Showing papers on "Dopaminergic published in 1978"

A Neurological Model for Childhood Autism

Abstract: • We analyze the behavioral and motor disturbances in childhood autism. On the basis of analogy to signs and conditions seen in adult neurology, we propose that the syndrome results from dysfunction in a system of bilateral neural structures that includes the ring of mesolimbic cortex located in the mesial frontal and temporal lobes, the neostriatum, and the anterior and medial nuclear groups of the thalamus. The mesolimbic cortex is cytoarchitectonically, angioarchitectonically, and neurochemically distinct and, along with the striatum, forms the entire target area of dopaminergic mesencephalic neurons. This raises the possibility that autism is related to neuromediator imbalance in those structures. Such dysfunction might be the result of macroscopic or microscopic changes in the target area or in structures functionally influencing them, consequent to a variety of causes such as perinatal viral infection, insult to the periventricular watershed area, or genetically determined neurochemical abnormalities.

Serotonergic component of neuroleptic receptors

Abstract: BINDING studies performed in vitro with 3H-haloperidol1–3, 3H-spiperone4–5, 3H-dopamine1–3,6 and 3H-apomorphine7,8 showed that the specific neuroleptic binding sites in the striatum are dopaminergic. The frontal cortex, however, was much more labelled by 3H-spiperone than by 3H-haloperidol9,10. The investigations reported here indicate that the neuroleptic receptor sites in the frontal cortex labelled by 3H-spiperone are predominantly serotonergic and virtually identical to those labelled by 3H-LSD. These conclusions were reached from a study of the relative binding affinities of a series of serotonin or dopamine agonists or antagonists for rat frontal cortex and striatal receptors. Significant correlations were obtained between the binding activities in the rat frontal cortex and in vivo potencies in the pharmacological anti-tryptamine test. Similarly, binding activities in the striatum were significantly correlated with the potencies in the anti-apomorphine test. We therefore suggest that serotonergic, as well as dopaminergic, receptors are involved in the mechanism of action of neuroleptic drugs.

Antipsychotic Drugs, Neurotransmitters, and Schizophrenia

Abstract: Inhibition of central dopamine functions appears to be a common basic property of antipsychotic drugs. The mesolimbic and nigrostriatal portions of the dopaminergic system are probably the main targets for the mental and the extrapyramidal actions, respectively, of these drugs. The fact that dopaminergic hyperfunction induced by amphetamines or dopa may lead to a disturbance mimicking paranoid schizophrenia lends further support for a key role of dopamine in mental functions. Although a primary disturbance in dopamine function in schizophrenia cannot be ruled out, the intimate relationship between dopaminergic and other neuronal systems must be emphasized. The possible involvement of other amine, amino acid, or peptide transmitters in schizophrenia cannot be disregarded.

Receptor basis for dopaminergic supersensitivity in Parkinson's disease

Abstract: IN patients with Parkinson's disease, the concentration of dopamine in the basal ganglia of the brain is markedly reduced in accordance with the degeneration of the nigrostriatal dopamine-containing neurones1,2. This fact provided the basis for the successful clinical introduction of L-dopa (L-3,4-dihydroxyphenylalaline) for Parkinson's disease3,6. It has been suggested that one of the critical factors compensating for the loss of dopamine neurones may be the development of “denervation supersensitivity” in the striatum, as severe cases react more sensitively to L-dopa than milder cases or controls7–9. By measuring dopamine receptors in the putamen and caudate of postmortem brains from Parkinson patients, we report here evidence in support of the theory of dopaminergic supersensitivity in Parkinson's disease.

