Sensitivityin vivo of centralα 2-and opiate receptors after chronic treatment with various antidepressants

Summary Recent studies suggest that the antidepressant activity could be explained by gradually developing modifications in the sensitivity of some central monoaminergic receptors. As concerns ₂-receptors, some largely indirect informations suggest that a subsensitivity develops following chronic treatment with desipramine or imipramine. However it is not clear whether this effect is shared by other antidepressants. In view of the important role of these receptors in the regulation of noradrenergic neurotransmission, single cell recording and microiontophoretic techniques were used in this work to systematically assess locus coeruleus (L.C.) ₂-receptor sensitivity following acute and chronic administration of various antidepressants. The responsiveness of L.C. ₂-receptors to iontophoretically applied clonidine was studied simultaneously with the responsiveness of L.C. opiate receptors to iontophoretically applied morphine in order to test the specificity in the putative modifications induced by the antidepressants. The compounds studied were desipramine (DMI), imipramine (IMI), clomi-pramine (CIMI), zimelidine (ZIM), mianserin (MIAN), iprindole (IPR) and chlorpromazine (CPZ). Long-term treatment with DMI, IMI and ZIM but not with the other clinically effective antidepressant drugs induced a decrease in the responsiveness of L.C. neurons to iontophoretically applied clonidine. None of the drugs tested altered the responsiveness of these neurons to iontophoretically applied morphine. Consequently the therapeutic effectiveness of antidepressant drugs can not be generally related to modulation of the sensitivity of central ₂ or opiate receptors.     

Heterologous supersensitization between serotonin2 and alpha2-adrenergic receptor-mediated intracellular calcium mobilization in human platelets

Summary Recent reports suggest that serotonin (5-HT)₂ receptor-mediated second messenger systems are enhanced in platelets of affective disorders. To make the mechanism of the enhanced response clear, we investigated 5-HT₂ and alpha ()₂-adrenergic receptor-induced intracellular calcium (Ca²⁺) mobilization in platelets of healthy volunteers, using fura-2. 5-HT₂ and ₂-adrenergic receptor-mediated Ca²⁺ mobilization was enhanced by prior exposure to the other type of agonist, so called heterologous supersensitization. The supersensitization was due to the enhancement of maximal response without change in agonist affinity. Chelating extracellular Ca²⁺ did not diminish the supersensitization. This enhancement of Ca²⁺ mobilization was not inhibited by H-7, an inhibitor of protein kinase C. However, this supersensitization was inhibited by pretreatment with sodium fluoride which directly activates guanine nucleotide binding regulatory proteins (G proteins). These results suggest that the supersensitization was caused from intracellular Ca²⁺ storage sites through a G protein-coupled pathway.Abbreviations fura-2/AM 1-(2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy)-2-(2-amino-5-methylphenoxy)-ethane-N,N,N, N-tetraacetic acid, pentaacetoxymethyl ester - H-7 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride - EGTA ethylenedioxybis(ethylamine)-N,N,N,N-tetraacetic acid - HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid - NaF sodium fluoride - Fmax maximal fluorescence intensity - Fmin minimal fluorescence intensity     

