Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apomorphine, a direct-acting dopamine agonist, stimulates release of growth hormone (hGH) and suppresses release of prolactin (PRL) from the anterior pituitary. Previous studies comparing the magnitude of these responses in schizophrenics and controls suggest that many acute (and some chronic) schizophrenics have exaggerated hGH responses; many chronic schizophrenics (and patients with tardive dyskinesia) have blunted hGH responses to apomorphine, and possibly blunted PRL responses. The present studies extend and confirm these findings in chronic schizophrenics; in addition, several studies were undertaken to further characterize these apomorphine-induced endocrine responses. Studies in which apomorphine was given on 2 or 3 separate occasions to each of five subjects indicate that the hGH response is a highly reproducible individual index, but PRL suppression is a less satisfactory measure. hGH responses to apomorphine were consistently antagonized by pretreatment with haloperidol, supporting the concept that the hGH-releasing effect of apomorphine is mediated by its action on dopamine receptors. Cyproheptadine pretreatment was associated with erratic increases or decreases in the hGH response to apomorphine, but did not alter PRL levels or apomorphine-induced PRL suppression. The relationship of these findings to biological hypotheses of schizophrenia and to neuroleptic-induced receptor changes is discussed.
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PMID:Neuroendocrine effects of apomorphine: characterization of response patterns and application to schizophrenia research. 54 Feb 9

Growth hormone (hGH) responses to centrally acting dopamine agonists were used as indices of CNS dopaminergic function in order to test hypotheses implicating dopaminergic alteration in the etiopathology of schizophrenia. Apomorphine, a direct acting dopamine receptor agonist, and L-Dopa, an indirect agonist dependent upon presynaptic conversion to dopamine for its action, both elicited elevations in plasma hGH in most young male schizophrenic- and control-subjects. A highly significant difference was seen between the distribution of hGH responses to apomorphine for schizophrenics and that for controls. Unusually high hGH response to apomorphine was seen in schizophrenics who subsequently failed to respond to neuroleptic therapy; intermediate hGH response was seen in controls; and low hGH response was seen in subsequent neuroleptic responders; differences in hGH response were statistically significant for all intergroup comparisons. No such differences were seen between responses of individuals to L-Dopa and to apomorphine. The findings suggest that the variability of hGH response to apomorphine is a reflection of dopamine receptor sensitivity, and that this variability may be an index of non-endocrine related dopaminergic sensitivity. They are consistent with hypotheses relating schizophrenia to alteration in dopamine receptors, although the type of receptor and the direction of alteration may be complex.
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PMID:Dopamine receptor alteration in schizophrenia: neuroendocrine evidence. 82 70

Apomorphine HC1 (2 mg subcutaneously), a dopamine receptor agonist, was administered to two schizophrenic patients with catalepsy. In one of these patients the clinical response to apomorphine was compared with that of sodium amytal and the growth hormone response apomorphine (0.75 mg subcutaneously) was compared with that of 25 control subjects. Apomorphine had no effect whereas sodium amytal caused rapid disappearance of catatonic symptoms including catalepsy. The peak growth hormone response to apomorphine was similar to that of controls. These data suggest that unlike experimental catalepsy in animals, catalepsy associated with schizophrenia may not be dependent on impaired dopaminergic function. Further case studies as well as the use of other dopamine receptor agonists are required before definite conclusions can be drawn.
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PMID:Dopaminergic function in two patients with catalepsy. 84 40

The present report is a comparative study of adenylate cyclase activity in various areas of the brain identified as dopaminergic. Low levels of dopamine were found to stimulate adenylate cyclase from the striatum, median eminence, olfactory tubercle, nucleus accumbens and amygdala. Apomorphine, known to mimic the pharmacological and physiological effects of dopamine, stimulated adenylate cyclase from these areas. Several different classes of drugs effective in the treatment of schizophrenia were potent inhibitors of the stimulation by dopamine of the enzyme from these various regions. The drugs studied included representatives of the phenothiazine, butyrophenone, dibenzodiazepine and dibenzoxazepine classes. The inhibition by the dibenzoxazepine, loxapine, which is structurally very similar to the dibenzodiazepine, clozapine, was competitive with respect to dopamine. The calculated inhibition constant (Ki) for loxapine of about 15 nM was similar to that observed for some of the more potent phenothiazines. The results, considered together with previously published data, support the possibility that the therapeutic effects as well as the extrapyramidal and endocrinological side effects, of these antipsychotic agents may be attributable to their ability to block the activation of adenylate cyclase in various select areas of the brain.
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PMID:Adenylate cyclase from various dopaminergic areas of the brain and the action of loxapine. 93 Jul 43

