) which caused marked shaking behavior did not alter the steady-state concentration of DA in any brain region, but, after an injection of α-methyltyrosine did enhance the rate of decline of DA in the nucleus accumbens, but not in the striatum or olfactory tubercle. The same dose of TRH increased the concentration of dihydroxyphenylacetic acid selectively in the nucleus accumbens, and caused a marked increase in the rate of synthesis of DA (accumulation of DOAP after the administration of a decarboxylase inhibitor) in the nucleus accumbens, and a modest and inconsistent increase in the striatum and olfactory tubercle. A single injection of MK-771 (3–100 mg/kg, i.p.) failed to change the rate of synthesis of DA in any brain region, while two injections of this compound (20 mg/kg, i.p.) slightly increased the rate of synthesis of DA in the striatum. These results suggest that TRH selectively increases the activity od DA neurons which terminate in the nucleus accumbens whereas its synthetic analog, MK-771, lacks this property. Since both compounds elicit similar body shaking behavior, it would appear that this behavior is not causally related to the actions of TRH on mesolimbic DA neurons which terminate in the nucleus accumbens.