Selective inhibitors of biosynthesis of aminergic neurotransmitters

Abstract: ALTHOUGH the enzymatic decarboxylation of amino acids is of substantial importance to biochemistry1, there are few inhibitors of the decarboxylase enzymes which combine activity with selectivity. Several of the amines formed by in vivo decarboxylation of amino acids (biogenic amines) have key roles in physiology. The neurotransmitters dopamine, 5-hydroxytryptamine, histamine and γ-aminobutyric acid result from such enzymatic decarboxylation; dopamine in turn serves as the precursor of noradrenaline2. The involvement of catecholamines in peripheral and central control of blood pressure has been the subject of many investigations; for example, elevated catecholamine levels were found in some of the 27 brain regions investigated in spontaneously hypertensive rats. Specifically, elevated noradrenaline and dopamine levels were found in regions implicated in the control of arterial blood pressure3. A widely reported biochemical theory of schizophrenia suggests disturbance of the dopaminergic system as the causative factor.4 Elevated histamine levels are believed to be involved in such diseases as allergy, hypersensitivity, gastric ulcer and inflammation5. Ornithine decarboxylase is also an important target for inhibition, as it is the initial enzyme in the biosynthesis of polyamines and increased levels of the latter have been associated with rapid cell division, including tumour growth6. Thus, selective inhibitors of these key enzymes could be of help in elucidating the complexities of neurophysiology and neurochemistry, as well as of service in medicine by correcting pathological levels of these agonists. We report here examples of the transformation of amino acids (C) into the corresponding substituted 3-fluoro-alanines (B), resulting in potent time-dependent decarboxylase inactivators (Table 1). In addition, we have prepared the fluoromethyl derivatives (D) corresponding to some of the amine products of these decarboxylases and find them also to be inactivators (Table 1).

Potent antidopaminergic activity of estradiol at the pituitary level on prolactin release

Abstract: Prior incubation of rat anterior pituitary cells with 17beta-estradiol led to an almost complete reversal of the inhibitory effect of two dopamine agonists, dihydroergocornine and RU 24213, on both basal prolactin release and thyrotropin releasing hormone-induced prolactin release. These experiments thus demonstrate a direct interference of dopamine action by a peripheral hormone. Prolactin secretion by pituitary cells in primary culture could possibly serve as an easily accessible model of a system under dopaminergic control.

The interplexiform cell system. I. Synapses of the dopaminergic neurons of the goldfish retina.

Abstract: Interplexiform cells are a class of retinal neuron that extends processes widely in both plexiform layers. In goldfish they contain dopamine and readily take up certain biogenic amines. Two of these amines, 6-hydroxyopamine (6-HDA) and 5, 6-dihydroxytryptamine (5,6-DHT), induce fine structural changes in the neurons that accumulate them, allowing the processes of the cells to be recognized by electron microscopy. Typically, the synaptic vesicles within the processes show electron-dense cores. The terminal cytoplasm may also show increased density, as may the cellular and cytoplasmic membranes, presumably an indication of degenerative changes induced by the drugs. 5, 6-DHT gives more readily observable changes than 6-HDA but labels both dopaminergic and indoleamine-accumulating neurons. The terminals of the indoleamine-accumulating terminals were therefore removed by intraocular injections of 5, 7-dihydroxytryptamine (5, 7-DHT) prior to the labelling with 5, 6-DHT. This procedure allowed an analysis of the dopaminergic terminals without interference by the terminals of the indoleamine-accumulating cells. The dopaminergic neurons were found to make synapses of the conventional type. In the outer plexiform layer they contacted both external horizontal cells and bipolar cell dendrites, but not hotoreceptor terminals or intermediate (rod) horizontal cells. No synapses onto the dopaminergic processes were found in the outer plexiform layer despite an extensive search. In the inner plexiform layer the dopaminergic processes were observed to be both pre- and postsynaptic to amacrine cells and their processes. No synaptic contacts between dopaminergic processes and bipolar cell terminals or ganglion cell dendrites were seen. We conclude that the dopaminergic interplexiform cells provide a centri­fugal pathway for information flow in the retina from inner to outer plexiform layer.

Long-term changes in dopaminergic innervation of caudate nucleus after continuous amphetamine administration

Abstract: Silicone pellets containing d-amphetamine base were implanted subcutaneously in rats. These pellets release amphetamine continuously for at least 10 days. Several days after implantation, swollen dopamine axons concomitant with large decreases in tyrosine hydroxylase activity were observed in the caudate nucleus. Decreased tyrosine hydroxylase activity was still present 110 days after pellet removal in the caudate but not in several other brain regions, nor in the caudate of rats injected with an equivalent amount of amphetamine in daily injections. This implies that continuous amphetamine administration has a selective neurotoxic effect on dopamine terminals in the caudate.

