Several ergot alkaloids, bromocriptine, ergocornine and lergotrile were shown to have potent agonist action at presynaptic dopamine receptors on striatal and mesolimbic nerve terminals in an in vivo model system. These agents blocked the increase in accumulation of striatal dihydroxyphenylalanine produced when impulse flow in the nigro-striatal dopamine system was inhibited by administration of gamma-butyrolactone. Administration of dopamine receptor blockers such as haloperidol prior to administration of the ergot alkaloids and apomorphine prevented the inhibitory effects of these agonists. However, when haloperidol was administered 50 min after the agonists although it completely blocked the effects of apomorphine it only partially antagonized the inhibitory effects of ergocornine and lergotrile and was ineffective in reversing the inhibitory effects of bromocriptine. Thus, this study in contrast to in vitro studies indicates that the ergot alkaloids do have potent effects on presynaptic dopamine nerve terminal receptors and that these agents, especially bromocriptine may interact non-competitively or irreversibly with presynaptic dopamine receptors.

4-Butyrolactone↗

PubMed1980

Evidence against specificity of electrical stimulation of the nucleus locus coeruleus in activating the sympathetic nervous system in the rat.

Electrical stimulation of the central nucleus locus coeruleus (LC) was previously shown to increase activity of the peripheral sympathetic nervous system (SNS) as measured by increases in plasma levels of the norepinephrine (NE) metabolite 3-methoxy-4-hydroxyphenethyleneglycol (MHPG) in the rat. Four experimental approaches were designed to test the specificity of the LC cell group in activating the SNS in the stimulation paradigm. Varying the stimulation current amplitude, varying the site of stimulating electrode placement, and electrolytic lesions of the LC yielded results consistent with the hypothesis that the site of SNS activation was within the anatomical region of the LC cell group. Neurochemical lesioning with intraventricular 6-hydroxydopamine, however, did not effectively block the plasma MHPG increase observed after stimulation of the LC region. The possibility that non-noradrenergic cells, fibers of passage, or terminals in the LC region of the midbrain may be responsible for SNS activation when the LC is electrically stimulated is discussed. These studies are pertinent to all studies of LC function which employ electrical stimulation of the LC nucleus, including investigations of the role of the LC in social behavior, intracranial self-stimulation, and blood pressure regulation.

Animals↗

PubMed1980

Clonidine reverses the increased norepinephrine turnover during morphine withdrawal in rats.

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Animals↗

PubMed1980

CSF GABA in psychotic disorders.

CSF GABA levels were not significantly different in a group of drug-free psychotic patients compared to a group of psychotic patients at two points during haloperidol treatment or a neurological comparison group. In the untreated group, CSF GABA was significantly negatively correlated with clinical ratings of anxiety and agitation. Early in haloperidol treatment CSF GABA was significantly positively correlated with CSF HVA.

Adolescent↗

PubMed1980

Evidence for an irreversible interaction of bromocryptine with central dopamine receptors.

The effects of the dopamine agonist bromocryptine on several measures dopaminergic function were assessed in the rat. Following inhibition of impulse flow with gamma-butyrolactone, and after dopa decarboxylase inhibition, dopa accumulation and its reversal by dopamine agonists is easily studied. In this model, bromocryptine (10 mg/kg, i.p.) caused a significant decrease in dopa accumulation in both the striatum and olfactory tubercle which was prevented, but not reversed, by the dopamine antagonist (+)-butaclamol (4 mg/mg, i.p.). The inactive isomer, (-)-butaclamol was without effect. Analysis of an vitro 3H-spiperone binding 2h after bromocryptine (10 mg/kg, i.p.) revealed a 30% decrease in the number of striatal dopamine receptors labelled (Bmax), with no change in receptor affinity for 3H-spiperone. No changes in binding were seen when animals were sacrificed 30 min or 48 h after bromocryptine. In extracellular single unit recording experiments, bromocryptine-induced depression of nigrostriatal dopamine cell firing was found to be largely reversible by the dopamine antagonist haloperidol when injected within 5 min of intravenous bromocryptine. However, when haloperidol was injected more than 20 min after bromocryptine, no reversal of bromocryptine-induced depression of cell firing was obtained. These results strongly suggest that bromocryptine interacts in an irreversible fashion with central dopaminergic receptors.

4-Butyrolactone↗

PubMed1980

Tolerance to fluphenazine and supersensitivity to apomorphine in central dopaminergic systems after chronic fluphenazine decanoate treatment.