Modulation of endomorphin-2-induced analgesia by dipeptidyl peptidase IV

The tetrapeptide, endomorphin-2 (Tyr-Pro-Phe-PheNH₂) possesses high affinity for μ opioid receptors, and produces potent analgesia in mice. Its structure appears to satisfy the substrate requirements of the proteinase, dipeptidyl peptidase IV which removes dipeptides from the amino terminus of peptides containing proline as the penultimate amino acid. A potent, stable and specific inhibitor of this enzyme, Ala-Pyrrolidonyl-2-nitrile, has been described which should potentiate endomorphin-2-induced analgesia. Further, since dipeptidyl peptidase IV has an absolute requirement for -Pro, a more metabolically-stable -Pro²-endomorphin-2 analog should produce longer analgesic actions at lower doses. The present study found that endomorphin-2 was degraded approximately twice as fast than the chromogenic substrate, Ala-Pro-2naphthylamide, by dipeptidyl peptidase IV, whereas -Pro²-endomorphin-2 was totally resistant to this enzyme's action. -Pro²-endomorphin-2 (ED₅₀=0.05 μg) was more potent than endomorphin-2 (ED₅₀=30 μg) in significantly increasing tail-flick latencies with longer durations of action. Both the peptide and analogue were equipotent (ED₅₀=0.5 μg) in significantly increasing jump thresholds. Ala-Pyrrolidonyl-2-nitrile (10–75 nmol) elicited a dose-dependent analgesia, and potentiated the analgesic actions of endomorphin-2, particularly on the tail-flick test. Whereas systemic naltrexone (2.5, 10 mg/kg) dose-dependently eliminated each of the three forms of analgesia on the jump test as well as the peak (15 min) effect on the tail-flick test, analgesia elicited by either endomorphin-2, -Pro²-endomorphin-2 or Ala-Pyrrolidonyl-2-nitrile returned after 30–60 min in naltrexone-treated rats on the tail-flick test. These data strongly suggest that dipeptidyl peptidase IV plays a role in the inactivation of endomorphin-2 in vivo, and thereby modulates its central analgesic actions.     

Effect of chronic administration of antidepressant drugs on 5-HT2-mediated behavior in the rat following noradrenergic or serotonergic denervation

Summary Chronic (14 day) administration of several pharmacologically-distinct antidepressant drugs resulted in marked reductions in the serotonin₂ (5-HT₂)-mediated quipazine-induced head shake response which were accompanied by significant reductions in the density of cortical -adrenergic and 5-HT₂ binding sites. Noradrenergic (DSP4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine]-induced) and serotonergic (5,7-DHT[5,7-dihydroxytryptamine]-induced) lesions either attenuated or blocked antidepressant-induced reductions in 5-HT₂-mediated behavior. DSP4- and 5,7-DHT lesions did not alter the down-regulation of 5-HT₂ binding sites produced by imipramine, desipramine, phenelzine or iprindole. To a large extent, the antagonism of antidepressant-induced reductions in 5-HT₂-mediated behavior was coincident with the blockade of down-regulation of -adrenergic binding sites by both noradrenergic and serotonergic denervation. The functional interrelationship of 5-HT₂ and -adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.     

Lack of G protein-coupled sigma receptors in rat brain membranes: receptor-mediated high-affinity GTPase activity and [35S]GTPγS binding studies

Summary. Although sigma () receptors have been identified as an independent receptor family distinct from opioid and phencyclidine receptors, the physiological roles of these receptors are largely unknown. It is controversial whether there exist metabotropic receptors that are coupled with heterotrimeric G proteins. In the present study, the stimulatory effects of ligands on high-affinity GTPase activity and [³⁵S]GTPS binding were determined in the membranes prepared from rat cerebral cortex, hippocampus, and striatum. In either G protein activation assay, none of the ligands examined had stimulatory effect in any brain regions, except for unambiguous concentration-dependent increase in [³⁵S]GTPS binding by (+)-3-(3-hydroxyphenyl)-N-(1-propyl) piperidine [(+)-3-PPP] in striatal membranes. However, the competition study clearly showed this response was mediated through dopamine D₂-like receptors, but not receptors. It is concluded that receptors are not coupled to heterotrimeric G proteins, at least those of G_i/o type.     

Characterization of [

The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and

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-opioid receptor upregulation in mice. On day 1 mice were implanted SC with a NTX or placebo pellet and injected IT and ICV with dH₂O or oligodeoxynucleotides. The oligodeoxynucleotides were designed so that they were either perfectly complementary to the first 18 bases of the coding region of mouse

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-opioid receptor mRNA, or had one (Mismatch-1) or four (Mismatch-4) mismatches. On days 3, 5, 7, and 9, mice were again injected IT and ICV with dH₂O or one of the oligodeoxynucleotides. After the final injections on day 9, placebo and NTX pellets were removed, and 24 h later mice were tested for morphine analgesia or sacrificed for saturation binding studies ([³H]DAMGO). Naltrexone increased the analgesic potency of morphine in dH₂O treated mice by ≈ 70%. In binding studies, NTX significantly increased density of brain (≈ 60%) and spinal cord (≈ 140%)

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-opioid receptors without affecting affinity. The

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-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by ≈ twofold in placebo-treated mice. The oligodeoxynucleotide with four mismatches (Mismatch-4) did not significantly alter morphine potency. When placebo-treated mice were treated with either the antisense to the mouse

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-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of

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-opioid receptors. Thus,

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-opioid antisense significantly reduced morphine potency without changing

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-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and

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-opioid receptor upregulation. These data suggest that opioid antagonist-induced supersensitivity and upregulation of

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-opioid receptors does not involve changes in gene expression.     

