cyclic-gmp and Dyskinesia--Drug-Induced

Topics: 4-Aminobutyrate Transaminase; Action Potentials; Alcohol Oxidoreductases; Aldehyde Oxidoreductases; Animals; Aspartic Acid; Brain; Cyclic GMP; Dyskinesia, Drug-Induced; Electric Stimulation; Electrophysiology; Epilepsies, Partial; gamma-Aminobutyric Acid; Glycine; Humans; Nervous System Diseases; Neurons; Seizures; Serotonin; Succinate-Semialdehyde Dehydrogenase; Succinates; Valproic Acid

Cerebrospinal fluid (CSF) HVA, MHPG, 5-HIAA, cAMP and cGMP concentrations were measured in schizophrenic patients with tardive dyskinesia before and after a three-week administration of oxypertine (n = 4), hydroxyzine pamoate (n = 4) or placebo (n = 4). The oxypertine administration resulted in a reduction of the CSF HVA concentration and an elevation of the MHPG and cAMP concentrations, associated with a clinical improvement in tardive dyskinesia. The hydroxyzine administration reduced the CSF 5-HIAA concentration in all the patients and the CSF HVA concentration in two of four patients with a clinical improvement. A reduction in the CSF HVA concentration associated with possible therapeutic effects of oxypertine or hydroxyzine may suggest the normalization of a hyperdopaminergic state. Discussions were held that functional disorders of not only the dopaminergic system but the norepinephrinergic and serotoninergic systems may relate to the pathogenesis of tardive dyskinesia.

Topics: Biogenic Amines; Clinical Trials as Topic; Cyclic AMP; Cyclic GMP; Dyskinesia, Drug-Induced; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Hydroxyzine; Indoles; Male; Methoxyhydroxyphenylglycol; Piperazines

Second messenger cAMP and cGMP represent a key step in the action of dopamine that modulates directly or indirectly their synthesis. We aimed to verify whether levodopa-induced dyskinesias are associated with changes of the time course of levodopa/dopamine stimulated cAMP and cGMP levels, and/or with changes of their catabolism by phosphodiesterase activity in rats with experimental hemiparkinsonism. Microdialysis and tissue homogenates of the striatal tissues demonstrated that extracellular and intracellular cAMP/cGMP levels were lower in dyskinetic animals during the increasing phase of dyskinesias compared to eukinetic animals, but cAMP/cGMP levels increased in dyskinetic animals during the phase of decreasing and extinction of dyskinesias. Dyskinesias and the abnormal lowering of striatal cGMP and cAMP after levodopa were prevented by pretreatment with the multipotent drug amantadine, outlining the inverse relationship of cAMP/cGMP to dyskinesias. Moreover, dyskinetic animals showed higher striatal hydrolyzing cGMP-phosphodiesterase but not hydrolyzing cAMP-phosphodiesterase activity, suggesting that low cGMP but not cAMP levels could be due to increased catabolism. However, expressions of isozyme phosphodiesterase-1B and -10A highly and specifically located in the basal ganglia were not changed after levodopa in dyskinetic and eukinetic animals: accordingly, selective inhibitors of phosphodiesterase-1B and -10A were ineffective on levodopa dyskinesias. Therefore, the isozyme(s) expressing higher cGMP-phosphodiesterase activity in the striatum of dyskinetic animal should be determined. These observations suggest that dopamine-mediated processes of synthesis and/or degradation of cAMP/cGMP could be acutely impaired in levodopa dyskinesias, opening new ways to understanding physiopathology and treatment.

Topics: Animals; Antiparkinson Agents; Caudate Nucleus; Cyclic AMP; Cyclic GMP; Down-Regulation; Dyskinesia, Drug-Induced; Levodopa; Male; Parkinsonian Disorders; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Putamen; Rats; Rats, Wistar

