Bernard Scatton

Reduction of cortical dopamine, noradrenaline, serotonin and their metabolites in Parkinson's disease

Dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, noradrenaline, serotonin and 5-hydroxyindoleacetic acid concentrations were measured in several cortical areas, hippocampus and, for comparison, in the caudate nucleus, from control subjects and parkinsonian patients. Substantial amounts of these compounds were detected in hippocampus, and entorhinal, cingulate and frontal cerebral cortices of control subjects. In patients who had discontinued L-DOPA at least 4 days before death (group I), the levels of dopamine and its metabolites were reduced in these cortical areas, although to a lesser extent than in the caudate nucleus. In patients on continuous L-DOPA treatment (i.e. having received the last dose of L-DOPA 0-24 h before death, group II), cortical dopamine levels were less reduced than in group I patients and dopamine metabolite levels were similar to those of controls. The ratio of the concentrations of homovanillic acid to dopamine was increased in the caudate nucleus and entorhinal cortex but not in the other cortical areas of group I parkinsonian patients. Cortical noradrenaline concentrations were also diminished, the decrement being similar in groups I and II. A reduction of serotonin and its metabolite in the caudate nucleus and hippocampus and a diminution of serotonin levels in the frontal cortex were observed in group I patients. In these patients, the 5-hydroxyindoleacetic acid to serotonin ratio was increased in the caudate nucleus and frontal cortex but not in the other cortical areas. The results are discussed in relation to the pathophysiology of the psychiatric and cognitive disturbances observed in some parkinsonian patients.

Differential regional development of tolerance to increase in dopamine turnover upon repeated neuroleptic administration.

Repeated treatment with haloperidol and sulpiride induced tolerance to the increases in homovanillic and dihydroxyphenyl acetic acids in the striatum, nucleus accumbens, tuberculum olfactorium and frontal cortex of the rat. The threshold dose inducing this effect appeared to be lower in the striatum than in the limbic regions. Similar results were found in the frontal cortex by measuring dopamine utilization. Moreover, tolerance developed earlier in the striatum than in the limbic areas. The possible reasons are discussed for the differential development of tolerance in the various DA areas investigated.

[3H]spiperone binding, dopamine and HVA concentrations in Parkinson's disease and supranuclear palsy

The density of D2-type dopamine receptors, measured by the binding of [3H]spiperone was normal in the substantia nigra, caudate nucleus and nucleus accumbens of Parkinsonian subjects and above control levels in the putamen, in spite of massive lesions of the dopaminergic neurons. Dopamine levels were reduced in the putamen, caudate nucleus, and nucleus accumbens by 97, 85 and 68%, respectively and by 78 and 93% in the pars compacta and pars reticulata of the substantia nigra. HVA levels were much less affected suggesting that increased activity of the remaining dopaminergic neurons compensated to some extent for the lesions. Neuroleptic treatment and the presence of dementia in the Parkinsonian subjects affected [3H]spiperone binding and dopamine concentrations. Dopamine and HVA levels in the striatum of subjects with supranuclear palsy indicate that the nigrostriatal system was lesioned to the same degree in this disease as in idiopathic Parkinsonism, but spiperone binding was reduced by half in all the structures studies.

Characterization of the excitatory amino acid receptor-mediated release of [3H]acetylcholine from rat striatal slices

The pharmacological nature of the interaction of excitatory amino acids with striatal cholinergic neurons was investigated in vitro. Agonists of excitatory amino acid receptors evoked the release of [3H]acetylcholine from slices of rat striatum, in the presence of magnesium (1.2 mM). Removal of magnesium from the medium markedly increased the release of [3H]acetylcholine evoked by all excitatory amino acid receptor agonists tested, with the exception of kainate. In the absence but not the presence of magnesium, a clear rank order of potency was found: N-methyl-DL-aspartate = ibotenate greater than L-glutamate greater than L-aspartate greater than or equal to cysteate greater than kainate = quisqualate. The excitatory amino acid receptor mediating [3H]acetylcholine release resembles the N-methyl-D-aspartate preferring (N-type) receptor, as previously characterized electrophysiologically, according to 3 criteria: (1) rank order of potency of agonists; (2) magnesium-sensitivity; and (3) antagonism by 2-amino-5-phosphonovalerate. The release of [3H]acetylcholine evoked by N-methyl-DL-aspartate was blocked by tetrodotoxin (0.5 microM). Moreover, N-methyl-DL-aspartate failed to evoke [3H]acetylcholine release from slices of hippocampus, where cholinergic afferents, rather than interneurons, are found. These results suggest that excitatory amino acids act at receptors on the dendrites of striatal cholinergic interneurons, giving rise to action potentials and release of acetylcholine from cholinergic nerve terminals.

