Changes In Receptor Sensitivity Research Articles

Lithium prophylaxis of recurrent affective disorders

The mode of action of lithium is reviewed in the light of advances in the understanding of calcium channelling and calmodulin-activated Ca ATPase. The relevance to changes in receptor sensitivity is discussed.

Possible change in noradrenergic receptor sensitivity following methylphenidate treatment: Growth hormone and MHPG response to clonidine challenge in children with attention deficit disorder and hyperactivity

Growth hormone (GH) and 3-methoxy-4-hydroxyphenelethylene glycol (MHPG) response was measured hourly for 4 hours in 8 children with Attention Deficit Disorder with Hyperactivity (ADD+H) following an acute single-dose of clonidine. The clonidine challenge was repeated before, during, and one day after 12 weeks of treatment with methylphenidate (MPH). Before MPH treatment, the plasma growth hormone (GH) rose to 31.3 ± 4.6 (Mean ± SE) ng/ml; during MPH treatment, the GH peak was only 14.8 ± 3.2 ng/ml; one day after discontinuation of MPH, GH rose to only 20.8 ± 3.9 ng/ml. MHPG release was inhibited by clonidine in all treatment conditions but tended to be more decreased during MPH treatment. Some children with ADD+H may have hypersensitivity of the post-synaptic alpha-1 noradrenergic receptor which is diminished by MPH treatment. The extent to which these effects are pharmacological or represent a change in receptor sensitivity requires further study.

Adenylate cyclase and the search for new compounds with the clinical profile of lithium

It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta 2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to i.v. salbutamol declined over 60%. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. In rat cortical slices Li inhibition of noradrenaline-induced cyclic AMP accumulation is clearly demonstrable only at concentrations close to 2 mM Li. However, fresh human brain slices from edges of surgically-removed tumors show Li inhibition at 1 mM Li concentrations. These results imply that in brain as well as periphery, human noradrenergic adenylate cyclase is inhibited by therapeutic concentrations of Li. Demeclocyclin, a tetracycline-derived antibiotic, was found to inhibit noradrenaline-sensitive adenylate cyclase in rat cortical slices and to inhibit amphetamine-induced hyperactivity in rats in an open field. Clinical trials should search for new compounds with the clinical profile of Li.

Response changes after repeated low apomorphine: dopamine autoreceptor desensitization or learning?

Repeated injection of rats with low doses of apomorphine (APO), which selectively interact with dopamine (DA) autoreceptors, caused a change in yawning responses that suggests initial low-APO-induced desensitization of DA autoreceptors, followed by a long-lasting rebound hypersensitivity. Repeated treatment with low APO followed by open-field testing, however, yielded totally different results. APO accelerated intrasession response decrement and upon repeated administration enhanced the intersession response decrement. Both for yawning and open-field behavior, the response change after the second dose of APO was only evident when the first as well as the second APO injection were followed by exposure of the rat to the same test situation. These results indicate that response changes after repeated treatment with low APO are not due to a simple DA-agonist-induced change in receptor sensitivity but that drug experience combined with environmental influences play a decisive role.

Adenylate cyclase and the search for new compounds with the clinical profile of lithium.

It is possible to evaluate the beta-adrenergic receptor-adenylate cyclase complex in the human periphery by measuring the plasma cyclic AMP rise after adrenergic agonists. A clinical trial of the beta 2 adrenergic agonist salbutamol in depression provided an opportunity to test whether adrenergic receptor subsensitivity does occur during clinical antidepressant treatment. After 1 and 3 weeks of oral salbutamol treatment, depression scores declined significantly in 11 depressed patients, while the plasma cyclic AMP response to i.v. salbutamol declined over 60%. The results support the concept that receptor sensitivity changes occur during human antidepressant therapy. Data are presented that Li, too, markedly reduces activity of beta-adrenergic adenylate cyclase in humans. The effect was evaluated by studying the effect of Li at therapeutic serum concentrations on the plasma cyclic AMP response to subcutaneous epinephrine. The Li effect is specific, since the plasma cyclic AMP response to glucagon is not inhibited. In rat cortical slices Li inhibition of noradrenaline-induced cyclic AMP accumulation is clearly demonstrable only at concentrations close to 2 mM Li. However, fresh human brain slices from edges of surgically-removed tumors show Li inhibition at 1 mM Li concentrations. These results imply that in brain as well as periphery, human noradrenergic adenylate cyclase is inhibited by therapeutic concentrations of Li. Demeclocyclin, a tetracycline-derived antibiotic, was found to inhibit noradrenaline-sensitive adenylate cyclase in rat cortical slices and to inhibit amphetamine-induced hyperactivity in rats in an open field. Clinical trials should search for new compounds with the clinical profile of Li.