The aim of the present study was to evaluate the role of the nitric oxide/cyclic guanosine monophosphate pathway in corticostriatal long-term depression induction in a model of levodopa-induced dyskinesia in experimental parkinsonism. Moreover, we have also analysed the possibility of targeting striatal phosphodiesterases to reduce levodopa-induced dyskinesia. To study synaptic plasticity in sham-operated rats and in 6-hydroxydopamine lesioned animals chronically treated with therapeutic doses of levodopa, recordings from striatal spiny neurons were taken using either intracellular recordings with sharp electrodes or whole-cell patch clamp techniques. Behavioural analysis of levodopa-induced abnormal involuntary movements was performed before and after the treatment with two different inhibitors of phosphodiesterases, zaprinast and UK-343664. Levodopa-induced dyskinesia was associated with the loss of long-term depression expression at glutamatergic striatal synapses onto spiny neurons. Both zaprinast and UK-343664 were able to rescue the induction of this form of synaptic plasticity via a mechanism requiring the modulation of intracellular cyclic guanosine monophosphate levels. This effect on synaptic plasticity was paralleled by a significant reduction of abnormal movements following intrastriatal injection of phosphodiesterase inhibitors. Our findings suggest that drugs selectively targeting phosphodiesterases can ameliorate levodopa-induced dyskinesia, possibly by restoring physiological synaptic plasticity in the striatum. Future studies exploring the possible therapeutic effects of phosphodiesterase inhibitors in non-human primate models of Parkinson's disease and the involvement of striatal synaptic plasticity in these effects remain necessary to validate this hypothesis.

Topics: Animals; Corpus Striatum; Cyclic GMP; Dyskinesia, Drug-Induced; Levodopa; Long-Term Synaptic Depression; Male; Microinjections; Neurons; Oxidopamine; Parkinsonian Disorders; Phosphodiesterase Inhibitors; Piperazines; Purinones; Pyrimidinones; Rats; Rats, Wistar

Dysregulation of dopamine receptors is thought to underlie levodopa-induced dyskinesias in experimental models of Parkinson's disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico-striatal-pallidal loop at the peak of levodopa-induced dyskinesias in rats with 6-hydroxydopamine lesions in the substantia nigra. In addition, we examined the role of phosphodiesterase (PDE) and the rate of cAMP and cGMP degradation on the severity of levodopa-induced dyskinesias in animals pretreated with PDE inhibitor, zaprinast. Unilateral lesion of substantia nigra led to an increase in cAMP but a decrease in cGMP levels in the ipsilateral basal ganglia. After chronic levodopa treatment, cAMP and cGMP were differentially regulated in eukinetic animals: the cAMP level increased in the cortex and striatum but decreased in the globus pallidus of both hemispheres, whereas the cGMP decreased below baseline levels in the contralateral cortico-striatal-pallidal regions. In dyskinetic animals chronic levodopa treatment led to an absolute decrease in cAMP and cGMP levels in cortico-striatal-pallidal regions of both hemispheres. Pretreatment with zaprinast reduced the severity of levodopa-induced dyskinesias, and partly prevented the decrease in cyclic nucleotides compared with pretreatment with saline-levodopa. In conclusion, using a rat model of hemiparkinsonism, we observed a significant reduction in the levels of cyclic nucleotides in both hemispheres at the peak of levodopa-induced dyskinesias. We propose that such a decrease in cyclic nucleotides may partly result from increased catabolism through PDE overactivity.

Topics: Animals; Animals, Newborn; Brain; Cerebral Cortex; Cyclic AMP; Cyclic GMP; Dopamine; Dopamine Agents; Down-Regulation; Dyskinesia, Drug-Induced; Globus Pallidus; Levodopa; Male; Neostriatum; Oxidopamine; Parkinsonian Disorders; Phosphodiesterase Inhibitors; Phosphorylation; Purinones; Rats; Rats, Sprague-Dawley; Second Messenger Systems; Substantia Nigra; Sympatholytics; Synaptic Transmission

The underlying pathophysiological basis of tardive dyskinesia (TD) remains speculative. Haloperidol (HP) inhibits neuronal nitric oxide (NO) synthase (NOS) activity in vitro, but has not to date been studied in an intact animal model. Recent animal studies have found that extrapyramidal dysfunction evoked by chronic HP is associated with suppression of striatal cyclic guanosine monophosphate (cGMP), as well as plasma nitrogen oxides. Striatal dopamine (DA) is central to motor control, while NO plays an important neuroregulatory role in striatal DA function. Recent case reports suggest that atypical antipsychotics, such as olanzapine (OLZ), may be effective in reversing TD. Here, rats treated with HP (1.5 mg/kg per day p.o.) for 28 days developed significant vacuous chewing movements (VCMs) together with significant suppression of striatal NOS activity. Acute challenge with OLZ (1 and 2 mg/kg i.p.) significantly reversed both HP-induced VCMs and suppression of striatal NOS activity. Therefore TD may involve attenuation of NO-mediated neuromodulation in the striatum. Reversal of VCMs and NOS suppression with OLZ suggests that disinhibition of striatal NOS activity may underlie the clinical benefit of OLZ in TD.