The Effect of μ-Opioid Receptor Antisense on Morphine Potency and Antagonist-Induced Supersensitivity and Receptor Upregulation

The present study examined the effect of in vivo antisense oligodeoxynucleotide treatment on naltrexone (NTX)-induced functional supersensitivity and

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-opioid receptor upregulation in mice. On day 1 mice were implanted SC with a NTX or placebo pellet and injected IT and ICV with dH₂O or oligodeoxynucleotides. The oligodeoxynucleotides were designed so that they were either perfectly complementary to the first 18 bases of the coding region of mouse

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-opioid receptor mRNA, or had one (Mismatch-1) or four (Mismatch-4) mismatches. On days 3, 5, 7, and 9, mice were again injected IT and ICV with dH₂O or one of the oligodeoxynucleotides. After the final injections on day 9, placebo and NTX pellets were removed, and 24 h later mice were tested for morphine analgesia or sacrificed for saturation binding studies ([³H]DAMGO). Naltrexone increased the analgesic potency of morphine in dH₂O treated mice by ≈ 70%. In binding studies, NTX significantly increased density of brain (≈ 60%) and spinal cord (≈ 140%)

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-opioid receptors without affecting affinity. The

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-opioid antisense and the oligodeoxynucleotide with one mismatch (Mismatch-1) significantly reduced the potency of morphine by ≈ twofold in placebo-treated mice. The oligodeoxynucleotide with four mismatches (Mismatch-4) did not significantly alter morphine potency. When placebo-treated mice were treated with either the antisense to the mouse

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-opioid receptor, Mismatch-4 or Mismatch-1 there were no significant changes in the density of

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-opioid receptors. Thus,

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-opioid antisense significantly reduced morphine potency without changing

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-opioid receptor density. When NTX and oligodeoxynucleotide treatments were combined, there was no change in NTX-induced supersensitivity and

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-opioid receptor upregulation. These data suggest that opioid antagonist-induced supersensitivity and upregulation of

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-opioid receptors does not involve changes in gene expression.     

GluR2/3, NMDAε1 and GABA<Subscript>A</Subscript> receptors in Creutzfeldt-Jakob disease

The excitatory ionotropic glutamate receptors N-methyl-d-aspartate (NMDA) and -amino-3-hydro-5methyl-4-isoxazole propionic acid (AMPA) receptors, and the inhibitory -aminobutyric acid (GABA) receptors are major regulators of synaptic transmission in the central nervous system. Glutamate receptors AMPA GluR2/3 and NMDA R2A: NR2A (NMDA1), and GABA_A (GABA_A R1) receptors were examined by immunohistochemistry in the cerebral cortex (frontal cortex) entorhinal cortex, hippocampus and cerebellar cortex in nine patients with sporadic Creutzfeldt-Jakob disease (CJD) and eight age-matched controls obtained 3–8 h after death. All patients with CJD showed methionine/methionine in codon 129 of the prion protein gene. Decreased GluR2/3 immunoreactivity was found in the frontal cortex, entorhinal cortex and Purkinje cells; reduced NMDA1 immunoreactivity was found in the frontal cortex, entorhinal cortex, and molecular and granular cell layers of the cerebellum. Decreased GluR2/3 and NMDA1 immunoreactivity was also observed in the molecular layer of the dentate gyrus, but not in the hippocampus proper in cases with hippocampal involvement. GABA_A R1 expression was markedly decreased in the granular cell layer of the cerebellum in CJD. Decreased GluR2/3 and NMDA1 expression correlated with prion protein deposition, neuron loss and spongiform degeneration in the cerebral cortex in every case. However, reduced GluR2/3 immunoreactivity in Purkinje cells was apparently independent of these parameters. In contrast to ionotropic glutamate receptors, GABA_A R1 immunoreactivity was moderately increased in the frontal cortex, entorhinal cortex and molecular layer of the cerebellum in CJD. The present results show marked and selective abnormalities in the expression of crucial neurotransmitter receptors in CJD, ionotropic glutamate receptors being more severely affected than ionotropic GABA receptors. These findings stress selective vulnerability of glutamate receptors versus GABA receptors in CJD.     

