Up-regulation Of D2 Dopamine Receptors Research Articles

Role of aripiprazole in treating medication induced tardive dyskinesia

Objectives: To review the effects of aripiprazole in treatment of medication induced tardive dyskinesaMethods: Medline search was was performed using key words of 'aripiprazole' and 'tardive dyskinesia', we searched overall articles published between 2000 and 2008.Result: Aripiprazole inhibits central dopaminergic neuron activity by a partial agonistic effects on presynaptic D2 dopamine autoreceptors and also acts as an antagonist at postsynaptic D2 dopamine receptors. Through this mechanism, aripiprazole exerts activity as a dopaminergic agonist in hypodopaminergic states, while acting as a dopamine antagonist when dopaminergic activity is increased. There is also evidence from basic science studies that aripiprazole causes D2 receptor up-regulationConclusions: It is plausible that aripiprazole, by virtue of its dopamine agonistic activity, can potentially normalize D2 dopamine receptor up-regulation, this properties may play a role in both prevention of the emergence of tardive dyskinesia and the treatment of Tardive dyskinesia. Double blind placebo-controlled studies would be needed to enlighten this issues.

Resolution of Ziprasidone-Related Tardive Dyskinesia With a Switch to Aripiprazole

Sir: Tardive dyskinesia (TD) is a serious, potentially irreversible side effect of antipsychotic medications. Prevalence rates of 20% with the typical antipsychotics have been reported.1 Although the risk is smaller, treatment with atypical antipsychotic agents still poses a risk of TD. There is 1 report of ziprasidone-related TD in a patient who had other risk factors for TD, including advanced age, female gender, and affective illness.2 However, the report did not address the management of the patient's TD. We report a case of ziprasidone-related TD that resolved after a switch to aripiprazole therapy was made. Case report. Ms. A, a 52-year-old African American woman, was admitted for a psychotic exacerbation. She had a 20-year history of DSM-IV paranoid schizophrenia treatment characterized by frequent relapses, noncom-pliance with treatment, multiple antipsychotic trials, and hospitalizations. Her past history of TD was not known; however, over the past few years she had gained weight and had also been diagnosed with diabetes. There was no history of any illicit drug abuse. Ziprasidone 60 mg p.o. b.i.d. was initiated in December 2002 during Ms. A's hospitalization, with good control of her psychotic symptoms. Within 2 months of initiation of treatment with ziprasidone, she was noted to have buccal-oral tardive dyskinesia and had an Abnormal Involuntary Movement Scale (AIMS)3 score of 3. Vitamin E was added at a dose of 800 mg twice a day to manage the TD. She was discharged home on treatment with vitamin E 800 mg p.o. b.i.d. and ziprasidone 60 mg p.o. b.i.d. During Ms. A's follow-up outpatient visits, although her psychotic symptoms were stable, TD persisted. She had also discontinued vitamin E. After 12 months of ziprasidone therapy, a decision to switch to aripiprazole 15 mg/day was made. Over the next 2 months, her tardive dyskinesia gradually but completely remitted, and her symptoms of schizophrenia remained stable. Her AIMS score dropped to zero. Aripiprazole is an atypical antipsychotic drug with a unique mechanism of action; it inhibits central dopami-nergic neuron activity by a partial agonistic effect on the dopamine autoreceptor and also acts as an presynaptic D2 antagonist at postsynaptic D2 dopamine receptors. Through this mechanism, aripiprazole exerts activity as a dopamine agonist in hypodopaminergic states, while acting as a dopa-mine antagonist when dopaminergic activity is increased.4 Alteration of the sensitivity of dopaminergic receptors to dopamine in the corpus striatum has been studied in experimental models, and it has been proposed that the lingual-facial-buccal dyskinesia seen in humans could be the human equivalent of stereotyped behavior seen in experimental animals with chronic chlorpromazine pretreatment.5 There is also evidence from basic science studies that aripiprazole causes little D2 receptor up-regulation.6 Therefore, it is plausible that aripiprazole, by virtue of its dopamine agonistic activity, can potentially normalize D2 dopamine receptor up-regulation. These properties may play a role in both prevention of the emergence of TD and the treatment of TD. There is 1 other report of improvement of TD with aripiprazole in which improvement continued even after a conventional antipsychotic was added to the patient's regimen.7 We propose that for schizophrenic patients who have tardive dyskinesia and who do not desire clozapine treatment or cannot be prescribed clozapine due to medical contraindications, aripiprazole may provide alternate phar-macotherapy to treat psychoses and tardive dyskinesia. However, more research is needed in this direction.

