Postsynaptic Receptor Supersensitivity Research Articles

Dose-dependent effects of noradrenergic denervation by DSP-4 treatment on forced swimming and beta-adrenoceptor binding in the rat.

DSP-4 is a neurotoxin highly selective for the noradrenergic nerve terminals originating from the locus coeruleus. Preliminary data suggested that its effect in a typical screening test for antidepressant drugs, the forced swimming test, is biphasic dependent on the dose. In the present study, DSP-4 was administered in four doses (5, 10, 30 and 50mg/kg) to male Wistar rats. Administration of the neurotoxin had a dose-dependent biphasic effect on immobility time in the forced swimming test 8 and 9 days later. Thus, DSP-4 at the dose of 10mg/kg increased immobility, but higher doses reduced this measure. The reduction of noradrenaline concentration in the frontal cortex and hippocampus was dose-dependent starting from the dose 10mg/kg. Cortical beta-adrenoceptor binding was increased by DSP-4 treatment at the doses 30mg/kg and 50mg/kg. These results suggest that the increase in immobility time in the forced swimming test is associated with presynaptic changes in noradrenaline availability, whereas the decrease in immobility observed after more complete denervation is associated with postsynaptic receptor supersensitivity.

Noradrenergic and neuroradiological abnormalities in tardive dyskinesia

Previous studies suggest that catecholaminergic overactivity and structural brain damage may contribute to the pathogenesis of tardive dyskinesia (TD). Although dopaminergic (DA) mechanisms, specifically postsynaptic receptor supersensitivity, have been extensively studied, equally plausible noradrenergic (NE) changes have been all but ignored. Likewise, the interaction of neurochemical and neuroradiological abnormalities has received little attention. Over the past 6 years, 111 inpatients were studied with a battery of neurological, behavioral, biochemical, and neuroradiological measures. Forty-one patients met specific diagnostic criteria for TD, based in part on global ratings on the Abnormal Involuntary Movement Scale. Subgroups of patients were also evaluated with the Brief Psychiatric Rating Scale and were assayed for plasma dopamine-β-hydroxylase (DBH) activity, platelet 3H-dihydroergocryptine ( 3H-DHE)-alpha 2 adrenergic receptor binding, lumbar cerebrospinal fluid (CSF) monoamines and metabolites [NE, 3-methoxy-4-hydroxyphenylglycol (MHPG), DA-sulfate, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC)], and CT scan indices of brain atrophy, including ventricle/brain ratio (VBR), bifrontal/bicaudate ratio, and cortical atrophy. All patients were studied in the steady state, primarily when free of neuroleptics. Patients with TD had significantly greater DBH activity than those without TD. In addition, 3H-DHE binding and CSF NE were significantly correlated with the severity of TD when present. Finally, TD patients with low DBH activities (below the mean) had significantly larger ventricles than non-TD patients with low DBH activities. Other data suggested that subcortical, rather than cortical, atrophy was more likely to be responsible for the larger VBR in the low DBH TD group. These results suggest an association of NE overactivity and TD in a portion of patients. Moreover, the presence of neuroradiological abnormalities in TD patients with low DBH activity underscores the contribution of heterogeneous factors to the pathogenesis of this disorder and may provide one possible explanation for the discrepant biochemical findings in TD reported by earlier investigators.

Lesioning of serotoninergic and noradrenergic nerve fibres of the rat brain does not decrease binding of 3H-clonidine and 3H-rauwolscine to cortical membranes.

alpha 2-Adrenoceptors located presynaptically on nerve terminals are known to modulate the release of neurotransmitters from noradrenergic and serotoninergic neurons. The pre- and/or postsynaptic localization of binding sites for alpha 2-adrenergic radioligands, the agonist 3H-clonidine and the antagonist 3H-rauwolscine, was investigated in the rat cerebral cortex by the use of specific neurotoxins. Intracerebroventricular injections of 6-hydroxydopamine (6-OH-DA) and 5,7-dihydroxytryptamine (5,7-DHT) were used to destroy the noradrenergic and serotoninergic neurons, respectively, and the success of the treatment was controlled by measurement of tritium accumulation in cortex slices incubated with 3H-noradrenaline or 3H-serotonin. In cortical membranes, 3H-rauwolscine bound to a single site (KD about 5 nmol/l; Bmax 217-247 fmoles/mg protein), whereas 3H-clonidine bound to a high affinity site (KD 0.6-1.4 nmol/l) and a low affinity site (KD 6-10 nmol/l). The total number of high plus low affinity 3H-clonidine binding sites was about two thirds of the number of 3H-rauwolscine binding sites. 6-OH-DA treatment significantly increased the number of high affinity 3H-clonidine binding sites without reducing the number of high plus low affinity binding sites, indicating a denervation supersensitivity. KD- as well as Bmax-values for 3H-rauwolscine remained unaltered after 6-OH-DA-treatment. Since an increase in postsynaptic alpha 2-adrenoceptors due to 6-OH-DA-administration might have masked a loss of presynaptic alpha 2-adrenergic binding sites, rats were chronically treated with high doses of clonidine in order to prevent a possible supersensitivity of postsynaptic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophysiological and neurochemical correlates of the neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on central catecholamine neurons in the mouse.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an agent which produces a parkinsonian syndrome in man. To explore the use of MPTP in a rodent model of parkinsonism, male albino mice (NMRI) were given MPTP (50 mg/kg, s.c.) twice with a 6-8 h interval. Up to 10 weeks after injection, mice were killed and high-pressure liquid chromatography was used to assay dopamine (DA) and noradrenaline (NA) concentrations in various regions of the CNS. At 4 and 10 weeks after injection, DA levels were significantly reduced in occipital cortex (-40%), hippocampus (-30%), and striatum (-60%). NA levels were reduced by 60-80% in frontal and occipital cortex, hippocampus, and cerebellum. Neither DA nor NA concentration was reduced in spinal cord. Dopaminergic denervation was also suggested by electrophysiological data which showed that treatment with MPTP increased the spontaneous discharge rate of caudate neurons and decreased the potency of locally administered phencyclidine, an indirect DA agonist. However, denervation was evidently not complete enough to produce postsynaptic receptor supersensitivity, as MPTP treatment did not increase the potency of locally applied DA, and it did not increase 3H-spiperone binding in striatal membrane preparations. These results suggest that MPTP causes regionally selective and long-term reductions of catecholamine transmission in the CNS of the mouse.

