Chronic Neuroleptic Administration Research Articles

Measurement of plasma homovanillic acid concentrations in schizophrenic patients

1. Several lines of evidence suggest that abnormalities of central dopaminergic transmission may be involved in the expression of some schizophrenic symptoms. However, elucidation of the role of dopamine (DA) in schizophrenia has eluded investigative efforts partially because no accurate and easily repeatable measure of brain DA activity exists. 2. The development of a technique to measure homovanillic acid in plasma has offered the possibility of performing serial measurements of this major DA metabolite. 3. Assuming that plasma homovanillic acid (PHVA) concentrations is an index of brain DA activity, measurement of PHVA can play a role in elucidating the DA abnormality in schizophrenia. 4. Results to date suggest that plasma homovanillic acid concentrations are lower in chronic schizophrenic patients compared to normal controls, and that PHVA values correlate with schizophrenic symptom severity. 5. In addition, PHVA levels were shown to initially rise and subsequently decline during chronic neuroleptic administration in treatment responsive but not in treatment refractory schizophrenic patients.

Regional homovanillic acid levels and oral movements in rats following chronic haloperidol treatment

Rats with more severe orofacial movements after 51 days of haloperidol administration showed lower levels of the dopamine metabolite homovanillic acid (HVA) in the caudate compared to animals who did not develop significant mouth movements. This effect was not observed in other brain regions sampled. This finding is consistent with the hypothesis that dopaminergic receptor supersensitivity in neostriatal structures plays some role in the development of orofacial movements in rats, in association with chronic neuroleptic administration.

Chronic neuroleptic-induced mouth movements in the rat: suppression by CCK and selective dopamine D1 and D2 receptor antagonists

Fluphenazine decanoate (25 mg/kg IM every 3 weeks x 6) resulted in spontaneous vacuous chewing mouth movements and jaw tremor in male Sprague-Dawley rats. These movements could be suppressed by the selective D1 or D2 dopamine antagonists SCH 23390 (0.5 mg/kg) and raclopride (0.5 mg/kg), respectively, and by CCK-8S (50 micrograms/kg). Fluphenazine-induced mouth movements were unaffected by the selective CCK antagonist MK-329, and by a dose of physostigmine (50 micrograms/kg) sufficient to stimulate mouth movements in placebo treated rats. Scopolamine (0.1 mg/kg) suppressed spontaneous mouth movements in placebo-treated rats, but the effect on fluphenazine-induced mouth movements was not significant. A higher dose of scopolamine (0.5 mg/kg) did suppress the neuroleptic-induced mouth movements, but also induced hyperactivity, characterized by increased sniffing and grooming. These findings indicate that mouth movements resulting from the chronic administration of neuroleptics to the rat may serve as a useful pharmacological model of tardive dyskinesia in the human, and suggest that a relative increase of D1 activity as well as impaired CCK function may contribute to the pathogenesis of this disorder.

Manners of arginine vasopressin secretion in schizophrenic patients--with reference to the mechanism of water intoxication.

Water intoxication occurs almost exclusively in many patients with chronic psychiatric disorder. To elucidate the mechanism of this syndrome, we undertook the following animal experiments and clinical study. Twelve rabbits were given neuroleptics for eight weeks. From measurement of arginine vasopressin (AVP) secretion response to osmotic stimuli (fluid deprivation, partaking ad lib. and water loading), we found that chronic neuroleptic administration might raise the sensitivity of AVP escretion response. Then we investigated the manners of AVP secretion during ad lib. drinking in seventeen schizophrenic patients with hyponatremia and sixteen schizophrenic patients without hyponatremia. Normal range of plasma AVP was obtained from healthy volunteers by water loading. Only in both schizophrenic groups was plasma AVP detected below 270 mOsm/kg osmolality. We observed that sensitivity of AVP secretion response to osmolality was decreased in schizophrenic patients, regardless of the presence of hyponatremia. We hypothesize that the primary low sensitivity of AVP secretion response to osmo-receptor and the secondary renal hypersensitivity of AVP receptor may play the major role in the occurrence of water intoxication, linked to SIADH, in schizophrenic patients.