Cortical modulation of striatal function

The effect of bilateral section of the corticostriatal projections or of selective bilateral ablation of the frontal cortex on behavioral and biochemical parameters related to striatal function were investigated in the rat. Either lesion almost completely prevented the cataleptogenic action of haloperidol: this effect was observed as soon as 3 days and lasted for at least 3 months after surgery, paralleling a reduction in striatal glutamate uptake. Also, such lesions enhanced the apomorphine-induced stereotyped behavior (as measured 21 days after surgery). In the striatum, dopamine, dihydroxyphenylacetic acid, acetylcholine and substance P levels as well as choline acetyltransferase and glutamic acid decarboxylase activities were unaffected 10 or 21 days after either type of lesion. In the substantia nigra, substance P levels were unchanged 10 days following suction of the frontal cortex, but glutamic acid decarboxylase was reduced at 21 days postsurgery. Cortical lesions only partially prevented the reduction in striatal acetylcholine concentrations and did not affect the increase in striatal dihydroxyphenylacetic acid caused by haloperidol. Finally, lesions of the corticostriatal pathways failed to affect the apomorphine-induced increase in striatal acetylcholine levels, reduction of the potassium (20 mM) evoked [3H]acetylcholine release in striatal slices preloaded with [3H]choline and decrease of striatal dihydroxyphenylacetic acid concentrations. These findings indicate that the frontal cortex influences extrapyramidal function by a mechanism which--in behavioral terms--is antagonistic to dopamine-mediated events. As indicated by the biochemical data, this mechanism does not involve changes in striatal dopaminergic and cholinergic neuron activity. This mechanism may utilize: (1) corticostriatal glutamatergic neurons as suggested by the reduction in striatal glutamate uptake following lesions; and (2) GABAergic pathways as suggested by the reduction of nigral glutamic acid decarboxylase activity as well as by the finding that GABA receptor agonists reinstate haloperidol-induced catalepsy.

Evidence for a GABAergic inhibitory influence on serotonergic neurons originating from the dorsal raphe

Systemic administration of progabide, dipropylacetamide and gamma-acetylenic-GABA diminished striatal 5-HTP accumulation; the effect of progabide was abolished after hemitransection. Intradorsal raphé (but not intrastriatal) infusion of GABA or GABA agonist agents reduced striatal 5-HTP accumulation. Infusion of picrotoxinin or bicuculline into the dorsal raphé was without effect. It is concluded that GABA exerts an inhibitory influence on striatal serotonergic transmission via stimulation of GABA receptors located in the dorsal raphé.

The gabaergic hypothesis of depression

UNLABELLEDn1. GABAergic mechanisms have been generally ignored in the study of mood disorders and antidepressant drug (AD) action. Recently data have accumulated indicating that GABAergic mechanisms may be involved in both of these. 2. Mood disorders: GABA levels are reported to be low in the CSF and plasma of depressed patients and are related to mood changes. GABAB receptors are decreased in the frontal cortex in two rodent behavioral models of depression and GABA release is reported diminished in the hippocampus. GABAergic drugs (progabide, fengabine) reverse the behavioral deficits in the rodent models and exert clear therapeutic effects in depressed patients. 3. AD action: In behavioral models imipramine upregulates GABAB receptors only in those animals which respond behaviorally to the AD. In naive rats repeated administration of varied ADs upregulates GABAB receptors in the frontal cortex whereas non-ADs (including amphetamine) do not. Bicuculline inhibits the action of imipramine in the learned helplessness model. GABAA receptor stimulation enhances noradrenaline release in the ventral NA pathway. 4.nnnCONCLUSIONSnGABAergic mechanisms likely play a role in the modulation of mood and increasing GABAergic tone exerts and antidepressant effect. Actions at GABA synapses appear to be a fundamental facet of ADs, perhaps together with beta-adrenoceptor mediated events.

