Up-regulation Of Dopamine Receptors Research Articles

Intranasal Delivery of Near-Infrared and Magnetic Dual-Response Nanospheres to Rapidly Produce Antidepressant-Like and Cognitive Enhancement Effects.

Restricted by synaptic plasticity, dopamine receptor (DR) upregulation takes a long time to work. Moreover, the impact of the blood-brain barrier (BBB) on delivery efficiency restricts the development of drugs. Taking inspiration from snuff bottles, a convenient, fast-acting, and nonaddictive nasal drug delivery system has been developed to rapidly reshape the balance of synaptic transmitters. This optical and magnetic response system called CFs@DP, comprised of carbonized MIL-100 (Fe) frameworks (CFs) and domperidone (DP), which can enter the brain via nasal administration. Under dual stimulation of near-infrared (NIR) irradiation and catecholamine-induced complexation, CFs@DP disintegrates to release iron ions and DP, causing upregulation of the dopamine type 1 (D1), type 2 (D2) receptors, and brain-derived neurotrophic factor (BDNF) to achieve a therapeutic effect. In vivo experiments demonstrate that the DR density of mice (postnatal day 50-60) increased in the prefrontal cortex (PFC) and the hippocampus (HPC) after 10 days of therapy, resulting in antidepressant-like and cognitive enhancement effects. Interestingly, the cognitive enhancement effect of CFs@DP is even working in noniron deficiency (normal fed) mice, making it a promising candidate for application in enhancing learning ability.

Localisation of clozapine during experimental autoimmune encephalomyelitis and its impact on dopamine and its receptors

Multiple sclerosis is a disease characterised by axonal demyelination in the central nervous system (CNS). The atypical antipsychotic drug clozapine attenuates experimental autoimmune encephalomyelitis (EAE), a mouse model used to study multiple sclerosis, but the precise mechanism is unknown and could include both peripheral and CNS–mediated effects. To better understand where clozapine exerts its protective effects, we investigated the tissue distribution and localisation of clozapine using matrix-assisted laser desorption ionization imaging mass spectrometry and liquid chromatography-mass spectrometry. We found that clozapine was detectable in the brain and enriched in specific brain regions (cortex, thalamus and olfactory bulb), but the distribution was not altered by EAE. Furthermore, although not altered in other organs, clozapine levels were significantly elevated in serum during EAE. Because clozapine antagonises dopamine receptors, we analysed dopamine levels in serum and brain as well as dopamine receptor expression on brain-resident and infiltrating immune cells. While neither clozapine nor EAE significantly affected dopamine levels, we observed a significant downregulation of dopamine receptors 1 and 5 and up-regulation of dopamine receptor 2 on microglia and CD4+-infiltrating T cells during EAE. Together these findings provide insight into how neuroinflammation, as modelled by EAE, alters the distribution and downstream effects of clozapine.

Therapeutic efficacy of repetitive transcranial magnetic stimulation in an animal model of Alzheimer\u2019s disease

Previous studies on repetitive transcranial magnetic stimulation (rTMS) suggested potential neurorestorative properties in Alzheimer’s disease (AD). This study aimed to investigate therapeutic effects of rTMS on an AD mouse model at high and low frequencies. The subject mice were allocated into the AD model group (AD induced by intracerebroventricular amyloid beta 42 oligomer [Aβ42] injection) and the saline-injected control group. Each group was subdivided according to rTMS treatment: high frequency (20 Hz), low frequency (1 Hz), and not rTMS-treated. Behavioural assessments with Y-maze test and novel object recognition task were performed; the results indicated cognition recovery by both the frequencies of rTMS after treatment in the AD model (Ps < 0.01). Tendency of further effects by high frequency compared to low frequency rTMS was also shown in Y-maze test. Neurotransmitter assay showed increment in dopamine concentration and upregulation of dopamine-receptor 4 (DR4) by rTMS in AD mice with higher response by high frequency stimulation (Ps < 0.05). Only high-frequency rTMS induced an elevation of brain-derived neurotrophic factor (BDNF) levels and enhanced the expression of Nestin and NeuN in the brain tissue (Ps < 0.05). Under in vitro conditions, Aβ42 incubated mouse hippocampal cell showed an increase in dopamine levels and BDNF by application of high-frequency rTMS treatment. In conclusion, rTMS might have a potential therapeutic effect on AD, and it seems to be related with dopaminergic activation. High frequency of stimulation seems to induce higher efficacy than that induced by low frequency, with elevated expressions of DR4 gene and neurogenic proteins.