Acute reduction in human platelet alpha 2-adrenoreceptor affinity for agonist by endogenous and exogenous catecholamines.

The binding characteristics of l-epinephrine to intact human platelets were assessed under conditions of physiological and pharmacological variations in plasma catecholamine concentration. In competition with the alpha 2-adrenoreceptor antagonist yohimbine, mean platelet receptor affinity for l-epinephrine was decreased 3.4-fold after 2 h of upright posture and exercise. This change in agonist affinity correlated significantly with the increases in plasma epinephrine and norepinephrine that were stimulated by upright posture and exercise. Supine subjects infused with l-norepinephrine or l-epinephrine for 2 h also averaged a 3.3- and 2.7-fold decrease in platelet alpha 2-adrenoreceptor affinity for agonist with no change in receptor number or antagonist affinity. The alpha 2-adrenoreceptor agonist affinity changes were specific for alpha-agonists since they were blocked by phentolamine, and incubation with 10(-5) M isoproterenol produced no change in alpha 2-adrenoreceptor affinity for l-epinephrine. In vitro exposure of intact human platelets to 10(-6) to 10(-10) M l-epinephrine for 2 h produced a concentration-related decrease in alpha 2-adrenoreceptor affinity for agonist. In all three paradigms, average slope factors approached 1.0 as affinity decreased, which is consistent with a heterogeneous receptor population that becomes more homogeneous after agonist exposure. Incubation of platelet-rich plasma with 10(-6) to 10(-8) M l-epinephrine resulted in a dose- and time-related loss of aggregatory response to l-epinephrine; this demonstrates that agonist affinity changes are correlated with changes in receptor sensitivity. These observations demonstrate that physiological variations in plasma catecholamines acutely modulate the intact human platelet alpha 2-adrenoreceptor's affinity for agonist, and can thereby alter the sensitivity of platelets to alpha 2-adrenergic agonist.

Dopamine-stimulated adenylate cyclase in hypothalamus: Influence of estrous cycle in female and castration in male rats

The activity of dopamine- and norepinephrine-stimulated adenylate cyclase in hypothalamus and amygdala was studied during the estrous cycle of the female and following castration of the male rat. In the medial hypothalamus but not in the anterior hypothalamus or amygdala, stimulation of adenylate cyclase by dopamine was enhanced during proestrus and following castration. There were no changes in norepinephrine-stimulated adenylate cyclase in medial hypothalamus. Thus, an interaction may exist between gonadal hormones and dopamine receptors linked to adenylate cyclase in medial hypothalamus. The rapidity of the changes in receptor sensitivity suggests that this interaction plays an important role in physiological regulation.

Influence of ergot derivatives on prolactin secretion in rats. Mechanisms of action and clinical implications

Ergot derivatives are the most effective compounds in the treatment of migraine attacks. It has been proposed that these compounds exert this effect by direct action on skull arteries or arteriovenous anastomoses, or by interfering with peripheral or central serotonin receptors. It is also possible that these compounds influence monoaminergic neurotransmission and, thereby, endorphins modulating the threshold for pain or sensory perception. In testing these hypotheses, changes in receptor sensitivity or function have to be considered since we have observed simultaneous tolerance and supersensitivity development in the same animal treated chronically with lisuride. We therefore propose that ergot derivatives can reduce the well documented higher sensitivity of migraine sufferers to various stimuli. In humans, prolactin-levels can be used for determining bioavailability of some ergot derivatives and for studying whether dopaminergic mechanism plays a role in their antimigraine effect.

Changes in the sensitivity of the central alpha- and beta-adrenergic systems during desmethylimipramine treatment as assessed by plasma growth hormone response in the baboon.

The tricyclic antidepressant desmethylimipramine (DMI) 2.5 mg/kg IM was administered to adolescent baboons once daily for 21 days, to investigate changes in alpha- and beta-noradrenergic function. Prior to DMI treatment, plasma growth hormone (GH) responses to the intravenous infusion of an alpha 2-adrenergic receptor agonist, clonidine, or a beta 2-adrenergic antagonist, ICI 118,551, were determined. DMI, 2.5 mg/kg, administered acutely did not stimulate the release of GH (up to 4 h post injection). The GH response to clonidine was decreased 4 h after DMI, 2.5 mg/kg. Alterations in plasma GH response to clonidine and ICI 118,551 were evident during and after chronic DMI administration. The GH response to clonidine was significantly diminished after 2 days, and gradually returned to the pretreatment amplitude over 7-21 days of treatment, with an overshoot 2 days after DMI withdrawal. After 21 days of DMI administration the GH response to ICI 118,551 was significantly enhanced, and remained consistently elevated during a withdrawal period of 21 days. These changes in the response to an alpha-adrenergic agonist and a beta-adrenergic antagonist indicate that the long term regulatory changes in receptor sensitivity, occurring between 2 and 21 days of DMI treatment, compensate for the acute effects of DMI on these responses.