Fluphenazine decanoate was administered chronically to rats on a schedule for which marked tolerance developed to acute fluphenazine effects on several parameters of dopaminergic neuronal function. DOPAC and HVA levels, indicators of dopaminergic activity, were quantitated in terminal areas of the mesocortical, mesolimbic and nigrostriatal systems. With this fluphenazine regimen tolerance developed not only in the nigrostriatal and mesolimbic but also in the mesocortical dopamine system to the elevation of metabolite levels induced by acute fluphenazine administration. Evidence was obtained that tolerance was functional rather than metabolic and was characterized by a large reduction in the accumulation of metabolites which normally follows a challenge dose of fluphenazine. Other experiments suggested that the results were not due to the effects of chronic fluophenazine on the noradrenergic innervation of the cortex and were not explained by altered catabolism or clearance of the dopamine metabolites. During withdrawal from chronic fluphenazine decanoate treatment supersensitivity to apomorphine developed in the striatum. The time courses of the disappearance of apomorphine supersensitivity and of the reversal of tolerance to a fluphenazine challenge were different.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1980

Presynaptic dopamine receptors: insensitivity to kainic acid and the development of supersensitivity following chronic haloperidol.

The effects of kainic acid lesions and chronic haloperidol treatment on rat striatal dopaminergic presynaptic receptors were studied. Following the gamma-butyrolactone-induced inhibition of dopaminergic impulse flow, and after dopa decarboxylase inhibition, dopa accumulation and its reversal by dopamine agonists was measured in vivo. 3H-apomorphine (a dopamine receptor ligand with purported presynaptic specificity) was used for in vitro binding experiments. Presynaptic dopamine receptors, as assessed by both methods, were unaffected by intrastriatal kainic acid injection 5-6 days before sacrifice. Seven days after termination of chronic haloperidol treatment (28 days, 0.5 mg/kg/day s.c.) both an increased apomorphine response using the dopa accumulation method and an increase in 3H-apomorphine binding were observed, indicating the development of presynaptic dopamine receptor supersensitivity.

4-Butyrolactone↗

PubMed1980

John Hain Parker (1913-1979).

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California↗

PubMed1980

Tyrosine hydroxylase regulation: apparent kinetic alterations following incubation of brain slices in a sodium-free medium.

In an attempt to determine if alterations in intraneuronal Ca2+ may regulate tyrosine hydroxylase activity, brain slices were subjected to experimental manipulations known to increase the intraneuronal concentration of free Ca2+ ions. Incubation of either striatal or olfactory tubercle slices in a Na+-free medium for 15 min at 37 degrees resulted in a marked increase in the activity of tyrosine hydroxylase present in the 20,000 g supernatant fraction of homogenates prepared from the slices. Tyrosine hydroxylase isolated from slices previously incubated in a Na+-free, choline-enriched medium or in a Na+-free, sucrose-enriched medium exhibited maximal activities when assayed at pH 6.0 and 7.0, respectively. However, the percentage stimulation of enzyme activity induced by incubation of the slices in a Na+-free medium was maximal when the enzyme assays were performed at pH 7.0. The observed increase in enzyme activity seems to be mediated by a decrease in the apparent Km of the enzyme for pteridine cofactor, regardless of whether the kinetic enzyme analyses were conducted at pH 6.0 or 7.0, and by an increase in the Ki of the enzyme for end-product inhibitor dopamine. The apparent kinetic changes in the enzyme do not seem to result from alterations in the endogenous dopamine content of the slices, and they are independent of any increase in dopamine release that might have occurred as a response to the augmented intraneuronal Ca2+ concentration. Furthermore, the activation of tyrosine hydroxylase produced by incubating slices in a Na+-free medium is observed even in slices depleted of dopamine by pretreatment of rats with reserpine 90 min before preparation of brain slices. The activation of tyrosine hydroxylase observed under these experimental conditions does not seem to be mediated by cAMP or by a cAMP-dependent phosphorylation process. It is suggested that the changes in tyrosine hydroxylase reported are mediated primarily by a rise in the free Ca2+ concentration within the nerve tissue. These observations are consistent with the hypothesis that the kinetic activation of tyrosine hydroxylase produced after depolarization of central dopaminergic neurons may occur through a Ca2+-dependent even other than transmitter release.

Animals↗

PubMed1980

GABA levels in CSF of patients with psychiatric disorders.