Effect of neuroleptic withdrawal on plasma prolactin: A possible marker of receptor adaptation

Stable schizophrenic and schizoaffective outpatients underwent abrupt withdrawal from a fixed dose of neuroleptic. Prolactin concentrations were determined preceding and following drug withdrawal. Basal prolactin concentrations were significantly lower 3, 4, or 5 days following drug withdrawal than on subsequent days. This rebound effect may be related to dopaminergic receptor changes in the tuberoinfundibular system that are induced by chronic neuroleptic administration.

Effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system

1. A review of the effects of long-term administration of antidepressants and neuroleptics on receptors in the central nervous system is presented. 2. The effects of antidepressants on adenylate cyclase activity and on receptor binding in brain tissue are discussed. Effects on a variety of receptor types are considered. 3. The utilization of electrophysiological, behavioral, and neurochemical studies to assess receptor function after chronic antidepressant administration is discussed, as is the use of peripheral receptor estimations in clinical studies. 4. Animal studies on the actions of chronic administration of neuroleptics on pre- and postsynaptic dopamine receptors are reviewed. Effects of these drugs on dopamine receptors in humans are considered from the following perspectives: postmortem and in vivo binding studies in schizophrenia, tardive dyskinesia, and central versus peripheral receptor estimation.

Modulation of second messenger function in rat brain by in vivo alteration of receptor sensitivity: Relevance to the mechanism of action of electroconvulisve therapy and antidepressants

1. The second messengers cyclic AMP and inositol triphosphate are the intracellular mediators for a number of neurotransmitters for which receptors exist on brain neurons. 2. Up- or down-regulation of these receptors in general produce corresponding changes in the associated second messenger systems. 3. Chronic andministration of antidepressants including electroconvulsive shock to rats produces a number of changes in cerebral receptors, notably down-regulation of beta-adrenergic and serotonin 5-HT 2 receptors and up-regulation of alpha-1 adrenergic receptors. 4. The changes in receptor number induced by such antidepressant treatments are in general accompanied by corresponding changes in the associated second mesenger reactions. 5. Antidepressant administration has also been shown to induce increased post-receptor mediated adenylate cyclase activity in cortical membranes, and similar effects have also been reported in striatum after chronic administration of neuroleptics. The relevance of these effects to the machanism of action of the drugs is discussed.

Acute haloperidol administration induces depolarization block of nigral dopamine neurons in rats after partial dopamine lesions

The effects of the antipsychotic drug haloperidol (HAL) on the electrophysiological activity of dopamine (DA)-containing cells in the substantia nigra was assessed in rats 6 weeks after partial 6-hydroxydopamine (6-OHDA)-induced lesions of the nigrostriatal DA pathway. Depleting 75% or more of striatal DA altered the response of DA neurons to acute HAL administration. Whereas acute HAL administration generally accelerates DA neuron firing in control rats, similar HAL doses given to lesioned rats not only increased firing rate but induced depolarization block of DA neuron spike generation similar to that resulting from chronic neuroleptic administration. In contrast, acute administration of doses of HAL up to lethal levels typically could not induce depolarization block of DA neurons in non-lesioned rats. This preparation thus could be an effective model for investigating the exacerbation of behavioral deficits produced by an increased demand placed upon a compromised DA system, as may occur in Parkinson's disease or with antipsychotic drug treatment.

Attenuation of the behavioral response to quisqualic acid and glutamic acid diethyl ester by chronic haloperidol administration

Long-term neuroleptic administration produces a behavioral supersensitivity to dopamine agonists. Tyrosine hydroxylase immunoreactive synapses in the striatum are closely associated with putative glutamate-mediated synapses, on dendrites and dendritic spines of the same neuronal population. The purpose of the present study was to determine whether chronic neuroleptic administration would alter the behavioral response to glutamatergic drugs. Mice were chronically administered haloperidol for 28 days. After four days of withdrawal, behavioral activity was measured following intraventricular administration of quisqualic acid or intraperitoneal injection of glutamic acid diethyl ester. Both agents decreased behavioral activity. This response to glutamatergic drugs at low dosages was attenuated by chronic haloperidol administration. It is concluded that chronic haloperidol administration alters the behavioral responsivity of animals to glutamatergic drugs.

Chronic neuroleptics alter the effects of the D1 agonist SK&F 38393 and the D2 agonist LY171555 on oral movements in rats.