Stress-induced facilitation of acoustic startle after d-amphetamine administration

Administration of d-amphetamine enhanced the startle response to an auditory stimulus. In contrast to saline treated mice, startle activity after amphetamine administration did not wane with repeated exposure to the auditory stimulus. Rather, the effects of amphetamine on startle activity increased as a function of stimulus presentation. Whereas exposure to isolation stress or inescapable shoch had no effect on startle activity, both types of stress potentiated the effects of amphetamine on startle arousal. The observation that stress sensitized animals to later amphetamine administration is consistent with the effects of stress on other amphetamine behaviors, e.g., stereotypy. Results were related to the development of dopamine post-synaptic receptor supersensitivity after exposure to stress and were discussed in terms of the role played by stress in the expression of behavioral arousal. in the etiology of schizophrenia.

Ehavioural evidence for supersensitivtiy of postsynaptic dopamine receptors in the mesolimbic system after chronic administration of desipramine

The effects of acute and chronic administration of desipramine (DMI) on a number of behaviors thought to be dependent on central dopaminergic (DA) systems were examined in the rat. Chronic but not acute administration of DMI potentiated the locomotor response to d-amphetamine within a narrow dosage range. The potentiation of the amphetamine response was observed up to 5 days after cessation of chronic DMI but had nearly returned to baseline by 10 days. Neither amphetamine-nor apomorphine-induced stereotypy was affected by chronic DMI. Chronic administration of iprindole but not fluoxetine potentiated amphetamine-induced locomotor activity. Chronic DMI administration did not affect the concentration or distribution of [ 3H]d-amphetamine in the brain. Furthermore, residual anticholinergic effects of DMI did not appear to be responsible for the potentiated amphetamine response. Chronic administration of DMI did not significantly influence the hypomotility induced by low doses of apomorphine. The increased locomotor activity and rearing produced by moderate doses of apomorphine were significantly increased by chronic DMI administration. The results suggest that chronic DMI may produce supersensitivity of postsynaptic receptors in the mesolimbic DA projection, a system that has been associated with the mediation of amphetamine- and apomorphine-induced increases in locomotor activity. There was no evidence for subsensitivity of presynaptic DA receptors after DMI. The findings are discussed with reference to the possible role of centra; DA neurons in the antidepressant mechanism of action of the tricyclic compounds.

Cyclic AMP and a possible animal model of receptor supersensitivity

Publisher Summary This chapter describes the cyclic AMP and a possible animal model of receptor supersensitivity. Levels of 5 HIAA have been found to be low in unipolar depressed patients, but normal in bipolar depression. The workers also suggested that clinical observations of changes in the facial dyskinesias with the phase of manic depressive illness may be related to changes in post synaptic receptor supersensitivity. The demonstration that receptor supersensitivity in brain can be linked to adenyl cyclase activity is then important. In the animal model described this is indicated. The locus coeruleus is a bilateral noradrenergic nucleus supplying cortex almost ipselaterally. The production of supersensitivity in dopaminergic receptors has been established by lesions of the cell bodies in the substantia nigra. Similar supersensitivity in the noradrenergic system should follow lesions of one LC, and this should be unilateral. In these experiments electrolytic lesions are made in one LC, and the animals was allowed to recover.

Differential effects of reserpine and alpha-methyl-P-tyrosine on norepinephrine and dopamine induced behavioral activity.

The locomotor activity of rats was monitored during the intraventricular infusion of either dopamine or norepinephrine after intraperitoneal pretreatment with saline, reserpine (5.0 mg/kg), or acute and chronic alpha-methyl-p-tyrosine (125 mg/kg-1 or 8 days). While the hyperactivity produced by norepinephrine was potentiated 24 h after reserpine, the response to dopamine was reduced by reserpine. Chronic, but not acute, alpha-methyl-p-tyrosine enhanced the effect of norepinephrine without altering the dopamine-induced activity. These results indicate: 1. dopamine-induced hyperactivity is due to its conversion to norepinephrine, and 2. prolonged depletion of central catecholamines may result in post-synaptic receptor supersensitivity.