Prolactin Release by Vasoactive Intestinal Polypeptide in Rats

Abstract: Synthetic vasoactive intestinal polypeptide (VIP) administered either intraventricularly or iv caused a significant and dose-related increase in plasma PRL levels in urethane-anesthetized rats. The administration of naloxone, an opiate receptor antagonist, significantly blunted the plasma PRL response to VIP. Increases in plasma PRL induced by VIP were also significantly suppressed by L-dopa, a precursor of dopamine, whereas pilocarpine, a cholinergic agonist, diphenhydramine, a histamine antagonist, and cyproheptadine, an antiserotoninergic agent, did not affect the plasma PRL response to VIP. In in vitro experiments, VIP alone did not stimulate PRL release from cultured pituitary cells, but it significantly attenuated the inhibitory action of dopamine, which was not blocked by naloxone. These results suggest that VIP stimulates rat PRL secretion, at least in part, through activation of an opiate receptor in the central nervous system and by blocking the inhibitory action of a dopaminergic mechanism at t...

Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity.

Abstract: Long-term treatment of rats with haloperidol produced an increased sensitivity to the locomotor and stereotypic effect of apomorphine. This behavioral dopaminergic supersensitivity was accompanied by increased binding of [3H] spiroperidol in the striatum. Rats treated concurrently with lithium and haloperidol failed to develop both behavioral sensitivity to apomorphine and increased striatal dopamine receptor binding. The ability of lighium to prevent recurrent manicdepressive episodes may be related, in part, to its ability to stabilize dopaminergic receptor sensitivity.

Neuroleptic-induced attenuation of brain stimulation reward in rats.

Abstract: In 30-min free-operant tests, the dopamine receptor blockers pimozide (.125, .25, and .50 mg/kg) and (+)-butaclamol (.1, .2, and .4 mg/kg) attenuated lever pressing for lateral hypothalamic brain stimulation. When discrete self-stimulation trials were offered in a straight alleyway, pimozide increased start box latencies, slowed running speeds, and reduced lever-pressing rates. However, performance early in both lever-pressing and runway sessions was normal; performance deteriorated as testing progressed, following patterns that paralleled those seen when animals were tested with reductions in the amplitude of stimulating current. Spontaneous recovery was obtained in both situations; experimenter-imposed 10-min time-outs caused renewed lever pressing and running. In contrast, alpha-noradrenergic receptor blockade by phenoxybenzamine (5, 10, and 20 mg/kg) failed to produce extinction-like response patterns. These data support the view that central dopaminergic systems are important components of the neural mechanisms mediating reward.

Direct evidence for presynaptic and postsynaptic dopamine receptors in brain

Abstract: CENTRAL dopamine (DA)-containing neurones are thought to be involved in several human diseases including Parkinson's disease and schizophrenia, and to act as sites of action of some drugs of abuse. One of these DA systems, the nigrostriatal projection (NSP), has its origin in the substantia nigra (SN), pars compacta and innervates the caudate-putamen (CP). In the SN the dendritic processes of DA neurones have been shown to contain DA and vesicles1–3 and there is evidence that DA can be released by cells in the SN4–6. It has therefore been proposed that one mechanism by which the activity of DA neurones is regulated is through the action of dendritically released DA on hypothesised ‘autoreceptors’ on DA perikarya or dendrites7–9. Recently, however, this view has been challenged by the observation that DA-sensitive adenylate cyclase, an enzyme thought to be coupled with the DA receptor10, is located on terminals of the striatonigral or pallidonigral projection11,12 rather than on the DA cells themselves13–15. Similarly, in the CP where the existence of autoreceptors on DA terminals has been suggested16, the DA-sensitive adenylate cyclase has been shown to be localised on postsynaptic structures rather than on the DA terminals17,18. An established method for studying the DA receptor involves measuring DA receptor binding with labelled DA agonists or antagonists19,20. To further elucidate the location of DA receptors in the SN and CP, we have examined the effects of selective lesions of the NSP on labelling of DA receptors in these structures. These lesions, which are placed in the axons of the NSP, are known to cause near-complete anterograde and retrograde degeneration of the terminals and cell bodies of this system21. The advantage of this lesion technique over previous approaches is that it avoids nonspecific damage of the areas studied. Our results provide direct evidence of presynaptic and postsynaptic dopamine receptors in rat brain.