Vacuous oral movements (OMs) in rats chronically administered haloperidol (HAL), fluphenazine (FLU), or no drug were studied following injections of one of three doses of either a D1 agonist (SK&F 38393) or a D2 agonist (LY171555). Oral movements were observed via closed-circuit television and simultaneously recorded using a computerized video analysis system which measured the distance between two fluorescent dots painted above and below the rat's mouth. SK&F 38393 induced a dose-dependent increase in tremorous oral movements and repetitive chewing movements in the controls; this effect was more pronounced in rats treated with chronic HAL or FLU, both during chronic neuroleptic treatment and even more so when they were tested after drug withdrawal following 5 or 14 months of chronic neuroleptic administration. Conversely, LY171555 produced an inhibition of oral activity at all dose levels in controls. This inhibition was attenuated during chronic administration of HAL or FLU, but returned to control levels (without any signs of supersensitivity) when the animals were retested shortly after discontinuation of neuroleptics. These results indicate that heightened oral movements in rodents following chronic neuroleptic administration can be more clearly induced by D1 than by D2 receptor activation.

Dopamine, GABA, cholecystokinin and opioids in neuroleptic-induced tardive dyskinesia

The long-term administration of neuroleptics causes tardive dyskinesia, which closely resembles levodopa-induced dyskinesias, and is brought about through complex mechanisms which are ill-defined. It is generally believed that the pathogenesis of tardive dyskinesia relates closely to the chronic blockade of dopamine receptor sites and that its pathophysiology results from a hypersensitivity of dopamine receptor sites. In the therapeutic management of neuroleptic-induced tardive dyskinesia, in addition to reserpine and lithium, diazepam, baclofen, or gamma-vinyl-gamma-aminobutyric acid have also been advocated. However, the reported beneficial effects of diazepam and GABA-mimetic agents in ameliorating the symptoms of tardive dyskinesia may occur through a mechanism which does not necessarily link transmission involving both dopamine and GABA. The presence of high concentrations of both cholecystokinin and opioids in the striatum also suggests that these peptides not only may influence dopaminergic transmission, but that they may also be relevant to the psychopathology of schizophrenia and to the therapeutic effects of neuroleptics. Indeed, the acute and chronic administration of neuroleptics alters the levels of cholecystokinin and opioids and their receptors in several brain regions including the striatum. However, neuroleptics also alter the biochemical integrity of neurotensin, neuropeptide Y, substance P and somatostatin, which may also play a role in the overall expression of the neuroleptic-induced extrapyramidal reactions.

Oral movements induced by interference with nigral GABA neurotransmission: Relationship to tardive dyskinesias

Previous studies have shown that the emergence of spontaneous dyskinetic behaviors, such as vacuous chewing movements, following several months of neuroleptic treatment in the rat, is correlated with depletion of nigral GABA. To explore the specificity of this relationship, we acutely interfered with nigral GABA transmission pharmacologically, by microinfusing either the GABA receptor antagonist, bicuculline, or the GABA-depleting agent, isoniazid, bilaterally into substantia nigra. We found that both acute treatments induced vacuous chewing movements in rats. Moreover, the time to onset of action of each of these drugs corresponded to the onsets of their respective effects on GABA transmission. In addition, we found that the application of muscimol into the target field of the nigrotegmental projection, which has been shown to block gnawing elicited by nigral GABA receptor stimulation, completely abolished elicitation of vacuous chewing movements by intranigral isoniazid. In contrast, bilateral microinfusions of muscimol into the nigrocollicular target region, in the deep layers of superior colliculus, blocked elicitation of gnawing by intranigral muscimol, but completely spared elicitation of vacuous chewing movements by intranigral isoniazid. We conclude that qualitatively different dyskinetic syndromes can be produced by bidirectional perturbations of nigral GABA function and are differentially mediated by nigrotegmental and nigrotectal projections. These syndromes may represent animal models of distinct components of extrapyramidal side effects of chronic neuroleptic administration.