Effect of destruction of central noradrenergic and serotonergic nerve terminals by systemic neurotoxins on the long-term effects of antidepressants onβ-adrenoceptors and 5-HT2 binding sites in the rat cerebral cortex

Summary The dependence of intact noradrenergic and serotonergic nerve terminals for the decrease in the number of-adrenoceptors and 5-HT₂ binding sites in the cerebral cortex produced by long-term treatment of rats with antidepressant drugs was examined. Noradrenergic nerve terminals were destroyed with the selective noradrenaline neurotoxin DSP4, and serotonergic nerve terminals were destroyed with p-chloroamphetamine (PCA). It was found that lesioning of the noradrenergic nerve terminals abolished the decrease in-adrenoceptors produced by desipramine, mianserin and zimeldine and partially antagonized that of the-adrenoceptor agonist clenbuterol. PCA pretreatment did not antagonize the long-term effects on the-adrenoceptor produced by these compounds.Lesioning of serotonergic nerve terminals affected the down-regulation of 5-HT₂ binding sites produced by long-term treatment with mianserin, desipramine and amiflamine. DSP4 pretreatment partially abolished the down-regulation of 5-HT₂ binding sites produced by long-term treatment with desipramine, while the effects of mianserin and amiflamine were unaffected by pretreatment with DSP4.     

Effects of dorsal rhizotomy and selective lesion of serotonergic and noradrenergic systems on 5-HT1a , 5-HT1b and 5-HT3 receptors in the rat spinal cord

Summary Autoradiographic studies were performed in combination with dorsal rhizotomy or selective lesion of descending serotonergic or noradrenergic systems in an attempt to identify the neuronal cell types endowed with the serotonin 5-HT_1a , 5-HT_1b and 5-HT₃ receptors in the rat spinal cord. Unilateral sectioning of seven dorsal roots (C4–T2) at the cervical level produced a marked decrease (–75%, 10 days after the surgery) in the binding of [¹²⁵I]iodozacopride to 5-HT₃ receptors in the superficial layers of the ipsilateral dorsal horn, further confirming the preferential location of these receptors on primary afferent fibres. In addition, a significant decrease (20%) in the binding of [³H]8-OH-DPAT to 5-HT_1A receptors and of [¹²⁵I]GTI to 5-HT_1B receptors was also observed in the same spinal area in rhizotomized rats, suggesting that a small proportion of these receptors are also located on primary afferent fibres. The labelling of 5-HT_1B receptors was significantly decreased (–12%) in the dorsal horn at the cervical (but not the lumbar) level, and that of 5-HT₃ receptors was unchanged in the whole spinal cord in rats whose descending serotonergic projections had been destroyed by 5,7-dihydroxytryptamine. Conversely, the labelling of 5-HT_1A receptors was significantly increased in the cervical (+13%) and lumbar (+42%) dorsal horn in 5,7-dihydroxytryptamine-lesioned rats. Similarly, [³H]8-OH-DPAT binding to 5-HT_1A receptors significantly increased (+26%) in the lumbar (but not the cervical) dorsal horn in rats whose noradrenergic systems had been lesioned by DSP-4. The labelling of 5-HT_1B receptors was also increased (+31% at the cervical level; +17% at the lumbar level), whereas that of 5-HT₃ receptors remained unchanged in these animals. These data indicate that complex adaptive changes in the expression of 5-HT_1A and 5-HT_1B receptors occurred in the rat spinal cord following the lesion of descending monoaminergic systems.Abbreviations CP 93129 3-(1,2,5,6-tetrahydropyrid-4-yl) pyrrolo [3,2-b]pyrid-5-one - 5,7-DHT 5,7-dihydroxytryptamine - DSP-4 N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine - GTI serotonin-O-carboxymethylglycyl-iodotyrosinamide - HEPES 4-(2-hydroxyethyl)-l-piperazine ethane sulfonic acid - 5-HT 5-hydroxytryptamine - i.c. intracisternally - NA noradrenaline - 8-OH-DPAT 8-hydroxy-2-(di-n-propylamino)tetralin     