Dexmedetomidine Ameliorates Sleep Deprivation-Induced Depressive Behaviors in Mice.

PurposeSleep deprivation induces depressive symptoms. Dexmedetomidine is a α2-adrenoreceptor agonist and this drug possesses sedative, anxiolytic, analgesic, and anesthetic-sparing effect. In this study, the action of dexmedetomidine on sleep deprivation-induced depressive behaviors was investigated using mice.MethodsFor the inducing of sleep deprivation, the mice were placed inside a water cage containing 15 platforms and filled with water up to 1 cm below the platform surface for 7 days. One day after sleep deprivation, dexmedetomidine at the respective dosage (0.5, 1, and 2 μg/kg) was intraperitoneally treated into the mice, one time per a day during 6 days. Then, forced swimming test and tail suspension test were conducted. Immunohistochemistry for tyrosine hydroxylase (TH), 5-hydroxytryptamine (5-HT; serotonin), tryptophan hydroxylase (TPH) and western blot for D1 dopamine receptor were also performed.ResultsSleep deprivation increased the immobility latency in the forced swimming test and tail suspension test. The expressions of TPH, 5-HT, and D1 dopamine receptor were decreased, whereas, TH expression was increased by sleep deprivation. Dexmedetomidine decreased the immobility latency and increased the expressions of TPH, 5-HT, and D1 dopamine receptor, whereas, HT expression was decreased by dexmedetomidine treatment.ConclusionsIn our results, dexmedetomidine alleviated sleep deprivation-induced depressive behaviors by increasing 5-HT synthesis and by decreasing dopamine production with up-regulation of D1 dopamine receptor.

Behavioural, biochemical and molecular changes induced by chronic crack-cocaine inhalation in mice: The role of dopaminergic and endocannabinoid systems in the prefrontal cortex

Crack-cocaine addiction has increasingly become a public health problem worldwide, especially in developing countries. However, no studies have focused on neurobiological mechanisms underlying the severe addiction produced by this drug, which seems to differ from powder cocaine in many aspects. This study investigated behavioural, biochemical and molecular changes in mice inhaling crack-cocaine, focusing on dopaminergic and endocannabinoid systems in the prefrontal cortex. Mice were submitted to two inhalation sessions of crack-cocaine a day (crack-cocaine group) during 11 days, meanwhile the control group had no access to the drug. We found that the crack-cocaine group exhibited hyperlocomotion and a peculiar jumping behaviour (“escape jumping”). Blood collected right after the last inhalation session revealed that the anhydroecgonine methyl ester (AEME), a specific metabolite of cocaine pyrolysis, was much more concentrated than cocaine itself in the crack-cocaine group. Most genes related to the endocannabinoid system, CB1 receptor and cannabinoid degradation enzymes were downregulated after 11-day crack-cocaine exposition. These changes may have decreased dopamine and its metabolites levels, which in turn may be related with the extreme upregulation of dopamine receptors and tyrosine hydroxylase observed in the prefrontal cortex of these animals. Our data suggest that after 11 days of crack-cocaine exposure, neuroadaptive changes towards downregulation of reinforcing mechanisms may have taken place as a result of neurochemical changes observed on dopaminergic and endocannabinoid systems. Successive changes like these have never been described in cocaine hydrochloride models before, probably because AEME is only produced by cocaine pyrolysis and this metabolite may underlie the more aggressive pattern of addiction induced by crack-cocaine.