The authors measured gamma-aminobutyric acid (GABA) levels in the lumbar CSF of patients with depression, with psychosis, or undergoing evaluation for a neurologic disorder. GABA levels in the CSF from depressed patients were significantly decreased compared with neurologic control patients. CSF GABA levels in psychotic patients were not different from those in neurologic patients, although the data suggested a decrease in CSF GABA levels in patients with schizoaffective disorder.

Adult↗

PubMed1980

Poststimulation catecholamine synthesis and tyrosine hydroxylase activation in central noradrenergic neurons. I. In vivo stimulation of the locus coeruleus.

The ability of increased neuronal activity to accelerate catecholamine biosynthesis and tyrosine hydroxylase activity in the rat brain was tested. Noradrenergic neurons of the locus coeruleus (LC) were stimulated unilaterally at 20 Hz and the cortex and/or hippocampus from stimulated and contralateral (control) sides of the brain were analyzed and compared. Rats were injected with a dopa decarboxylase inhibitor and the accumulation of endogenously synthesized dopa used as an in vivo index of tyrosine hydroxylase activity. Thirty minutes after termination of 15 min of unilateral LC stimulation, dopa accumulation was 35% greater in the ipsilateral cortex + hippocampus. In untreated rats, at the end of 15 min of LC stimulation, there was an ipsilateral depletion of cortical norepinephrine (NE) which recovered within 30 min. When rats were injected with [3H]tyrosine (i.v.) during this half-hour recovery period, a poststimulation increase in [3H]catecholamine synthesis was observed in both the cortex (63%) and hippocampus (55%). In the cortex, there was more newly synthesized [3H]dopamine than [3H]NE, but LC stimulation preferentially increased the synthesis of [3H]NE. The hippocampus contained negligible amounts of [3H]dopamine and was used in subsequent studies. Tyrosine hydroxylase activity was assayed in vitro in supernatants derived from stimulated and control hippocampi. Ten minutes of LC stimulation (20 Hz) maximally activated hippocampal tyrosine hydroxylase and this activation was maintained for up to 20 min after stimulation was terminated. The results illustrate a stimulation-induced activation of NE biosynthesis and tyrosine hydroxylase activity in central NE neurons in vivo. This activation is maintained in the immediate poststimulation period and is not necessarily due to removal of end product inhibition by NE.

Animals↗

PubMed1980

Poststimulation catecholamine synthesis and tyrosine hydroxylase activation in central noradrenergic neurons. II. Depolarized hippocampal slices.

The ability of neuronal depolarization to increase catecholamine biosynthesis in the poststimulation period was investigated in a preparation of central noradrenergic tissue, maintained in vitro. Rat hippocampal slices were superfused with oxygenated Krebs-Ringer phosphate saline (KRP) or depolarized with KRP containing 55 mM KCl. Slices were then transferred to fresh, nondepolarizing KRP containing [3H]tyrosine for further incubation. Ten minutes of K+ depolarization resulted in a 78% increase in [3H]catecholamine synthesis, measured in the poststimulation period, relative to nondepolarized, control slices. This activation of catecholamine synthesis was maintained for up to 10 min following termination of K+ depolarization. Depolarization in the presence of tetrodotoxin did not block the poststimulation increase in catecholamine synthesis. The increased catecholamine synthesis in the poststimulation period can be accounted for by increased tyrosine hydroxylation since: 1) the synthesis of [14C]catecholamines from [14C]dopa was not increased by K+ depolarization and 2) K+ depolarization led to a 71% increase in the accumulation of [3H]dopa newly synthesized from [3H]tyrosine in the presence of the decarboxylase inhibitor, brocresine. Under these conditions, no significant depletion of tissue norepinephrine could be detected. The depolarization-induced increase in catecholamine synthesis was independent of the presence of Ca++ in the superfusion and/or incubation media, suggesting its dissociation from Ca++-dependent transmitter release. The absence of enhanced [3H]catecholamine synthesis following depolarization of slices in a Ca++-free K+-KRP containing 1.0 mM ethylene glycol bis(beta-aminoethyl ether)-N,N'-tetraacetic acid (EGTA) suggested that there is an absolute requirement for tissue Ca++ during the stimulation-induced synthesis activation process. There appears to be a depolarization-related phenomenon whose triggering is Ca++-independent, but which, in the presence of Ca++, is manifested as an increase in catecholamine biosynthesis (tyrosine hydroxylase activity).

Animals↗