[3H] UK-14,304, a new agonist ligand of α2-adrenoceptors: a comparative study with human and rat tissue

Summary [³H] UK-14,304 was used to investigate ₂-adrenoceptors in rat brain and human platelets. Receptor pharmacology revealed that the ligand binds with high affinity to ₂-adrenoceptors. Psychoactive substances like neuroleptics, antidepressants, and-carbolines displace [³H] UK-14,304 from its binding sites in the lower micromolar range. A Hill number around 2 for most neuroleptics suggests a positive cooperativity with the ₂-adrenoceptors.Comparative studies with [³H] UK-14,304 and [³H] clonidine utilizing platelet membranes from human volunteers demonstrated that the former ligand is more suitable to investigate possible changes of ₂-adrenoceptors; [³H] UK-14,304 labels more receptors with a lower standard deviation, whereby the volume of the blood sample amounted to 35 ml instead of 50 ml required for [³H] clonidine as ligand. No sex differences of binding constants were detected, however an inverse correlation of maximum number of binding sites and affinity was found for female subjects with both ligands.No age-dependent changes of B_max and K_D-values were observed in the range of 24 to 59 years.     

Effects of chronic antidepressant treatment on α1- and α2-adrenoceptors in the rat anococcygeus muscle

Summary The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the ₂-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the ₁-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied.Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic ₁-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic ₂-adrenoceptors to xylazine. These results show that the adaptative changes of -adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize ₁-adrenoceptors.     

Adrenergic receptors in the cerebellum of olivopontocerebellar atrophy

Summary Using autoradiographic techniques we studied the changes that in adrenergic receptors occurred in the cerebellum of two olivopontocerebellar atrophy (OPCA) patients as compared with a control group. In OPCA cerebellum the densities of total -adrenoceptors were reduced along the cortex but increased in the white matter. Although mainly the ₁ subtype was decreased along the cerebellar cortex, the increase of -receptors over the white matter was due to a selective raise in the ₂ subtype. These findings suggest a post-synaptic neuronal location for the ₁ subtype and a glial location for the ₂-adrenoceptor. On the other hand, alpha₂-adrenoceptors were clearly reduced all along the cerebellar cortex of these OPCA brains, this probably being secondary to the loss of presynaptic adrenergic terminals arising from the locus coeruleus. These results help clarify both the subcellular location of adrenoceptors in human cerebellum and the neurochemical pathophysiology of OPCA.     

Immunohistochemical demonstration of increase in prostaglandin F2-alpha after recirculation in global ischemic rat brains

Summary Immunohistochemical localization of prostaglandin F₂ (PG F₂) was studied in 24 rats. In 21 rats, global brain ischemia was produced for 5 min by Pulsinelli's method. Prior to decapitation, 13 were recirculated for 5 min, while the remaining eight were not. Three recirculated rats were pretreated with indomethacin before the occlusion. Hypotension was induced during the occlusion to 40–50 mm Hg of mean arterial blood pressure in 11 rats including those unrecirculated, recirculated and pretreated with indomethacin. Three normal rats without occlusion of arteries served as control. The brains were snap frozen and 10-m cryostat sections were incubated in rabbit anti-PG F₂ serum and stained by the indirect immunofluorescence method after fixation in carbodiimide and in Zamboni's solution. Positive staining for PG F₂ was noted mainly in pial vessels in normal and ischemic rats both with and without hypotension. The rats recirculated without hypotensive ischemia revealed a positive reaction in the walls of pial and parenchymal vessels. All rats recirculated after the hypotensive occlusion showed positive staining in blood vessels, in the cytoplasm of neurons (especially in hippocampi) and in the interfascicular oligodendrocytes. The above results indicate that recirculation after ischemia results in an increase in PG F₂ in parenchymal vessels, neurons and oligodendrocytes.     