Increased dopamine D2 receptor binding and enhanced apomorphine-induced locomotor activity in μ-opioid receptor knockout mice

Previous studies from our laboratory have indicated possible interactions between opioidergic and dopaminergic neurons in the central nervous system. In this study, apomorphine-induced locomotor activity and the D1 and D2 subtype dopamine receptor binding were examined in mice lacking the μ-opioid receptor genes. The ambulatory time, vertical time and total motor distance of locomotor activity were measured after administration of apomorphine (2 mg/kg, i.p.) for a period of 90 min. The autoradiographic studies of D1 and D2 dopamine receptors were conducted using [ 3 H ] SCH23390 and [ 3 H ] raclopride as ligand, respectively. In wild type mice that received apomorphine, 2 mg/kg, i.p., the locomotor activity such as ambulatory time, vertical time and total motor distance were not significantly altered as compared with that of the saline control group. However, the locomotor activity measured was significantly increased in the same dose of apomorphine treated μ-opioid receptor knockout mice between 5 and 40 min after administration. The results obtained also show that the binding of D2 dopamine receptor in μ-opioid receptor knockout mice was significantly higher than that of the wild type in the caudate putamen. However, the binding of the D1 dopamine receptor in μ-opioid receptor knockout mice was not significantly different from that of the wild type. It appears that the apomorphine treated μ-opioid receptor knockout mice showed enhancement in locomotor activity. The enhanced locomotor activity may be related to the compensatory up-regulation of D2 dopamine receptors in mice lacking μ-opioid receptor genes.

Chronic levodopa is not toxic for remaining dopamine neurons, but instead promotes their recovery, in rats with moderate nigrostriatal lesions.

Orally administered levodopa remains the most effective symptomatic treatment for Parkinson's disease (PD). The introduction of levodopa therapy is often delayed, however, because of the fear that it might be toxic for the remaining dopaminergic neurons and, thus, accelerate the deterioration of patients. However, in vivo evidence of levodopa toxicity is scarce. We have evaluated the effects of a 6-month oral levodopa treatment on several dopaminergic markers, in rats with moderate or severe 6-hydroxydopamine-induced lesions of mesencephalic dopamine neurons and sham-lesioned animals. Counts of tyrosine hydroxylase (TH)-immunoreactive neurons in the substantia nigra and ventral tegmental area showed no significant difference between levodopa-treated and vehicle-treated rats. In addition, for rats of the sham-lesioned and severely lesioned groups, immunoradiolabeling for TH, the dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) at the striatal level was not significantly different between rats treated with levodopa or vehicle. It was unexpected that quantification of immunoautoradiograms showed a partial recovery of all three dopaminergic markers (TH, DAT, and VMAT2) in the denervated territories of the striatum of moderately lesioned rats receiving levodopa. Furthermore, the density of TH-positive fibers observed in moderately lesioned rats was higher in those treated chronically with levodopa than in those receiving vehicle. Last, that chronic levodopa administration reversed the up-regulation of D2 dopamine receptors seen in severely lesioned rats provided evidence that levodopa reached a biologically active concentration at the basal ganglia. Our results demonstrate that a pharmacologically effective 6-month oral levodopa treatment is not toxic for remaining dopamine neurons in a rat model of PD but instead promotes the recovery of striatal innervation in rats with partial lesions.

D2 dopamine receptor upregulation is associated with poor treatment response and extrapyramidal side effects in schizophrenia: A follow-up study with 123I-IBZM spect in the drug-naive state and after neuroleptic treatment

D2 dopamine receptor upregulation is associated with poor treatment response and extrapyramidal side effects in schizophrenia: A follow-up study with 123I-IBZM spect in the drug-naive state and after neuroleptic treatment

Prolonged expression of Fos-related antigens, Jun B and TrkB in dopamine-denervated striatal neurons.