Topics: Animals; Antipsychotic Agents; Benzodiazepines; Corpus Striatum; Cyclic GMP; Dyskinesia, Drug-Induced; Haloperidol; Male; Mastication; Nitric Oxide; Nitric Oxide Synthase; Olanzapine; Pirenzepine; Rats; Rats, Sprague-Dawley

The irreversible nature of haloperidol-induced tardive dyskinesia suggests a neurotoxic etiology, although the causes are unknown. Since nitric oxide demonstrates neurotoxic as well as neuroprotectant properties, and antipsychotics can inhibit nitric oxide (NO) synthase in vitro, this study investigates the NO-cGMP pathway as a pre-determining factor in chronic haloperidol-associated dyskinesia in rats. Sprague-Dawley rats were administered either water, oral haloperidol (0.25 mg/kg per day po), the guanylyl cyclase-nNOS inhibitor, methylene blue (MB; 5 mg/kg per day ip) or haloperidol plus MB for 3 weeks. In a second protocol, rats received water or haloperidol orally for 17 weeks, followed by 3 weeks withdrawal. Either saline (ip) or MB (ip) was administered for 3 weeks prior to haloperidol withdrawal. Vacous chewing movements (VCMs) were continuously monitored, followed by the determination of serum nitrogen oxides (NO(x)) and striatal cGMP at week 20. Chronic haloperidol engendered significant VCMs, with acute withdrawal resulting in significantly reduced plasma NO(x) and striatal cGMP. Furthermore, NO(x) and cGMP suppression was amplified by pre-withdrawal MB administration. Sub-acute haloperidol similarly induced incremental VCMs, but without effect on NO(x) or cGMP. However, haloperidol plus MB also induced significantly greater VCMs with decreased cGMP compared to haloperidol alone. Thus, NO(x)-cGMP inhibition persists pronounced after long-term haloperidol treatment and withdrawal. MB potentiation of these effects suggests that haloperidol inhibits a NO-dependent neuro-protective response to oxidative stress in the striatum that may pre-determine TD development.

Topics: Animals; Antipsychotic Agents; Brain Mapping; Corpus Striatum; Cyclic GMP; Dyskinesia, Drug-Induced; Haloperidol; Male; Motor Activity; Nitric Oxide; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Substance Withdrawal Syndrome

Haloperidol persists in brain tissue long after discontinuation while haloperidol-induced tardive dyskinesia often worsens after withdrawal of the drug. The mechanism of haloperidol-associated tardive dyskinesia is unknown, although neurotoxic pathways are suspected. Nitric oxide (NO) synthase (NOS) inhibitors exacerbate haloperidol-induced catalepsy, while haloperidol itself is a potent neuronal NOS inhibitor in vitro. Since NO and cGMP are involved in striatal neural plasticity, this study investigates a possible relation between cGMP and extrapyramidal symptoms as early predictors of haloperidol-associated tardive dyskinesia. Sprague-Dawley rats were administered either water or oral haloperidol (0.25 mg/kg/d p.o.) for 17 weeks, followed by 3 weeks withdrawal. Saline (i.p.) or the nNOS/guanylate cyclase inhibitor, methylene blue (5 mg/kg/d i.p.), were co-administered with haloperidol for the first three weeks of treatment. Vacous chewing movements (VCM's) were continuously monitored, followed by the determination of striatal cGMP and peripheral serum nitrogen oxide (NOx) levels. Chronic haloperidol engendered significant VCM's, with acute withdrawal associated with significantly reduced striatal cGMP levels as well as reduced serum NOx. Furthermore, suppressed cGMP levels were maintained and VCM's were significantly worse after early administration of methylene blue to the chronic haloperidol group. However, serum NOx was unchanged from control. We conclude that the central effects of chronic haloperidol on striatal NO-cGMP function persist for up to 3 weeks post-withdrawal. Moreover, suppression of striatal cGMP constitutes an early neuronal insult that determines the presence and intensity of haloperidol-associated motor dysfunction.

