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Biomedical subjects

S J Enna

Publications and source records attributed to S J Enna.

At least 55 records · Page 3Linked to original sources
PubMed1987

In vivo or in vitro exposure to imipramine reduces alpha 2-adrenoceptor-mediated inhibition of cyclic AMP production in rat brain cerebral cortical slices.

The effect of in vivo or in vitro exposure to imipramine on alpha 2-adrenoceptor-mediated inhibition of cAMP production in rat brain slices was examined. Chronic administration (10 mg/kg once daily for 14 or 21 days) of imipramine or in vitro exposure (100 microM, 60 min) to the antidepressant significantly reduced the ability of UK-14,304, an alpha 2-adrenoceptor agonist, to inhibit forskolin-stimulated cAMP accumulation in cerebral cortical slices. This reduction was due to a decrease in the maximal response to the alpha 2-adrenergic agonist rather than to a decrease in its potency. Besides yielding a rapid and direct method for studying the effect of imipramine on brain receptors in vitro, these findings provide biochemical evidence in support of the notion that this drug, and perhaps other antidepressants, modifies alpha 2-adrenoceptor function in the central nervous system.

Adrenergic alpha-Agonists↗
PubMed1987

Supersensitive beta-adrenergic receptors are down-regulated in rat brain by mianserin administration.

Experiments were undertaken to determine whether alterations in rat brain monoaminergic tone influence the manner in which mianserin administration modifies beta-adrenergic receptor function. Whereas the chronic administration of mianserin had little effect on isoproterenol-stimulated cAMP accumulation in control cerebral cortical slices, treatment with this antidepressant prevented or reversed beta-adrenergic receptor super-sensitivity resulting from reserpine or 6-hydroxydopamine administration. In contrast, 5,7 dihydroxytryptamine treatment had no effect on beta-adrenergic receptor activity, or on the ability of mianserin to modify isoproterenol-stimulated cAMP accumulation. The results indicate that antidepressant-induced alterations in beta-adrenergic receptor activity may, in some cases, be a function of receptor sensitivity at the time of drug administration.

5,7-Dihydroxytryptamine↗
PubMed1987

The GABA agonist THIP, attenuates antinociception in the mouse by modifying central cholinergic transmission.

The effect of THIP, a direct-acting gamma-aminobutyric acid (GABA) receptor agonist, on the antinociceptive response to a variety of agents was examined using the mouse tail-immersion assay. Alone, THIP produced an antinociceptive response in smaller doses (5 mg/kg) but was ineffective at doses exceeding 10 mg/kg. Treatment with THIP (15 mg/kg) was found to block the antinociceptive response to an inhibitor of the uptake of GABA, an inhibitor of GABA-transaminase, a direct-acting GABA receptor agonist and to a cholinesterase inhibitor. In contrast, THIP had no effect on the antinociceptive responses to morphine, clonidine or oxotremorine. The results indicate that large doses of THIP reduce cholinergic activity in a pathway important for mediating the antinociceptive action of GABAergic drugs and physostigmine.

Afferent Pathways↗
PubMed1987

Modulation of receptor-mediated cyclic AMP production in brain.

Alpha-Adrenergic and GABAB receptor agonists regulate adenylate cyclase either negatively, by direct inhibition of the enzyme, or positively, by augmenting agonist-stimulated production of cyclic AMP. While the inhibition of adenylate cyclase is most likely to be mediated by a direct stimulation of Gi protein, the enhancement of production of cyclic nucleotide appears to involve protein kinase C and perhaps PLA2. alpha-Adrenergic and GABAB receptor augmentation of accumulation of cyclic AMP is also influenced by pituitary-adrenal hormones, suggesting a link between brain function and the endocrine system. The number of components associated with the modulation of neurotransmitter receptor-coupled second messenger production provides multiple targets for the pharmacological manipulation of this system. By influencing the modulatory response rather than receptor activity directly, it may be possible to produce subtle alterations in the function of the central nervous system yielding safer and perhaps more effective therapies for the treatment of mental illness.