Morphine and β-endorphin inhibit release of noradrenaline from cerebral cortex but not of dopamine from rat striatum

Abstract: β-ENDORPHIN is a large polypeptide containing 31 amino acid residues, the first five of which are identical with methionine-enkephalin1 which has potent naloxone-sensitive analgesic properties2 and opiate activity in receptor binding assays in guinea pig ileum3,4. It has been shown that morphine depresses the potassium-induced release of 3H-noradrenaline in the rat cerebral cortex5 and of 3H-dopamine in the rat striatum6. These effects are blocked by the opiate antagonist naloxone and are probably due to the activation of presynaptic inhibitory opiate receptors located in noradrenergic and dopaminergic nerve endings of the rat brain. While met-enkephalin reproduced the effects of morphine in rat cortex slices7, it failed to reduce the release of dopamine from the rat striatum6. In view of these results, it was considered of interest to examine under similar experimental conditions, the effects of morphine and of β-endorphin on the potassium-stimulated release of 3H-dopamine from striatal slices and of 3H-noradrenaline from cerebral cortex slices of the rat8. In contrast to Loh et al.6, who more recently have not been able to reproduce their data (E. L. Way, personal communication), we find no evidence for the inhibition of the potassium-stimulated overflow of 3H-dopamine by β-endorphin and morphine in the striatal slices of the rat.

Age-related Changes in the Nigrostriatum: A Behavioral and Biochemical Analysis

Abstract: Rotational behavior was examined prior to (Exp. 1) and following unilateral lesions (Exp. 2) in the substantia nigra of young and old rats. Before lesioning no preferences for turning to the left or right were seen in either age group following graded doses of amphetamine. However, after radiofrequency lesions of the left substantia nigra both young and old rats turned predominantly to the left, and the ratio of left to right turns increased as a function of amphetamine dose. However, there were significant differences between young and old rats in the effect of amphetamine on rotational behavior, with old rats showing decided decrements in response strength. Direct dopaminergic stimulation under apomorphine or dopaminergic receptor blockade with haloperidol produced no such age related deficits. The results are discussed in terms of possible presynaptic alterations in dopaminergic functioning with aging.

Effect of guanine nucleotides on striatal dopamine receptors

Abstract: GUANINE NUCLEOTIDES have been shown to regulate the sensitivity of adenylate cyclase to hormones in several systems1–5, including the dopamine-sensitive adenylate cyclase in the caudate nucleus2,4. It has also been reported that in the presence of GTP the affinities of glucagon receptors6, β-adrenergic receptors7,8, prostaglandin E1 receptors9 and opiate receptors10 for agonists are decreased. For β-adrenergic receptors this effect of GTP has been described as ‘agonist-specific’, as it is seen with agonists but not with antagonists7,8. We report here a similar effect of GTP on the ability of dopamine-receptor agonists to compete for 3H-spiroperidol binding sites on rat striatal membranes. The presence of 0.3 mM GTP led to a four-to-fivefold increase in the Kd values for the inhibition of 3H-spiroperidol binding by dopamine-receptor agonists. No changes in Kd values were observed for antagonists. Dopamine-receptor agonists and antagonists have been defined by the stimulation or inhibition of dopamine-sensitive adenylate cyclase in the neostriatum11,12 or by their effects on the canine renal artery13. Controversy exists, however, as to whether binding studies using labelled neuroleptics such as spiroperidol actually measure dopamine receptors. Our finding of an agonist-specific effect of GTP supports the conclusion that 3H-spiroperidol is binding to functional dopamine receptors in the caudate nucleus.

Synaptic organization of the dopaminergic neurons in the rabbit retina.