Topics: Animals; Chronic Disease; Corpus Striatum; Cyclic GMP; Dopamine Antagonists; Dyskinesia, Drug-Induced; Enzyme Inhibitors; Extrapyramidal Tracts; Haloperidol; Male; Mastication; Methylene Blue; Motor Activity; Nitric Oxide; Rats; Rats, Sprague-Dawley

SR146131 is a potent and selective agonist at cholecystokinin subtype 1 (CCK1) receptors in vitro. The present study evaluates the activity of the compound in vivo. SR146131 completely inhibited gastric and gallbladder emptying in mice (ED50 of 66 and 2.7 micrograms/kg p.o., respectively). SR146131 dose dependently reduced food intake in fasted rats (from 0.1 mg/kg p.o.), in nonfasted rats in which food intake had been highly stimulated by the administration of neuropeptide Y (1-36) (from 0.3 mg/kg p.o.), in fasted gerbils (from 0.1 mg/kg p.o.), and in marmosets maintained on a restricted diet (from 3 mg/kg p.o.). SR146131 (10 mg/kg p.o.) also increased the number of Fos-positive cells in the hypothalamic paraventricular nucleus of rats. Locomotor activity of mice was reduced by orally administered SR146131 (from 0.3 mg/kg p.o.). When administered intrastriatally, SR146131 elicited contralateral turning behavior in mice. Furthermore, orally administered SR146131 (0.3-10 mg/kg), also reduced the levels of cerebellar cyclic GMP. Finally, SR146131 (0.1 microgram/kg to 1 mg/kg, p.o.) significantly and dose dependently antagonized fluphenazine-induced mouth movements in rats. The CCK1 antagonist SR27897B prevented all the effects of SR146131. Conversely, SR146131 was unable to elicit any agonist or antagonist effects in a model of CCK2 receptor stimulation in vivo. SR146131 is a very potent and selective nonpeptide CCK1 agonist in vivo. SR146131 is more potent than any other CCK1 agonists reported to date. Because pharmacodynamic studies suggest that SR146131 should have a high absolute bioavailability, it may be a promising drug for the treatment of eating and motor disorders in humans.

Topics: Animals; Appetite Stimulants; Callithrix; Cerebellum; Cyclic GMP; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Eating; Female; Gallbladder Emptying; Gastric Acid; Gastric Emptying; Gerbillinae; Indoles; Male; Mice; Motor Activity; Neuropeptide Y; Paraventricular Hypothalamic Nucleus; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin A; Receptors, Cholecystokinin; Species Specificity; Stereotyped Behavior; Thiazoles

Lumbar cerebrospinal fluid (CSF) homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), 5-hydroxyindoleacetic acid (5-HIAA), cyclic AMP (cAMP) and cyclic GMP (cGMP) were measured in chronic schizophrenics with tardive dyskinesia before and three weeks after the initial treatment with sodium valproate (VPA), cyproheptadine, oxypertine or hydroxyzine pamoate. HVA levels significantly decreased after the administration of VPA, cyproheptadine or oxypertine. Cyclic GMP levels significantly increased after the administration of VPA or cyproheptadine. Elevation of the cAMP level was observed after the administration of VPA, cyproheptadine or oxypertine. An elevation of the MHPG level was observed during oxypertine treatment and a reduction of the 5-HIAA level was observed during hydroxyzine pamoate treatment. Decreases in HVA and increases in cGMP levels during treatment might be indicative of normalization of the dopaminergic-cholinergic imbalance in the brain. Lumbar CSF HVA and gamma-aminobutyric acid (GABA) were also measured in patients with tardive dyskinesia before and eight weeks after Ca-hopantenate treatment. No significant changes were observed before or after this treatment. The hypothesis is discussed that the pathogenesis of tardive dyskinesia may involve functional disorders not only of the dopaminergic or cholinergic system but also of the norepinephrinergic, serotoninergic and GABA-ergic systems.

Topics: Adult; Aged; Cyclic AMP; Cyclic GMP; Cyproheptadine; Dyskinesia, Drug-Induced; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Hydroxyzine; Indoles; Male; Methoxyhydroxyphenylglycol; Middle Aged; Piperazines; Valproic Acid

The latencies and incidence of deltamethrin-induced motor symptoms were compared in rats pretreated with saline or 3-acetylpyridine (3-AP) (75 mg/kg i.p. 4 days before). 3-AP produced considerable degeneration of the inferior olive and hence the climbing fiber afferents to the cerebellar cortex. The times of onset of whole body tremor and spontaneous choreiform episodes were accelerated significantly in lesioned rats. Therefore the olivocerebellar tract is not important in mediating deltamethrin symptoms, but is necessary to compensate for the disruption of motor activity and coordination induced by deltamethrin at another site. Cerebellar cyclic guanosine monophosphate (cyclic GMP) levels were elevated significantly during the deltamethrin syndrome. The increase in cyclic GMP levels correlated directly with the duration of motor symptoms. This suggests that deltamethrin has an indirect effect on cerebellar cyclic GMP levels. Lesion of the olive-cerebellar tract did not abolish this rise in cerebellar cyclic GMP levels. The sequential development of the motor symptoms, whole body tremor followed by choreiform episodes was found to have an additive effect in raising cerebellar cyclic GMP levels. This suggests that both the nature and the general level of motor activity can influence cerebellar cyclic GMP levels.