Adenylyl Cyclases↗
PubMed1987

(R)-nipecotic acid ethyl ester: a direct-acting cholinergic agonist that displays greater efficacy at M2 than at M1 muscarinic receptors.

Previous reports have suggested that the ethyl ester of (R)-nipecotic acid ethyl ester [(R)-NAEE] displays cholinomimetic properties in vivo. The present study was undertaken to characterize more fully this action by examining the effects of (R)-NAEE in a number of pharmacological and biochemical tests of cholinergic action. (R)-NAEE was found to produce negative inotropic and chronotropic effects on the guinea pig atria (pD2 = 5.91 and 5.62, respectively), and was capable of stimulating contractions in the guinea pig ileum (pD2 = 5.95) and rat jejunum (pD2 = 5.40) at concentrations similar to bethanechol. Both the cardiac and intestinal effects of (R)-NAEE were reversed by atropine. Moreover, (R)-NAEE competed with N-[3H]methylscopolamine and [3H]pirenzepine for muscarinic binding sites in a variety of tissues. Like carbachol, (R)-NAEE inhibited GTP-stimulated adenylate cyclase in rat striatal membranes (EC50 = 52 microM), whereas, unlike carbachol, (R)-NAEE was unable to stimulate inositol phosphate accumulation in rat cerebral cortical slices, behaving as an antagonist in this latter system (pA2 = 5.0). The results indicate that (R)-NAEE interacts directly with cholinergic muscarinic receptors, being an agonist for the M2 subtype and an antagonist at M1 sites.

Adenylyl Cyclase Inhibitors↗
PubMed1986

Antidepressant administration has a differential effect on rat brain alpha 2-adrenoceptor sensitivity to agonists and antagonists.

The aim of this study was to characterize the action of antidepressants on rat brain alpha 2-adrenoceptor function by examining their effect on the yohimbine-sensitive component of the cAMP response to adrenoceptor agonists. Using a prelabeling technique for measuring cAMP accumulation, it was found that chronic (2 weeks) administration of antidepressants increased the potency of yohimbine, an alpha 2-adrenoceptor antagonist, to inhibit norepinephrine-stimulated cAMP accumulation in rat brain cerebral cortical slices. In contrast, antidepressant treatment decreased the ability of the alpha-adrenoceptor agonist 6-fluoronorepinephrine to augment isoproterenol-stimulated cAMP accumulation. The results suggest that antidepressants alter rat brain alpha 2-adrenergic function by shifting the receptor to antagonist-preferring state. Such an effect may contribute to the change in noradrenoceptor responsiveness that is characteristic of antidepressant administration.

Adrenergic alpha-Agonists↗
PubMed1986

A procedure for measuring alpha 2-adrenergic receptor-mediated inhibition of cyclic AMP accumulation in rat brain slices.

The alpha 2-adrenergic receptor regulation of cyclic adenosine monophosphate (cAMP) accumulation in rat brain slices was examined. using a prelabeling technique for measuring second messenger production. The mixed alpha-adrenergic agonist 6-fluoronorepinephrine, as well as the more selective alpha 2-agonists clonidine and UK-14,304, caused a concentration-dependent inhibition of forskolin-stimulated cAMP accumulation in cerebral cortical slices, whereas phenylephrine, a selective alpha 1-adrenergic agonist, had no inhibitory effect in this system. Moreover, alpha 2-adrenergic receptor antagonists were more potent than alpha 1-adrenergic antagonists in blocking the inhibitory response to UK-14,304. Neither alpha 1- nor alpha 2-adrenergic agonists displayed any inhibitory effect when cAMP accumulation was stimulated by isoproterenol, vasoactive intestinal peptide or 2-chloroadenosine. The results provide further evidence that some alpha 2-adrenergic receptors are negatively coupled to adenylate cyclase in brain, and yield a procedure for studying this phenomenon in intact central nervous system tissue.

2-Chloroadenosine↗
PubMed1986

The parafasciculus thalami as a site for mediating the antinociceptive response to GABAergic drugs.