Previous work suggests that the dopamine agonist apomorphine decreases prepulse inhibition (PPI) of the acoustic startle response in rats. To better understand the dopamine substrates of this apomorphine response, we investigated the effects of four pharmacologically distinct dopamine antagonists on the apomorphine-induced loss of PPI. Apomorphine (0.5 mg/kg s.c.) markedly decreased PPI for all prepulse intervals tested. This effect of apomorphine on PPI was reversed by pretreatments with the D2 antagonists spiperone and raclopride but not by pretreatment with the D1 antagonist SCH 23390. The atypical antipsychotic clozapine exhibited an "inverted-U" shaped dose-response curve, reversing the apomorphine-induced loss of PPI at low doses but not at high doses. High doses of both SCH 23390 and clozapine decreased PPI independent of apomorphine treatment. The effects of apomorphine on baseline startle amplitude were also differentially modified by these drugs: apomorphine potentiated startle amplitude in spiperone- and raclopride-pretreated animals, but apomorphine decreased startle amplitude in animals pretreated with SCH 23390 or high doses of clozapine. Prepulse inhibition has been shown to be markedly impaired in humans with schizophrenia. Since our present findings suggest that the activation of D2 dopamine receptors is responsible for the loss of PPI in rats, overactivity of D2 dopamine receptors might also be a substrate for PPI deficits in schizophrenia.
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PMID:Effects of spiperone, raclopride, SCH 23390 and clozapine on apomorphine inhibition of sensorimotor gating of the startle response in the rat. 182 26

In searching for reliable animal models of negative schizophrenic symptomatology, we considered the possibility that a deficient response to rewarding stimuli might be the basis for some features of the disease. Apomorphine (0.015 and 0.03 mg/kg) and 3-PPP (1 mg/kg) caused such a reward deficit when rats were shifted from continuous reinforcement to a fixed ratio (FR4) schedule of food delivery. Further experiments indicated that this effect could be accounted for by a decreased ability of secondary reinforcers to sustain responses, rather than by motor impairment, appetite loss, or reduced reward value of the food. If this deficit is due to decreased dopaminergic transmission produced by low doses of dopamine agonists, our model might suggest that some symptoms of schizophrenia (anhedonia for instance) are not incompatible with deficient dopaminergic transmission. Low to moderate doses of sulpiride, amisulpride, pimozide, and pipotiazine, but not fluphenazine, metoclopramide, haloperidol, thioridazine, and chlorpromazine, reversed the apomorphine-induced reward deficit. Although any extrapolation from animal data requires caution, it may be tentatively proposed that only some neuroleptics, at dosages insufficient to block dopamine transmission postsynaptically, can be effective in reducing negative schizophrenic symptoms.
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PMID:Performance deficit induced by low doses of dopamine agonists in rats. Toward a model for approaching the neurobiology of negative schizophrenic symptomatology? 286 89

1. Apomorphine (Apo), a short acting dopamine (DA) receptor agonist, stimulates growth hormone (GH) secretion, decreases prolactin secretion, induces yawning, penile erections and other physiological effects in man. An effect on behavior, movement disorders and alcoholism has also been described. 2. Apo-mediated responses are used to evaluate DA function in psychiatric and neurological disorders. Many of the studies in schizophrenia using the GH response to Apo as an index of central DA function are difficult to interpret because of failure to control for key variables. 3. The GH response to Apo is a useful system to evaluate the effects of various drugs including peptides which may not cross the blood brain barrier on DA function in man. 4. Apo is a potent sedative. Specific antimanic, antischizophrenic, and anticraving effects in alcoholics have not been convincingly demonstrated. Side effects of Apo and failure to use active placebo make double-blind studies difficult. 5. Apo improves parkinsonian symptoms and certain forms of reflex epilepsy but beneficial effects in other involuntary movement disorders requires further documentation. 6. Apo may be a useful agent to evaluate DA function in impotent patients and predict a therapeutic response to long-acting dopaminergic agents. 7. Impairment of DA function may play a role in diabetic impotence. 8. The development of a simple polygraphic method to monitor the yawning response to Apo may facilitate clinical studies on the basic physiology of yawning in man and the use of the yawning response as a measure of central DA function in schizophrenia and other clinical disorders. 9. The use of Apo with 18F-fluorodeoxyglucose positron emission tomography to examine regional DA function in man opens up a promising area of research. 10. Though long-acting orally active aporphine DA agonists and antagonists have been developed the problem of tolerance may limit their therapeutic potential.
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PMID:Apomorphine in the evaluation of dopaminergic function in man. 329 Sep 92