Abstract: A number of substances were tested for their ability to label amine-accumulating neurons in the rabbit retina after fixation with OsO4 or glutaraldehyde and OsO4. Useful results were obtained with 5,6-dihydroxytryptamine (5,6-DHT) and 6-hydroxydopamine (6-HDA). Labelled processes were characterized by small (40–50 mm) pleomorphic synaptic vesicles containing electron-dense cores, and at times by swelling of mitochondria and by increased electron density of membranes and cytoplasm. Fluorescence microscopy showed that 5,6-DHT labelled both dopaminergic and indoleamine-accumulating neurons. In most experiments, therefore, the indoleamine-accumulating neurons were removed with 5,7-dihydroxytryptamine. In such retinas the dopaminergic processes labelled by 5,6-DHT were found to make synapses of the conventional type, characterized by an accumulation of synaptic vesicles on the presumed presynaptic side and some aggregation of material on the cytoplasmic side of the synaptic membranes and within the synaptic cleft. The dopaminergic processes were found to contact each other and also non-dopaminergic amacrine cells and their processes. Conventional synapses onto dopaminergic processes were observed from both labelled and unlabelled amacrine processes. The input from labelled neurons was observed on varicose dopaminergic processes whereas input from non-labelled elements was found on the intervaricose parts of the dopaminergic processes. No Contacts of dopaminergic processes with bipolar or ganglion cells were observed. Injections of 6-HDA gave the same results, although this drug gave less distinct labelling which made the observations less decisive than with 5,6-DHT. In retinas treated with 5,6-DHT alone (i.e., in which the indoleamine-accumulating neurons remained) numerous processes were observed which were both pre- and postsynaptic to bipolar terminals. These observations suggest that the indoleamine-accumulating processes synapse with bipolar cells. The results show that the dopaminergic neurons form a network involving only amacrine cells, suggesting a regulatory function for them. By analogy with the dopaminergic interplexiform cells of the goldfish retina, it is suggested that the dopaminergic neurons in the rabbit may regulate lateral inhibitory effects mediated by amacrine cells. Furthermore, the finding that the dopaminergic and indoleamine-accumulating cells apparently have a different synaptic organization suggests that it is appropriate to categorize amacrine cells according to their transmitter content as well as their morphology.

Amphetamine-type reinforcement by dopaminergic agonists in the rat

Abstract: Intravenous self-administration of d-amphetamine (025 mg/kg/injection) decreased in a dose-related fashion after injections of the dopaminergic agonists apomorphine and piribedil The dopaminergic agonists appear to suppress amphetamine intake in the same way as do ‘free’ amphetamine injections, by extending drug satiation in a given interresponse period Clonidine, an alpha noradrenergic agonist, did not have similar effects Apomorphine and piribedil did not increase 14C-amphetamine levels in rat brains, nor did they retard disappearance of 14C-amphetamine; thus their amphetamine-like effects are not due to alterations of amphetamine metabolism Rats responding for amphetamine continued to respond for apomorphine or piribedil when the latter drugs were substituted for the former Rats experienced in amphetamine self-administration readily initiated and maintained responding for apomorphine and piribedil The dopaminergic blocker (+)-butaclamol disrupted responding for apomorphine and piribedil, although it produced no marked increase in responding for the dopaminergic agonists, as it does for amphetamine These data add to the evidence that actions in the dopaminergic synapse account for amphetamine's reinforcing properties

Haloperidol-induced presynaptic dopamine supersensitivity is blocked by chronic lithium