The effects of low calcium and background light on the sensitivity of toad rods.

1. We have examined the effects of decreases in extracellular Ca(2+) concentration on the intracellularly recorded light responses of rods from the toad, Bufo marinus. In agreement with previous results (Brown & Pinto, 1974; Lipton, Ostroy & Dowling, 1977), Ca(2+) concentrations below 10(-6) M produced a depolarization of rod resting membrane potential of approximately 30-40 mV and a corresponding increase in the maximum amplitude of the rod's light responses, so that saturating flashes in normal and low Ca(2+) Ringer produced hyperpolarizations to approximately the same membrane potential.2. The rod's sensitivity was reduced in low Ca(2+) Ringer by an amount dependent upon the extracellular Ca(2+) concentration. At 10(-6) M-Ca(2+), sensitivity was approximately 0.6 log units below normal. Thereafter, it dropped nearly linearly with [Ca(2+)](o) to a value approximately 4.0 log units below normal at 10(-9) M-Ca(2+). Most of the decline occurred within 1-2 min after the solution change as the membrane potential depolarized, but sensitivity continued to fall slowly with time at the lowest Ca(2+) concentrations. Exposure to low Ca(2+) solutions altered the kinetics of the receptor response to brief flashes, delaying response onset and time-to-peak but affecting the time course of decay very little.3. The sensitivity of the rod to maintained steps of light was also reduced in low Ca(2+). Furthermore, the changes in sensitivity produced by background illumination were very much smaller in low Ca(2+) than in normal Ringer. In some cases backgrounds actually increased sensitivity.4. In 10(-8) M-Ca(2+), backgrounds which themselves produced no response in the rod and no changes in rod sensitivity produced large decreases in response latency for responses of all amplitudes, and pronounced changes in time-to-peak and time-to-decay for moderate and large amplitude responses.5. Since the effects of background light and low Ca(2+) on the wave form of the rod are distinct and in some cases antagonistic, and since the changes in receptor sensitivity produced by backgrounds and low Ca(2+) are not additive, the decreases in sensitivity produced by exposure to low Ca(2+) appear to be caused by a mechanism distinct from normal light adaptation. We suggest that they are caused by an increase in the buffering capacity of the receptor cytosol for Ca(2+) and that Ca(2+) is the excitatory messenger or ;internal transmitter', as originally suggested by Yoshikami & Hagins (1971).

Sympathetic modulation of mechanoreceptor sensitivity in frog skin.

1. Sympathetic effects on the mechanical sensitivity of frog cutaneous mechanoreceptors were examined in vivo. 2. Functionally identified units were tested with repetitive mechanical stimuli of threshold intensity during electrical stimulation of the sympathetic trunk. 3. Sympathetic activity resulted in increased sensitivity for three classes of afferents; slowly adapting compression receptors, slowly adapting stroke receptors, and rapidly adapting stroke receptors. Decreased sensitivity was produced in the fourth class, rapidly adapting compression receptors. 4. Preliminary tets of several possible modes of sympathetic influence indicated that blood flow changes, changes in probe-skin coupling and changes in tissue compliance could not account for the observed changes in receptor sensitivity. Na+ and Cl- ions, secreted by cutaneous mucous glands were found to be possible contributors to the decreased sensitivity of rapidly adapting compression receptors. Direct neurotransmitter action on the receptors, a likely mechanism of sympathetic action, was not tested. 5. The data indicate that systematic changes in cutaneous sensibility occur with modest changes in sympathetic efferent activity. Possible mechanisms of these sympathetic effects are discussed.

Long-term L-dopa pretreatment of mice: central receptor subsensitivity or supersensitivity?