Electrophysiological (single cell) experiments were undertaken to examine whether neurons in the rat parafasciculus thalami (PF) are involved in mediating the antinociceptive response to GABAergic drugs. The results indicated that: noxious stimuli excite most PF neurons; microiontophoretic application of morphine, GABA or the GABA agonist, THIP, attenuated the spontaneous firing rate of PF neurons; morphine, THIP and GABA reduced the neuronal excitation induced by noxious stimuli; application of the GABA receptor antagonist, bicuculline, prevented the effects of THIP and GABA on PF activity; while naloxone blocked the response to morphine on PF neurons, it failed to influence the actions of GABA and THIP; and the injection of THIP or GABA into the PF produced an antinociceptive response as assessed by the rat tail-immersion assay, whereas pentobarbital was inactive. The findings suggest that GABA receptors located in the PF may mediate the antinociceptive response to GABAergic drugs, and that the action of these agents is unrelated to opiate receptors.

Animals↗
PubMed1986

Phorbol esters down-regulate protein kinase C in rat brain cerebral cortical slices.

The effect of phorbol esters on cyclic AMP production in rat cerebral cortical slices was studied using a prelabelling technique to measure cyclic nucleotide accumulation. Cholera toxin-stimulated cyclic AMP accumulation was enhanced approximately 2-fold by phorbol 12-myristate, 13-acetate (PMA) which alone had no effect on cyclic AMP production. The augmentation by PMA was maximal within the first hour of incubation, decreasing progressively thereafter. Protein kinase C activity was decreased 80-90% during a 3 hr exposure to PMA, as was 3H-phorbol 12,13-dibutyrate binding. Both phosphatidyl serine and arachidonic acid were found to enhance protein kinase C activity in a concentration-dependent manner, an effect that was attenuated by prolonged incubation of the brain tissue with PMA. The results indicate that exposure of brain slices to phorbol esters causes a down-regulation of rat brain protein kinase C, and that this modification corresponds with a decrease in the ability of PMA to augment cyclic AMP production, suggesting a functional relationship between the two systems in rat brain.

Animals↗
PubMed1986

Stereoselective syntheses of the trans-decahydroquinoline-5-carboxylic acid epimers. Diastereomeric zwitterionic probes of gamma-aminobutyric acid related biological properties in vitro and in vivo.

The syntheses of the 5 beta and 5 alpha epimers of trans-(4a alpha,8a beta)-decahydroquinoline-5-carboxylic acids (3 and 4) from vinylogous bicyclic imide 10 are described. The reduction of trans-5-(1,3-dithian-2-ylidene)octahydro-2(1H)-quinolinone (13) to afford the 5 alpha-(1,3-dithian-2-yl) compound 16 was a key step in the synthesis of trans-4 while hydroboration-H2O2 treatment of phenylmethyl trans-octahydro-5-methylene-1(2H)-quinolinecarboxylate (21) to afford the 5 beta-hydroxymethyl compound 22 was a key step in the synthesis of 3. These trans diastereomers 3 and 4 and the previously prepared cis analogues 1 and 2 were investigated for their ability to interact with GABAA and GABAB receptors and picrotoxin binding sites as well as with neuronal GABA transport systems in brain tissue. Like 1 and 2, tonic-clonic seizures were induced when trans-3 or -4 were administered to mice intracerebroventricularly. Only trans-4 weakly inhibited [3H]GABA binding to GABAA and GABAB receptors in vitro. Large doses (10 mg/kg) of diazepam reversed the convulsant activity of both trans-3 and trans-4. Although trans-3 is the more potent convulsant, trans-4 may have GABA antagonist activity in vivo. However, none of the decahydroquinoline diastereomers have a pronounced effect on GABA receptors that can currently be studied in vitro. Results obtained in vivo lead us to propose that these diastereoisomers may serve as unique conformational probes relating certain zwitterionic topographies to stimulatory activity in the central nervous system.