1. Interpretation of neuroendocrine studies in schizophrenia requires consideration of (a) the large number of variables that affect drug-induced endocrine responses (b) the effect of prior neuroleptic therapy (c) heterogeneity of schizophrenia (d) heterogeneity of receptors (e) uniqueness of the hypothalamic-pituitary axis (f) selectivity and pharmacokinetics of administered drugs. 2. Apomorphine increases growth hormone secretion by an effect on dopamine receptors that are not linked to adenylate cyclase and which are located outside the blood brain barrier. 3. Hypothalamic-pituitary histaminergic H2 and alpha-adrenergic function are unchanged in chronic schizophrenia. 4. Schizophrenic symptoms persist despite complete blockade of dopamine receptors modulating prolactin secretion. 5. Studies on dopamine receptors modulating prolactin secretion are unlikely to shed light on the pathophysiology of schizophrenia. 6. Screening for drugs which block apomorphine-induced growth hormone secretion but do not increase prolactin may provide a way of detecting anti-schizophrenic drugs which are devoid of side effects associated with hyperprolactinemia and which do not induce parkinsonism or tardive dyskinesia.
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PMID:Drug-induced growth hormone and prolactin responses in schizophrenia research. 613 95

The hormonal effects of apomorphine, a direct-acting dopamine receptor agonist, in schizophrenic patients are of interest in view of the therapeutic efficacy of dopamine receptor antagonists. In this study, apomorphine (0.75 mg s.c.) and placebo were administered to unmedicated acute and chronic schizophrenics and controls. Apomorphine-induced prolactin suppression did not discriminate between the groups. However, an inverse relationship between basal prolactin levels and the severity of positive symptoms was detected in the patients with acute schizophrenia, consistent with a role for dopamine in the genesis of these symptoms. Growth hormone increments after apomorphine administration were blunted in the chronic schizophrenic patients, particularly those with 'negative' symptoms. It is argued that this blunting is not due to previous neuroleptic therapy and may represent evidence of structural change in the hypothalamus in this group of patients.
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PMID:Hormonal effects of apomorphine in schizophrenia. 672 95

The release of recently taken up [3H]dopamine ([3H]DA) elicited by electrical stimulation (3 Hz, 2 min, 16 mA) from slices of the rabbit caudate nucleus is inhibited by apomorphine (0.01-0.1 microM) in a concentration-dependent manner. This action is mediated through the activation of presynaptic inhibitory DA autoreceptors. The inhibition of [3H]DA release by apomorphine (0.1 microM) was antagonized 2 hr, but not 24 hr after the single administration of haloperidol (1 mg/kg s.c.). After 2 days of withdrawal after 28 days of chronic treatment with haloperidol (1 mg/kg s.c.) once daily, apomorphine (0.01-0.1 microM) was more effective in inhibiting [3H]DA release elicited by electrical stimulation when compared with rabbits injected chronically with either the vehicle for haloperidol or with saline. In superfused slices of the rabbit caudate nucleus, exposure to S-sulpiride (0.1 and 1 microM) increased in a concentration-dependent manner the release of [3H] DA elicited by electrical stimulation. After 28 days of chronic treatment with haloperidol, the facilitation of [3H]DA release by S-sulpiride was significantly reduced when compared with the controls. The inhibition of central noradrenergic transmission by DA receptor agonists was studied in hypothalamic slices prelabeled with [3H]norepinephrine ([3H-NE]). Apomorphine (0.01-1 microM) inhibited the electrically evoked (5 Hz, 2 min, 26 mA) release of [3H]NE from hypothalamic slices of untreated rabbits. The sensitivity to the inhibitory effect of apomorphine on [3H]NE overflow remained unaffected after 2 days of withdrawal following 28 days of chronic treatment with haloperidol. In summary, our results indicate that chronic haloperidol administration induces changes in sensitivity of the DA autoreceptors regulating dopaminergic neurotransmission but does not affect the sensitivity of DA receptors modulating NE release in the central nervous system. These results suggest that the DA autoreceptors that regulate dopaminergic neurotransmission may play a physiological role in the modulation of transmitter release and consequently are susceptible to the development of changes in sensitivity after chronic receptor blockade. The possible implication of changes in sensitivity of the DA autoreceptor during the treatment of schizophrenia with neuroleptics is discussed.
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PMID:Changes in sensitivity of release modulating dopamine autoreceptors after chronic treatment with haloperidol. 687 65


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