Previous studies have demonstrated that striatal dopamine-denervation leads to a long-term increase in Fos-related antigen(s) (FRA's) in striatal neurons. Because Fos-family proteins bind to DNA by dimerizing to Jun-family proteins we investigated the expression of Jun B protein 2 weeks and 1 month after striatal dopamine-denervation, produced by medial forebrain bundle transection. We also investigated the effects of this lesion on TrkB-immunoreactivity in the striatum. FRA's (as previously reported) and Jun B were expressed in striatal neurons following dopamine-denervation, and in addition, there was an increase in expression of TrkB in the striatum on the dopamine-denervated side. These results show that striatal dopamine depletion leads to a long-term up-regulation of FRA's and Jun B in the striatum, and this may be related to other biochemical changes previously reported to occur in striatal neurons (e.g.: D2-dopamine receptor up-regulation) after dopamine depletion. In addition, FRA and Jun B expression may induce increased production of TrkB after dopamine-denervation.

Neurochemical Basis for the Absence of Overt “Stereotyped” Behaviors in Rats With Up-Regulated Striatal D2 Dopamine Receptors

Because of substantial evidence for the hyperdopaminergic hypothesis of tardive dyskinesia (TD), animal models, especially rats, treated chronically with neuroleptics continue to be used to study this disorder. The rat model has been criticized because, unlike TD, in rats there is an apparent lack of spontaneous abnormal movements even when striatal D2 dopamine receptor (DAr) density is substantially increased. Our data suggest a mechanism by which rats suppress these abnormal movements normally associated with elevated DAr levels. We correlated neurochemical with behavioral changes using several animal models, including nonneuroleptic ones, which elicit varied levels of DAr upregulation. There was (as expected) a robust, significant, positive correlation between striatal DAr density and apomorphine-induced stereotypic behaviors. In contrast, there was a significant negative correlation between increased DAr density and synthesis capacity for striatal DA (Vmax for tyrosine hydroxylase). We conclude that this decrease in Vmax is a compensatory adjustment of the nigrostriatal DA tract for the increased DAr density induced in our animal models. Our data further suggest the generalization that an observed increase in receptor density doesn't necessarily predict a functional change (spontaneous behavior, neuropathology) because compensatory neural mechanisms exist. In TD these compensatory neural mechanisms may fail, leading to spontaneous behaviors.

Cyclo(leu-gly) reverses the permanent dopamine receptor up-regulation induced by ovariectomy

Several neuropsychiatric diseases, including tardive dyskinesia and schizophrenia, are thought to involve increased neurotransmission at dopaminergic synapses. Although many animal models of this dopaminergic hyperactivity have been studied, the ovariectomized (OVX) rat model, which we recently developed, appears to be unique. The brain D2 DA receptor up-regulation (increases in receptor number) and the behavioral hypersensitivity to dopamine (DA) agonists that develop in this model after a few months appear to be permanent. Using this model, it is now possible to screen for agents that can reverse a permanent dopaminergic supersensitivity. In this report, we document such a reversal by cyclo(leu-gly) (CLG), a dopaminergic neuromodulator, in the OVX model. Female Fisher rats were ovariectomized and allowed to recover for 3 months. Following a challenge dose of apomorphine (0.45 mg/kg, i.p.) OVX rats showed significantly more stereotypic sniffing (+ 175%) than sham controls. Following lower doses of APO (125 and 150 μ/kg, i.p.), OVX rats showed significantly more locomotor activity (+ 105 and + 365%). CLG (4 daily doses, 8 mg/kg, s.c.) reversed these hypersensitive responses. In parallel, OVX rats showed a significant increase (+ 35%) in [3H]-spiroperidol binding (Bmax) in corpus striatum relative to sham rats; this dopamine receptor up-regulation was also reversed by CLG. We conclude (1) that the long-term OVX rat is useful for modelling the permanent or irreversible aspect of supersensitivity to DA; and (2) CLG may be useful in the treatment of dopaminergic diseases.

Tardive dyskinesia, dopamine receptors, and neuroleptic damage to cell membranes.

The long-term treatment of schizophrenic patients with neuroleptics is associated with neuroleptic accumulation in neuromelanin-containing cells with ensuing nigral cell damage. Thus, in addition to early or short-term up-regulation of D2 dopamine receptors, the late stage denervation supersensitivity may result in a further proliferation of D2 dopamine receptors in those parts of the human striatum controlling mouth-lips-tongue motion. Young individuals, upon reduction or removal of the neuroleptic, may have neural sprouting with subsequent D2 down-regulation and reversal of their dyskinesia. Older individuals may not readily exhibit sprouting and D2 down-regulation, possibly accounting for a more persistent form of dyskinesia.

Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologic effects on D1 and D2 dopamine receptors

Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis-flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose-dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis-flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis-flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)