The effect of acute and repeated treatments with l-Dopa in oral doses of 200 mg/kg plus benserazide (50 mg/kg) was studied using locomotor activity in mice as a model of central catecholaminergic function. Mice pretreated with l-Dopa once daily for 1, 4 or 10 days responded to a challenge dose of l-Dopa (same dose as above) 1 day later with a more pronounced increase in motor activity than vehiclepretreated animals. Dexamphetamine-induced (0.5, 1.0 or 2.0 mg/kg) stimulation was found not to be significantly different in the two pretreatment groups when mice were challenged 1 day after one or four pretreatment doses of l-Dopa. However, a reduced response to dexamphetamine was observed in l-Dopa-pretreated mice (compared to vehicle-treated mice) on withdrawal of the mice from a 10-day l-Dopa pretreatment schedule. One day after one l-Dopa dose, with or without premedication with α-methyl-p-tyrosine (200 mg/kg) plus reserpine (10 mg/kg), mice responded to apomorphine (1.0 mg/kg) with significantly less activity than vehicle-pretreated mice. In contrast, 1 day after ten doses of l-Dopa, there was a shift to the left of the dose-response curve to apomorphine, which did not, however, occur 4 days after withdrawal. Hence, marked dopamine receptor sensitivity changes seem not to be of primary importance for l-Dopa hyperactivity in l-Dopa-pretreated mice. The present study also suggests that dopaminergic changes are not of consequence in the activity induced by dexamphetamine in l-Dopa-pretreated animals.

Central Biogenic Amine Metabolism in Children with the Syndrome of Chronic Multiple Tics of Gilles de la Tourette: Norepinephrine, Serotonin, and Dopamine

Central nervous system metabolism in children with the syndrome of Gilles de la Tourette (TS) and contrasting pediatric patients was assessed by measuring the cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA) with and without the administration of probenecid. Reduced accumulation of CSF HVA and 5-HIAA was found in TS. This may represent a primary decrease in brain turnover of dopamine and serotonin or a long-term adaptation to overactivity in these systems, perhaps as a result of changes in receptor sensitivity. In the CSF of a child with profound TS, an elevated level of the major metabolite of norepine.

Chronic treatment with clomipramine or maprotiline depletes platelet serotonin and modifies its diurnal rhythm

1. 1. Endogenous depressive patients were treated either with clomipramine (a predominantly 5HT uptake inhibitor) or maprotiline (a selective NA uptake inhibitor). 2. 2. Platelet 5HT rapidly decreased after clomipramine to a minimum (20% pretreatment values) within two weeks, and an abnormal 5HT diurnal rhythm tended towards the control pattern or was abolished. 3. 3. Unexpectedly, after maprotiline a transient increase in 5HT was followed by a decrease; the abnormal 5HT diurnal rhythm was exaggerated. The effect of maprotiline on platelet 5HT was probably secondary. 4. 4. Platelet 5HT measurements may be useful as an indirect estimation of clomipramine plasma level and efficacy of uptake inhibition; the therapeutic effect may however be less related to this presynaptic event than long-term post-synaptic changes in receptor sensitivity modifying abnormal 5HT rhythms.

Drug interactions during metabolism in the liver.

The ability of foreign compounds to induce the oxidation of drugs by liver microsomal enzymes was first recognised hy Conney and the Millers (1956) when they showed increased amino-azo dye N-demethylase activity in rats pretreated with polycyclic hydrocarbons and by Remmer (1962) who, during investigations of drug tolerance, demonstrated that the loss of hypnotic potency of hexobarbitone in dogs following chronic dosing with the drug was due to an increased rate of oxidation, not to a change in receptor sensitivity. An intense period of activity followed these early findings so that in his extensive review in 1967 Conney was able to list over 200 compounds which would stimulate drug metabolism by liver microsomal enzymes in animals. These compounds range from insecticides to steroids to therapeutic agents, and exhibit little or no physical or chemical properties in common.

Recent Progress: Supersensitivity of Central Neurons — A Brief Review of an Emerging Concept

The concept that "denervation" or "pharmacological disuse" supersensitivity develops in central neuronal systems subsequent to sustained attenuation of normal neurohumoral mechanisms is reviewed. Particular emphasis is placed on biochemical and electrophysiological parameters of supersensitivity in dopaminergic (striatal) neuronal systems. The possible applicability of theories invoking changes in receptor sensitivity to the phenomenon of narcotic tolerance and physical dependence and to psychoactive drug therapy is discussed.

Psychopharmacological evidence for increase in receptor sensitivity following chronic morphine treatment.

The behavioral effects of cholinergic and adrenergic agents on fixed ratio responding (FR5) were examined in control rats and in rats chronically treated with morphine (5 mg/kg/day). Tolerance to the effects of morphine on total responses was observed, but not on rate of responding. Following tolerance development, the directly acting muscarinic agonist, pilocarpine, depressed the behavior of the morphine-treated animals to a significantly greater degree than that of the controls. Similarly, drugs which directly or indirectly stimulate alpha adrenergic and central dopaminergic receptors also affected the behavior of the morphine-treated rats to a significantly greater degree. One interpretation of these findings is that muscarinic cholinergic, alpha adrenergic, and central dopaminergic receptors become supersensitive to their respective neurotransmitters during chronic treatment with morphine. Such a change in receptor sensitivity could constitute a mechanism underlying the development of tolerance to morphine.