Topics: Animals; Cerebellum; Cyclic GMP; Dyskinesia, Drug-Induced; Harmaline; Male; Motor Activity; Neural Pathways; Nitriles; Olivary Nucleus; Pyrethrins; Pyridines; Rats

Topics: Animals; Behavior, Animal; Brain; Brain Chemistry; Catecholamines; Cerebrovascular Circulation; Cyclic GMP; Dyskinesia, Drug-Induced; Electroencephalography; Glucose; Ion Channels; Pyrethrins; Rats; Structure-Activity Relationship; Syndrome

Many types of psychotherapeutic drugs (especially antidepressants) directly and indirectly interact with neurotransmitter receptors, the recognition sites for the chemical messengers released by neurons. These interactions can result in increased or decreased sensitivity of certain receptors. Hypotheses exist to explain some therapeutic and adverse effects of these drugs on the basis of these changes in sensitivity of receptors for neurotransmitters. This paper briefly presents some recently acquired knowledge about these drug-receptor interactions and shows how they can affect the sensitivity of receptors.

Topics: Antidepressive Agents, Tricyclic; Antipsychotic Agents; Binding, Competitive; Clone Cells; Cyclic GMP; Dyskinesia, Drug-Induced; Humans; Ion Channels; Neurotransmitter Agents; Psychotropic Drugs; Receptors, Dopamine; Receptors, Drug; Receptors, Histamine H1

Lumbar CSF HVA, MHPG, 5HIAA, cAMP, and cGMP were measured in 12 chronic schizophrenics with tardive dyskinesia before and 3 weeks after sodium valproate (VPA) or cyproheptadine treatment. HVA levels significantly decreased and cAMP and cGMP levels significantly increased during the administration of VPA or cyproheptadine. There were no significant correlations between the degree of improvement in tardive dyskinesia and the changes of amine metabolities or cyclic nucleotides. None of the pretreatment values for CSF amine metabolites or cyclic nucleotides were different from those of 15 chronic schizophrenics without tardive dyskinesia as controls. Decrease of HVA and increase of cGMP during the treatment might indicate the normalization of dopaminergic-cholinergic imbalance in the brain. Furthermore, significantly low levels of 5HIAA were observed in the patients with drug-induced tremor. It is suggested that neuroleptic-induced tremor may be attributed to serotonergic dysfunction in the brain.

Topics: Adult; Chronic Disease; Cyclic AMP; Cyclic GMP; Cyproheptadine; Dyskinesia, Drug-Induced; Female; Homovanillic Acid; Humans; Hydroxyindoleacetic Acid; Male; Methoxyhydroxyphenylglycol; Middle Aged; Neurotransmitter Agents; Schizophrenia; Tremor; Valproic Acid

Male albino rats were permanently cannulated bilaterally in the caudate/putamen nucleus and subsequently injected unilaterally with cyclic AMP or cyclic GMP. Both of these cyclic nucleotides failed to produce any obvious change in motor activity. The concomitant intrastriatal injection of carbachol and cyclic AMP resulted in enhancement of the carbachol-induced dyskinesias. Under similar conditions, cyclic GMP blocked the carbachol effects. The dibutyryl (db) derivatives of cyclic AMP and cyclic GMP both enhanced the carbachol-induced dyskinesias and both db cyclic nucleotides induced dyskinesias when injected intrastriatally alone. The concomitant intrastriatal injection of dopamine and carbachol resulted in a blockade of the carbachol-induced dyskinesias. Dopmaine had no effect on db cyclic AMP and db cyclic GMP dyskinesias. The db cyclic AMP effects characteristically involved the distal limb musculature, while the db cycle GMP effects largely involved the proximal limb and trunk muscles. The hypothesis for opposing action of cyclic AMP and cyclic GMP in the CNS and the discrepancy between the effects of intrastriatal injection of cyclic AMP and dopamine were discussed.

Topics: Animals; Bucladesine; Carbachol; Corpus Striatum; Cyclic AMP; Cyclic GMP; Dopamine; Drug Interactions; Dyskinesia, Drug-Induced; Injections; Male; Rats