Reduced brain monoamine synthesis by systemic treatment with terbutaline,a β2-receptor agonist

Summary The effects of acutely (5 mg/kg s.c.) or subchronically (2.5 mg/kg s.c., twice daily, 4 days) administered terbutaline, a ₂-receptor agonist, on thein vivo rate of tryptophan and tyrosine hydroxylation in various rat brain parts were studied. The accumulation of 5-hydroxytryptophan (5-HTP) during 30 min following treatment with NSD 1015, 100 mg/kg i.p., an inhibitor of L-aromatic amino acid decarboxylase, appeared reduced in several brain parts by the terbutaline treatments, the effect being significant in the limbic forebrain and the hemispheres after subchronic administration. This treatment also reduced the simultaneously measured accumulation of 3, 4-dihydroxyphenylalanine (DOPA) in the same brain parts as well as in corpus striatum, where the effect was seen also after acutely administered terbutaline. The concentration of tryptophan in the various brain parts was not significantly affected by the terbutaline treatments and the tyrosine levels were only reduced in some brain parts (the hemispheres and the brain stem). The central effects obtained by terbutaline treatment may be mediated indirectlyvia peripheral inputs toe.g. the monoamine carrying neurons and/orvia putative changes in cerebral blood flow.     

Platelet phospholipase A<Subscript>2</Subscript> activity in Alzheimer’s disease and mild cognitive impairment

Summary. Phospholipase A₂ (PLA₂) controls the metabolism of phospholipids in cell membranes. In the brain, PLA₂ influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (A), which are the major components of the senile plaques in Alzheimers disease (AD). Reduced PLA₂ activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA₂ activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA₂ activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA₂). PLA₂ activity was significantly lower in AD than in controls (p<0.001). Mean PLA₂ activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA₂ activity was significantly correlated with a worse cognitive performance both at the MMSE (p=0.001) and the cognitive sub-scale of the CAMDEX inventory (p=0.002). Our data replicate previous findings of reduced platelet PLA₂ activity in AD. Both reduced PLA₂ activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA₂ inhibits the physiological secretion of the APP, a mechanism that increases A formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA₂ values in platelets would be at a higher risk to develop AD during a longitudinal follow up.     

Cardiacβ 2-adrenoceptors and the inotropic response to exercise in man

To find out what role, if any, ₂-adrenoceptors play in cardiac contractility, the heart rate, stroke volume and cardiac output of twelve healthy male and female volunteers (aged 18–28 years) were studied at rest (standing) and during two stages of treadmill exercise, 2 h after ingestion of propranolol (100 mg) or atenolol (100 mg) or a placebo, on different occasions, in a double-blind crossover manner. Cardiac output was measured by a carbon dioxide—rebreathing method. Atenolol and propranolol caused equal reductions in heart rate at rest, and in heart rate and cardiac output during exercise (p < 0.001, two-way analysis of variance). Neither atenolol nor propranolol had any significant effect on resting cardiac output, resting stroke volume or stroke volume during exercise. Since atenolol (100 mg) has been shown to be ₁-adrenoceptorselective, we conclude that cardiac inotropic function during exercise is largely ₁-adrenoceptor-mediated with little or no ₂-adrenoceptor involvement.     

Increasedα 2;-adrenoceptor density in the frontal cortex of depressed suicide victims

Summary The density of brain ₂-adrenoceptors, quantitated by means of the binding of the agonist [³H]clonidine, was studied in post-mortem cortical membranes of matched control subjects and depressed suicide victims. In the depressed suicide group, the specific high affinity binding of [³H]clonidine was found to be significantly increased (B_max, 72% greater; p<0.01) without significant changes in the K_D value for the radioligand. These preliminary results indicate that ₂-adrenoceptor density in the high affinity state _2H) is increased in the brain of depressed patients and add strong support to the hypothesis that endogenous depression is related to supersensitive ₂-adrenoceptors.