Animals↗
PubMed1986

An examination of the involvement of phospholipases A2 and C in the alpha-adrenergic and gamma-aminobutyric acid receptor modulation of cyclic AMP accumulation in rat brain slices.

Experiments were undertaken to define the role of two calcium-associated enzyme systems in modulating transmitter-stimulated production of cyclic nucleotides in rat brain. Cyclic AMP (cAMP) accumulation was examined in cerebral cortical slices using a prelabeling technique. The enhancement of isoproterenol-stimulated cAMP production by alpha-adrenergic and gamma-aminobutyric acid-B (GABAB) agonists was reduced by exposing the tissue to EGTA, a chelator of divalent cations, or quinacrine, a nonselective inhibitor of phospholipase A2. Likewise, chronic (2 weeks) administration of corticosterone decreased the alpha-adrenergic and GABAB receptor modulation of second messenger production. Neither cyclooxygenase nor lipoxygenase inhibitors selectively influenced the facilitating response of alpha-adrenergic and GABAB agonists. Other experiments revealed that although norepinephrine and 6-fluoronorepinephrine stimulated inositol phosphate (IP) production in cerebral cortical slices with potencies equal to those displayed in the cyclic nucleotide assay, selective alpha 1-adrenergic agonists were less efficacious on IP formation and were without effect in the cAMP assay. Conversely, a selective alpha 2-adrenergic receptor agonist facilitated the cAMP response to a beta-adrenergic agonist without affecting IP formation. The rank orders of potency of a series of alpha-adrenergic antagonists suggest that IP accumulation is mediated solely by alpha 1-adrenergic receptors, whereas the augmentation of cAMP accumulation is regulated by a mixed population of alpha-adrenergic sites. The results suggest that the alpha-adrenergic and GABAB receptor-mediated enhancement of isoproterenol-stimulated cAMP formation appears to be more closely associated with phospholipase A2 than phospholipase C and may be mediated by arachidonate or some other fatty acid.

Adrenergic alpha-Agonists↗
PubMed1986

Phorbol esters enhance neurotransmitter-stimulated cyclic AMP production in rat brain slices.

The effect of phorbol esters on cyclic AMP production in rat CNS tissue was examined. Using a prelabeling technique for measuring cyclic AMP accumulation in brain slices, it was found that phorbol 12-myristate, 13-acetate (PMA) enhanced the cyclic AMP response to forskolin and a variety of neurotransmitter receptor stimulants while having no effect on second messenger accumulation itself. A short (15-min) preincubation period with PMA was required to obtain maximal enhancement, whereas the augmentation was lessened by prolonged exposure (3 h) to the phorbol. The response to PMA was concentration dependent (EC50 = 1 microM) and regionally selective, being most apparent in forebrain, and was not influenced by removal of extracellular calcium or by inhibition of phosphodiesterase or phospholipase A2. Only those phorbols known to stimulate protein kinase C augmented the accumulation of cyclic AMP. Moreover, the membrane substrates phosphorylated by endogenous C kinase and by a partially purified preparation of this enzyme were similar. The results suggest that phorbol esters, by activating protein kinase C, modify the cyclic AMP response to brain neurotransmitter receptor stimulation in brain by influencing a component of the adenylate cyclase system beyond the transmitter recognition site.

2-Chloroadenosine↗
PubMed1986

Activation of alpha-2 adrenergic receptors augments neurotransmitter-stimulated cyclic AMP accumulation in rat brain cerebral cortical slices.