Regional effects of neuroleptics of dopamine metabolism and dopamine-sensitive adenylate cyclase activity

The effect of haloperidol, chlorpromazine, thioridazine and sulpride on the levels of DOPAC and HVA, as an index of DA turnover, and on the activity of DA-stimulated adenylate cyclase was investigated inthe striatum, the nucleus accumbens and the tuberculum olfactorium of the rat brain. Haloperidol, chlorpromazine and thioridazine caused a more marked increase in DA turnover in the striatum than in the mesolimbic areas, while the reverse was true for sulpiride. In contrast, although the relative potency of these compounds varied greatly, the Ki of each drug for the DA-sensitive adenylate cyclase was similar in three structures of rat brain. The results indicate that in the three brain structures investigated there was no correlation between the differential effects of neuroleptics on dopamine turnover in vivo and the blockade by these drug of the DA-sensitive adenylate cyclase activity in vitro.

[3H]RX 781094: A new antagonist ligand labels α2-adrenoceptors in the rat brain cortex

Abstract [ 3 H]RX 781094 [(imidazolinyl-2)-2 benzodioxane-1,4 [ 3 H]chlorhydrate], a specific α 2 -adrenoceptor antagonist radioligand, has been used to characterize α 2 -adrenoceptors in rat cortical membranes. [ 3 H]RX 781094 binding is reversible, saturable and stereospecific. It labels with high affinity a single population of non-interacting sites. The K D value was 3.9 ± 0.4 nM and the B max 189.0 ± 12.4 fmol/mg protein. Competition curves with different α-adrenoceptor agonists and antagonists showed that the binding sites labelled with [ 3 H]RX 781094 had the pharmacological characteristics of α 2 -adrenoceptors. Pretreatment with reserpine (2.5 mg/kg s.c., 24 h before the experiment) did not affect the K D or B max values of [ 3 H]RX 781094 binding. Chemical destruction of noradrenergic pathways by systemic injection of DSP4 or intracerebral injection of 6-hydroxydopamine did not modify the K D or the B max of [ 3 H]RX 781094 binding. It is concluded that the major proportion of α 2 -adrenoceptors labelled with [ 3 H]RX 781094 are not localised to noradrenergic nerve terminals.

Lack of involvement of α2-adrenoceptors in the regulation of striatal dopaminergic transmission

Abstract The effect of the α2-adrenoceptor antagonists RX 781094, rauwolscine and piperoxan on the metabolism of striatal dopamine and acetylcholine and of cerebral noradrenaline has been investigated in the rat. All compounds increased hypothalamic DOPEG-SO4 levels, cerebral MOPEG-SO4 concentrations and noradrenaline utilization. Rauwolscine and piperoxan also enhanced HVA and DOPAC levels and dopamine utilization in the striatum whereas RX 781094 did not. Moreover, rauwolscine and piperoxan, but not RX 781094, reduced striatal acetylcholine concentrations in vivo and antagonized the dopamine-induced inhibition of potassium-evoked release of [3H]acetylcholine from striatal slices. Finally, rauwolscine and piperoxan competitively antagonized the apomorphine-induced decrease in striatal DOPAC levels. These results altogether indicate that rauwolscine and piperoxan, but not RX 781094, possess dopamine receptor blocking properties. The divergent effects of these α-adrenoceptor antagonists on striatal dopamine turnover, together with the inability of clonidine to antagonize the rauwolscine and piperoxan-induced elevation of striatal DOPAC, strongly argue against an involvement of α2-adrenoceptors in the regulation of striatal dopaminergic transmission.