Effect of dietary iron loading on recognition memory in growing rats.

While nutritional and neurobehavioral problems are associated with both iron deficiency during growth and overload in the elderly, the effect of iron loading in growing ages on neurobehavioral performance has not been fully explored. To characterize the role of dietary iron loading in memory function in the young, weanling rats were fed iron-loading diet (10,000 mg iron/kg diet) or iron-adequate control diet (50 mg/kg) for one month, during which a battery of behavioral tests were conducted. Iron-loaded rats displayed elevated non-heme iron levels in serum and liver, indicating a condition of systemic iron overload. In the brain, non-heme iron was elevated in the prefrontal cortex of iron-loaded rats compared with controls, whereas there was no difference in iron content in other brain regions between the two diet groups. While iron loading did not alter motor coordination or anxiety-like behavior, iron-loaded rats exhibited a better recognition memory, as represented by an increased novel object recognition index (22% increase from the reference value) than control rats (12% increase; P=0.047). Western blot analysis showed an up-regulation of dopamine receptor 1 in the prefrontal cortex from iron-loaded rats (142% increase; P=0.002). Furthermore, levels of glutamate receptors (both NMDA and AMPA) and nicotinic acetylcholine receptor (nAChR) were significantly elevated in the prefrontal cortex of iron-loaded rats (62% increase in NR1; 70% increase in Glu1A; 115% increase in nAChR). Dietary iron loading also increased the expression of NMDA receptors and nAChR in the hippocampus. These results support the idea that iron is essential for learning and memory and further reveal that iron supplementation during developmental and rapidly growing periods of life improves memory performance. Our investigation also demonstrates that both cholinergic and glutamatergic neurotransmission pathways are regulated by dietary iron and provides a molecular basis for the role of iron loading in improved memory.

A leptin-mediated central mechanism in analgesia-enhanced opioid reward in rats.

Opioid analgesics are commonly used in chronic pain management despite a potential risk of rewarding. However, it remains unclear whether opioid analgesia would enhance the opioid rewarding effect thereby contributing to opioid rewarding. Utilizing a rat paradigm of conditioned place preference (CPP) combined with ankle monoarthritis as a condition of persistent nociception, we showed that analgesia induced by either morphine or the nonsteroid anti-inflammatory drug ibuprofen increased CPP scores in arthritic rats, suggesting that analgesia itself had a rewarding effect. However, arthritic rats exhibited a significantly higher CPP score in response to morphine than ibuprofen. Thus, the rewarding effect of morphine was enhanced in the presence of persistent nociception, producing a phenomenon of analgesia-enhanced opioid reward. At the cellular level, administration of morphine activated a cascade of leptin expression, glial activation, and dopamine receptor upregulation in the nucleus accumbens (NAc), while administration of ibuprofen decreased glial activation with no effect on leptin expression in the NAc. Furthermore, the morphine rewarding effect was blocked in leptin deficient ob/ob mice or by neutralizing leptin or interleukin-1β in the NAc without diminishing morphine analgesia. The data indicate that systemic opioid can activate a leptin-mediated central mechanism in the NAc that led to the enhanced opioid rewarding effect. These findings provide evidence for an interaction between opioid analgesia and opioid rewarding, which may have implications in clinical opioid dose escalation in chronic pain management.