A central 6-hydroxydopamine lesion prevents fluphenazine-induced increase in plasma homovanillic acid

Plasma and brain levels of the dopamine metabolite, homovanillic acid, were measured in rats after acute and chronic treatment with fluphenazine. After acute administration, homovanillic acid levels were increased in the whole frontal cortex, caudate nucleus, nucleus accumbens, anterior cingulate (supragenual) cortex, prefrontal cortex and plasma. Following chronic administration, the effects of single doses of fluphenazine in increasing homovanillic acid were markedly attenuated in the caudate nucleus, nucleus accumbens, the whole frontal cortex, anterior cigulate cortex and plasma, but not in the prefrontal (anteromedial) cortex. Following fluphenazine administration plasma homovanillic acid levels were correlated with homovanillic acid concentrations in whole frontal cortex ( r = 0.63, p < 0.01) and caudate nucleus ( r = 0.51, p < 0.05). Further, prior intracerebroventricular administration of 6-hydroxydopamine prevented the fluphenazine-induced increase in plasma homovanillic acid. These data suggest that in the rat, plasma and brain (caudate nucleus and whole frontal cortex) homovanillic acid levels change in a similar fashion during acute and chronic neuroleptic administration.

Human platelet 5-hydroxytryptamine receptors: binding of [3H]-lysergic acid diethylamide (LSD). Effects of chronic neuroleptic and antidepressant drug administration.

Chronic treatment with phenothiazines and thioxanthenes has been found to enhance 5-HT-induced aggregation of human platelets. A method has been developed to study 5-HT2 receptor binding sites on platelets utilising [3H]-LSD and more recently 125I/LSD. Results are presented which suggest that the LSD binding site is indeed the 5-HT2 binding site and that the LSD binding characterises the specific receptor responsible for 5-HT-induced shape change and aggregation. In a group of patients receiving phenothiazines or thioxanthenes, the Bmax of LSD binding was increased. The mean binding affinity was decreased possibly due to a persistence of neuroleptic in the platelet membrane preparation. Analysis showed that this was not the reason why the mean binding capacity was increased. The results show that chronic phenothiazine and thioxanthene delta treatment 'up-regulates' platelet 5-HT2 binding sites and that this may be accompanied by increased sensitivity to platelet aggregation by 5-HT. In normal subjects desipramine treatment increased the Bmax of platelet LSD binding and this was accompanied by an increased prolactin response to tryptophan which is thought to be mediated by central 5-HT function.

The therapeutic latency of neuroleptic drugs and nonspecific postjunctional supersensitivity.

It is suggested that the antidopaminergic effects of neuroleptics are not directly responsible for the antipsychotic effect but, rather, that the antipsychotic effect is related to secondary changes in the efficacy of transmission at corticostriatal excitatory synapses. Arguments are presented in support of the following: (1) acute dopaminergic antagonism produces a relatively nonspecific sedation or deactivation, but most of the amelioration of psychosis develops slowly; (2) the development of dopaminergic supersensitivity is responsible for tolerance to the sedative effects of neuroleptics; and (3) excitatory synapses of the corticostriatal pathway, mediated by glutamic acid, are located on the same dendritic spines as the striatal dopaminergic synapses. Concomitant with the development of dopaminergic supersensitivity, these glutamate synapses become subsensitive. The glutamatergic subsensitivity is a result of the nonspecific nature of postsynaptic denervation supersensitivity. It is suggested that subsensitivity of striatal glutamate-mediated synapses is directly responsible for the antipsychotic effect of neuroleptic drugs. In support of this hypothesis, chronic neuroleptic administration was found to decrease the behavioral responsivity of mice to the glutamate agonist, quisqualic acid, and to the the antagonist, glutamic acid diethyl ester.

Neuroleptic-induced oral dyskinesias: effects of progabide and lack of correlation with regional changes in glutamic acid decarboxylase and choline acetyltransferase activities.