Abstract: SUPERSENSITIVITY following the interruption of synaptic transmission within the dopamine (DA) system has now been established by behavioural1–3, biochemical4–6 and electrophysiological7,8 evidence. Following production of lesions which interupt DA input1, or treatment with pharmacological agents which chronically disrupt dopaminergic transmission3,9,10, an increase in the sensitivity of postsynaptic (receiving input from dopaminergic neurones) responses of cells to DA and DA agonists has been observed. However, several studies have suggested that in vivo, presynaptic DA or ‘autoreceptors’ (that is, dopaminoceptive sites on DA-containing cells) may have an important physiological role in the modulation of DA synthesis and release11–13. Thus, alterations in the sensitivity of presynaptic cells may have profound effects on the availability of the neurotransmitter. To date, only one study has attempted to investigate whether dopaminergic supersensitivity could be a presynaptic, as well as a postsynaptic, phenomenon; following long-term treatment of rats with a phenothiazine, an increase in the sensitivity of DA-containing neurones in the substantia nigra to the DA agonist, apomorphine, has been observed14. We present here electrophysiological evidence for increased presynaptic sensitivity following chronic haloperidol treatment, as measured by both the direct iontophoretic application of DA and the systemic administration of apomorphine to DA-containing cells in the zona compacta region of the substantia nigra. In addition, it has been found recently that rats treated concurrently with lithium and haloperidol fail to develop postsynaptic supersensitivity, as measured by alterations in behavioural sensitivity15,16 and DA-receptor binding16. Several groups have theorised that alterations in catecholamine receptor sensitivity may be a factor in the aetiology of affective disorders, especially manic-depressive illness17,18. As lithium therapy has been shown to be effective in preventing recurrent episodes of mania and depression in manic-depressive illness19, it is of interest to determine whether, at the level of individual DA neurones in the CNS, chronic lithium treatment could also affect the development of presynaptic supersensitivity. We provide here electrophysiological evidence for the blockade of presynaptic supersensitivity development following chronic lithium treatment.

Stimulation of dopamine synthesis in caudate nucleus by intrastriatal enkephalins and antagonism by naloxone

Abstract: The intraventricular injection of methionine-enkephalin (50 to 100 micrograms) or [d-Ala2]-methionine-enkephalinamide (1.5 to 12 micrograms), a synthetic enkephalin analog resistant to enzyme degradation, caused a marked dose-dependent increase in dihydroxyphenylacetic acid and homovanillic acid concentrations in the rat striatum. The [d-Ala2] analog increased the accumulation of dopa in the striatum after aromatic amino acid decarboxylase inhibition, indicating that it increased dopamine synthesis. At the highest doses used both enkephalins failed to modify brain serotonin metabolism. The monolateral microinjection of the [d-Ala2]] analog (3 to 6 micrograms) into the caudate nucleus increased the concentration of dihydroxyphenylacetic acid in the injected side, whereas bilateral injection increased the concentration of this compound in both caudate nuclei and caused catalepsy. The stimulant effect of the [d-Ala2] analog on dopamine synthesis in the striatum persisted after destruction of striatal postsynaptic dopamine receptors with kainic acid. The biochemical and behavioral effects of enkephalins were prevented by naloxone, a specific narcotic antagonist. The results indicate that enkephalins stimulate dopamine synthesis by an action on opioid receptors localized on dopaminergic nerve terminals.

d-Amphetamine-induced depression of central dopamine neurons: evidence for mediation by both autoreceptors and a striato-nigral feedback pathway

Abstract: The mechanism by which intravenous d-amphetamine (d-A) depresses the activity of dopamine (DA)-containing neurons in the substantia nigra was studied in anesthetized rats using single cell recording and microiontophoretic techniques. Kainic acid (KA) injections into the caudate nucleus were used to selectively destroy neuronal feedback pathways to the substantia nigra originating from the striatum. These lesions caused a five-fold increase in the amount of i.v. d-A needed to produce 50% inhibition of DA cells compared to control animals. Furthermore, in the lesioned animals even near lethal doses did not cause total abolition of the firing of DA cells. This was in marked contrast to unlesioned animals in which relatively low doses of d-A caused DA cells to temporarily cease firing entirely. Low non-convulsant doses of the GABA antagonist, picrotoxin, were found to reverse d-A-induced depression of DA cells in non-lesioned animals, but even high doses had no effect in lesioned ones. These results suggest that at low doses i.v. d-A produces its depressant effects on DA cells primarily through a striato-nigral feedback pathway, one link of which is GABAergic. At high doses d-A appears to also inhibit DA cells through an action within the substantia nigra, perhaps at DA dendrodendritic synapses. Microiontophoretically applied dopamine was found to be equally potent in inhibiting DA cells in non-lesioned, lesioned, and picrotoxin-treated animals. Thus, the ability of microiontophoretically applied DA to inhibit DA cells appears to be mediated by an interaction with DA autoreceptors and not by the release of GABA from afferent terminals as has recently been suggested.