Estradiol and isotype-selective estrogen receptor agonists modulate the mesocortical dopaminergic system in gonadectomized female rats

The mesocortical dopaminergic pathway projecting from the ventral tegmental area (VTA) to the prefrontal cortex (PFC) contributes to the processing of reward signals. This pathway is regulated by gonadal steroids including estradiol. To address the putative role of estradiol and isotype-selective estrogen receptor (ER) agonists in the regulation of the rodent mesocortical system, we combined fMRI, HPLC–MS and qRT-PCR techniques. In fMRI experiments adult, chronically ovariectomized rats, treated with either vehicle, estradiol, ERα agonist 16α-lactone-estradiol (LE2) or ERβ agonist diarylpropionitrile (DPN), received a single dose of d-amphetamine-sulphate (10mg/kg, i.p.) and BOLD responses were monitored in the VTA and the PFC. Ovariectomized rats showed no significant response to amphetamine. In contrast, the VTA of ER agonist-substituted ovariectomized rats showed robust amphetamine-evoked BOLD increases. The PFC of estradiol-replaced animals was also responsive to amphetamine. Mass spectroscopic analysis of dopamine and its metabolites revealed a two-fold increase in both dopamine and 3,4-dihydroxyphenylacetic acid content of the PFC in estradiol-replaced animals compared to ovariectomized controls. qRT-PCR studies revealed upregulation of dopamine transporter and dopamine receptor in the VTA and PFC, respectively, of ER agonist-treated ovariectomized animals. Collectively, the results indicate that E2 and isotype-selective ER agonists can powerfully modulate the responsiveness of the mesocortical dopaminergic system, increase the expression of key genes related to dopaminergic neurotransmission and augment the dopamine content of the PFC. In a broader sense, the findings support the concept that the manifestation of reward signals in the PFC is dependent on the actual estrogen milieu of the brain.

Microinjection of CART (cocaine- and amphetamine-regulated transcript) peptide into the nucleus accumbens inhibits the cocaine-induced upregulation of dopamine receptors and locomotor sensitization

Repeated exposure to addictive drugs enhances dopamine receptor (DR) signaling and the ultimate phosphorylation of the cyclic adenosine 5′-monophosphate (cAMP)-response element-binding protein (CREB)-regulated cocaine- and amphetamine-regulated transcript (CART) expression in the nucleus accumbens (NAcc). These effects are known to contribute to the expression of behavioral sensitization. CART peptides are neuropeptides that modulate drug reward and reinforcement. The present experiments investigated the effects of CART 55–102 microinjection into the NAcc on (1) the phosphorylation of CREB, (2) cAMP/protein kinase A (PKA) signaling and (3) extracellular signal-regulated kinase (ERK) phosphorylated kinase signaling. Here, we show that repeated microinjections into the NAcc of CART 55–102 peptides (1.0 or 2.5μg, 0.5μl/side) attenuates cocaine-induced enhancements of D1R, D2R and D3R phosphorylation in this sites. Furthermore, the microinjection of CART 55–102 followed by repeated injections of cocaine (15mg/kg) dose-dependently blocked the enhancement of cAMP levels, PKA activity and pERK and pCREB levels on the fifth day of cocaine administration. The cocaine-induced locomotor activity and behavioral sensitization in rats were also inhibited by the 5-day-microinjection of CART peptides. These results suggest that the phosphorylation of CREB by cocaine in the NAcc was blocked by the CART 55–102 peptide via the inhibition of D1R and D2R stimulation, D3R phosphorylation, cAMP/PKA signaling and ERK phosphorylated kinase signaling. These effects may have played a compensatory inhibitory role in the behavioral sensitization of rats that received microinjections of CART 55–102.

Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper-responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic-lesioned and control rats showed reliable stress-induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion-induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum.

High frequency electro-acupuncture enhances striatum DAT and D1 receptor expression, but decreases D2 receptor level in 6-OHDA lesioned rats