Norepinephrine-stimulated cyclic AMP (cAMP) accumulation in brain is mediated by both alpha and beta adrenergic receptors. The functional activity of these receptors can be differentiated by examining the response to isoproterenol alone and isoproterenol + 6-fluoronorepinephrine, and alpha adrenergic agonist. The present study was undertaken to define the pharmacological characteristics of the alpha adrenergic component associated with cAMP accumulation in brain. Using a prelabeling technique it was found that norepinephrine- or isoproterenol plus 6-fluoronorepinephrine-stimulated cAMP accumulation was only inhibited partially by an alpha-1 adrenergic receptor antagonist. In contrast, alpha-2 adrenergic receptor antagonists inhibited completely that portion of the response exceeding that produced by isoproterenol alone (alpha adrenergic augmentation). Furthermore, selective alpha-1 adrenergic agonists were incapable of enhancing the cAMP response to isoproterenol, whereas alpha-2 adrenergic agonists were active in this regard. Partial agonists for the alpha-2 adrenergic receptor were ineffective as augmentors. The data suggest that the alpha adrenergic component of the norepinephrine response in rat brain slices has characteristics of both alpha-1 and alpha-2 receptors, with the alpha-2 adrenergic component being a major contributor in this regard.

Adenylyl Cyclases↗
PubMed1985

GABA uptake inhibitors produce a greater antinociceptive response in the mouse tail-immersion assay than other types of GABAergic drugs.

Antinociception produced by the GABA uptake inhibitors d,l- SKF-89976A and SKF-100330A was characterized and compared to that produced by other types of GABAergic drugs. Using the mouse tail-immersion assay it was found that the antinociception produced by the uptake inhibitors was antagonized by scopolamine, a cholinergic muscarinic receptor antagonist. However, neither SKF compound demonstrated any significant affinity for muscarinic receptor binding sites suggesting that they are not direct-acting cholinomimetics. In vitro uptake experiments revealed that the SKF compounds selectively inhibit GABA transport, having no effect on the accumulation of aspartic acid, glutamic acid, beta-alanine or glycine. Moreover, antinociception and GABA uptake inhibition were stereoselective for SKF-89976A, with the d-isomer being more active in both tests. When comparing antinociceptive responses at maximally effective doses it was also found that the SKF compounds were substantially more efficacious than direct-acting GABA receptor agonists or a GABA transaminase inhibitor. These data suggest that uptake inhibitors may be facilitating GABA transmission in a system that is less affected by other types of GABAergic compounds.

Analgesics↗
PubMed1985

Synergistic interaction between alpha- and beta-adrenergic receptors in rat brain slices: possible site for antidepressant drug action.

Experiments were undertaken to examine the characteristics of the adrenergic receptor-coupled cAMP system in rat brain slices. It was found that the potentiation of isoproterenol-stimulated cAMP accumulation by 6-fluoronorepinephrine, an alpha-adrenergic agonist, is largely dependent upon the degree of beta-receptor occupancy, with prazosin-sensitive alpha-adrenergic receptors contributing less to this interaction. Chronic administration of a variety of antidepressants decreased the potentiating interaction between 6-fluoronorepinephrine and isoproterenol even under conditions where there were no obvious effects on the alpha- or beta- adrenergic components themselves. Chronic administration of imipramine had no effect on the interaction between 6-fluoronorepinephrine and adenosine, suggesting that the drug selectively modifies the coupling between the alpha- and beta-adrenergic systems. The results suggest that antidepressants influence the coupling between 6-fluoronorepinephrine and isoproterenol receptors independent of any effect on the individual recognition sites.

Animals↗
PubMed1985

The effect of mouse spinal cord transection on the antinociceptive response to the gamma-aminobutyric acid agonists THIP (4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol) and baclofen.

The antinociceptive responses to the gamma-aminobutyric acid receptor agonists THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridine-3-ol) and baclofen were examined in spinally transected mice to define the central nervous system site of action for these drugs. Nociception was assessed using a tail-immersion assay. The results indicated that spinal transection (T6-T10) completely abolished the antinociceptive responses to THIP and baclofen, attenuated those to oxotremorine and morphine, but did not reduce the response to clonidine. The results suggest that the antinociceptive responses to THIP and baclofen are mediated by an action at supraspinal sites rostral to T6.

Analgesics↗
PubMed1985

Securinine alkaloids: a new class of GABA receptor antagonist.

Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CD50 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 microM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and beta-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicuculline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indicated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo- and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.

Alkaloids↗