The development of vacuous chewing movements (VCMs), and changes in glutamic acid decarboxylase (GAD) and choline acetyltransferase (ChAT) activities in extrapyramidal nuclei were examined in rats treated chronically with neuroleptics. Animals were injected with flupenthixol (FLU) or haloperidol (HAL) decanoate for 16, 40 or 48 weeks and were then sacrificed. Another group of rats was treated with FLU or HAL for 48 weeks, and then withdrawn from the neuroleptics for 16 weeks before sacrifice. VCMs were assessed weekly, and the effects of the GABA agonist progabide on VCMs and locomotor activity were examined. GAD and ChAT activities were determined at death. The concentrations of Calbindin D28K (CaBP) and parvalbumin (PV) were determined in rats receiving 48 weeks of neuroleptic treatment. VCMs first appeared after 8-10 weeks of neuroleptic administration, reached asymptotic rates after 18-20 weeks, and then remained stable for the remainder of the chronic drug administration period. During withdrawal, there was a steady decline in the VCM rate. The GABA receptor agonist progabide reduced VCMs and locomotor activity. Significant decreases in nigral GAD activity were observed after 40, but not after either 16 or 48 weeks of neuroleptic administration. CaBP and PV were unchanged after 48 weeks of neuroleptic treatment. In addition, ChAT activities in 16, 40 or 48 week treated animals did not show consistent changes after either neuroleptic. Chronic neuroleptic administration followed by 16 weeks of withdrawal also did not have any significant effects on GAD or ChAT activity in any of the brain areas examined.(ABSTRACT TRUNCATED AT 250 WORDS)

In vivo electrochemistry - principles and applications

Differential pulse voltammetry (DPV) with electrically pretreated carbon fibre microelectrodes has been used to monitor dopamine (DA) and serotonin (5HT) metabolism in specific regions of the rat brain in vivo . Using this technique we have located the 5HT receptor subtype responsible for controlling 5HT release and metabolism in the suprachiasmatic nucleus. The autoreceptor involved in the control of DA metabolism has also been studied and the effects of chronic neuroleptic administration on their sensitivity determined.

Chronic haloperidol effects on oral movements and radial-arm maze performance in rats

Rats were examined for were examined for the development of adverse motor and cognitive effects during and after 24 weeks of chronic haloperidol (HAL) administration using an 8-arm maze and a computerized apparatus for measuring spontaneous oral movements. In the maze, HAL caused a significant decline in choice accuracy only during the first week of administration, whereas it caused a significant decline in locomotor speed throughout drug administration. There were no effects of HAL on maze behavior after withdrawal. Haloperidol reduced the number of mouth movements during drug administration, but after withdrawal there was a significant increase. This replicated a previous finding from our lab. The oral movements which did occur in the HAL-treated rats were slower than normal. The timing of the HAL-induced cognitive dysfunction was similar to the Parkinson-like disorder shown by patients given chronic neuroleptics, whereas the timing of the increase in oral movements after the withdrawal of HAL was more related to the appearance of tardive dyskinesia. There was evidence in both tests of a persisting sedation during chronic neuroleptic administration.

Homovanillic acid in caudate and pre-frontal cortex following acute and chronic neuroleptic administration.

Homovanillic acid (HVA) was measured in rat caudate and pre-frontal cortex after single and repeated doses of several types of neuroleptic drugs. Twice daily administration of low or high doses of haloperidol, fluphenazine, or (-) sulpiride resulted in greater tolerance to the initial HVA increase in caudate compared to prefrontal cortex.

The effects of chronic lithium on behavioral and biochemical indices of dopamine receptor supersensitivity in the rat.

The effects of dietary lithium on several indices of dopamine receptor supersensitivity were examined in rats during withdrawal from chronic administration of haloperidol. Chronic haloperidol enhanced the locomotor stimulant action of d-amphetamine, and this effect was attenuated by lithium. In contrast, lithium did not affect the amphetamine response in animals that had not previously received haloperidol. Apomorphine-induced hypothermia was not influenced by the chronic haloperidol treatment. On the other hand, during withdrawal from chronic haloperidol, spontaneous locomotor activity (20 h) and apomorphine-induced stereotypy were increased, but neither of these effects was attenuated by lithium. In addition, lithium did not affect the chronic haloperidol-induced increase in 3H-spiperone binding sites in the striatum. Lithium alone had no effect on any of these measures except for causing a slight prolongation of the hypothermic effect of apomorphine. The results indicate that not all DA-receptor-mediated responses are enhanced by chronic administration of neuroleptics (e.g., apomorphine-induced hypothermia). In addition, while lithium reduces the effects of chronic haloperidol administration on d-amphetamine-induced locomotor activity, this is not because lithium prevents haloperidol-induced supersensitivity of postsynaptic DA receptors because more direct measures of this phenomenon (e.g., 3H-spiperone binding, apomorphine-induced stereotypy) are not affected by lithium.