The direct effects of electro-acupuncture (EA) on the dopaminergic neurotransmitter system in Parkinson's disease (PD) patients remain elusive. In the present study, 0, 2 or 100Hz EA was applied to acupoints Sanyinjiao (SP6), Yanglingquan (GB34) and Zusanli (ST36) in a rat model unilaterally lesioned by 6-hydroxydopamine. Rotational behavior tests were performed and the animals were then decapitated. Levels of striatal dopamine (DA), dopamine transporter, and D1- and D2-like DA receptors were subsequently evaluated. EA at 100Hz was shown to significantly enhance survival of dopaminergic neurons in the substantia nigra (52.10±11.41% of the level on the non-lesioned rats vs. 21.22±5.52% in the non-EA group, P<0.05) and reduce motor deficits (207.80±31.14 vs. 476.11±68.80turns/30min, P<0.05), whereas it only slightly restored the 6-hydroxydopamine-induced loss of striatal DA (P>0.05 vs. the non-EA group). There was a 253.78% increase in dopamine transporter protein expression in the striatum in the 100Hz EA group (P<0.05 vs. the non-EA group). Moreover, high frequency EA induced increases in striatal D1-like receptor mRNA and protein levels of 81.88% and 62.62%, respectively (P<0.001 and P<0.05 vs. the non-EA group). However, the D2-like DA receptor up-regulation observed in the non-EA group was suppressed in high frequency group (P>0.05 vs. the sham operation group). These findings suggest that high-frequency EA might work by acting on presynaptic dopamine transporter and postsynaptic dopamine receptors simultaneously to achieve a therapeutic effect in PD patients and models. This might shed some light on the mechanism by which EA affects the DA neurotransmitter system.

Infusion of Sydenham's chorea antibodies in striatum with up-regulated dopaminergic receptors: A pilot study to investigate the potential of SC antibodies to increase dopaminergic activity

BackgroundSydenham's chorea (SC) is a neurological manifestation of rheumatic fever. Autoimmune mechanism of SC is supported by clinical improvement with immunomodulatory therapy; presence of circulating serum anti-basal ganglia antibodies; increase in Th2 group of cytokines in serum and CSF of patients. However, a role of the antibodies in the pathogenesis can only be established by their passive transfer. Chorea is a manifestation clearly related to increased dopaminergic (DA) activity. The purpose of this study was to investigate the potential of antibodies from patients with Sydenham's chorea to cause behavior alterations on rats with unilateral post-synaptic dopamine receptor up-regulation. MethodsRats previously submitted to 6-hydroxidopamine (6-OH-DA) unilateral lesion of substantia nigra pars compacta (SNc) and tested with apomorphine to ensure DA receptors up regulation, received intrastriatal infusion of antibodies from SC patients (n=4) or healthy controls (n=3) during 48h. 24h post infusion initiation (24PI) and 48h post infusion initiation (48PI), we registered the occurrence of spontaneous contra lateral rotations (CLR). FindingsSC group exhibited significantly higher number of CLR than control group at 24PI (p=0.049) and 48PI (p=0.048). ConclusionThe limited sample of the present study restricts us to affirm that SC is really an immune-mediated condition. However the significant result of this pilot study points to preliminary evidence that SC antibodies may affect DA activity in rats with up-regulated striatal DA receptors.

The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses

Several human and experimental studies have shown that early life adverse events can shape physical and mental health in adulthood. Stress or elevated levels of glucocorticoids (GCs) during critical periods of development seem to contribute for the appearance of neurospyschiatric conditions such as anxiety and depression, albeit the underlying mechanisms remain to be fully elucidated. The aim of the present study was to determine the long-term effect of prenatal exposure to dexamethasone- DEX (synthetic GC widely used in clinics) in fear and anxious behavior and identify the neurochemical, morphological and molecular correlates. Prenatal exposure to DEX triggers a hyperanxious phenotype and altered fear behavior in adulthood. These behavioral traits were correlated with increased volume of the bed nucleus of the stria terminalis (BNST), particularly the anteromedial subdivision which presented increased dendritic length; in parallel, we found an increased expression of synapsin and NCAM in the BNST of these animals. Remarkably, DEX effects were opposite in the amygdala, as this region presented reduced volume due to significant dendritic atrophy. Albeit no differences were found in dopamine and its metabolite levels in the BNST, this neurotransmitter was substantially reduced in the amygdala, which also presented an up-regulation of dopamine receptor 2. Altogether, our results show that in utero DEX exposure can modulate anxiety and fear behavior in parallel with significant morphological, neurochemical and molecular changes; importantly, GCs seem to differentially affect distinct brain regions involved in this type of behaviors.

Severe psychotic exacerbation during combined treatment with aripiprazole/haloperidol after prior treatment with risperidone

Aripiprazole is a new generation antipsychotic drug that shows a partial agonistic activity at D2 and 5-HT1A receptors. This raises the question of whether aripiprazole can exacerbate psychotic symptoms due to dopamine agonism. We report the case of a 40-year-old woman with an ICD-10 defined schizoaffective disorder. Risperidone was started to treat psychotic symptoms. Psychotic symptoms disappeared but because of galactorrhea risperidone needed to be discontinued. Subsequently, an antipsychotic treatment regimen with aripiprazole and haloperidol was prescribed. After initiating aripiprazole and haloperidol the patient's psychotic symptoms increased drastically. Therefore aripiprazole and haloperidol were discontinued. Olanzapine together with a low dosage of risperidone were prescribed and psychotic symptoms declined again. Concurrent causes for this serious adverse event may be the partial agonistic activity of aripiprazole at D2 receptors as well as an up-regulation of dopamine receptors during prior treatment with risperidone. Both aspects may have contributed to the severe psychotic exacerbation. Clinicians should be aware of this possible, serious adverse event while switching to aripiprazole or prescribing aripiprazole with other antipsychotics.

Imaging analysis of clock neurons reveals light buffers the wake-promoting effect of dopamine

How animals maintain proper amounts of sleep yet still be flexible to changes in the environmental conditions remains unknown. Here we showed that environmental light suppresses the wake-promoting effects of dopamine in fly brains. A subset of clock neurons, the 10 large lateral-ventral neurons (l-LNvs), are wake-promoting and respond to dopamine, octopamine as well as light. Behavioral and imaging analyses suggested that dopamine is a stronger arousal signal than octopamine. Surprisingly, light exposure not only suppressed the l-LNv responses but also synchronized responses of neighboring l-LNvs. This regulation occured by distinct mechanisms: light-mediated suppression of octopamine responses is regulated by the circadian clock, whereas light regulation of dopamine responses occurs by upregulation of inhibitory dopamine receptors. Plasticity therefore alters the relative importance of diverse cues based on the environmental mix of stimuli. The regulatory mechanisms described here may contribute to the control of sleep stability while still allowing behavioral flexibility.

A53T-Alpha-Synuclein Overexpression Impairs Dopamine Signaling and Striatal Synaptic Plasticity in Old Mice

BackgroundParkinson's disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression or the A53T missense mutation of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons.Methodology/Principal FindingsHere, we used two mouse lines overexpressing human A53T-SNCA and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. To characterize the progression, we employed young adult as well as old mice. Analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also made in SNCA-deficient (knockout, KO) mice. However, the elevated DA levels in the striatum of old A53T-SNCA overexpressing mice may not be transmitted appropriately, in view of three observations. First, a transcriptional downregulation of the extraneural DA degradation enzyme catechol-ortho-methytransferase (COMT) was found. Second, an upregulation of DA receptors was detected by immunoblots and autoradiography. Third, extensive transcriptome studies via microarrays and quantitative real-time RT-PCR (qPCR) of altered transcript levels of the DA-inducible genes Atf2, Cb1, Freq, Homer1 and Pde7b indicated a progressive and genotype-dependent reduction in the postsynaptic DA response. As a functional consequence, long term depression (LTD) was absent in corticostriatal slices from old transgenic mice.Conclusions/SignificanceTaken together, the dysfunctional neurotransmission and impaired synaptic plasticity seen in the A53T-SNCA overexpressing mice reflect early changes within the basal ganglia prior to frank neurodegeneration. As a model of preclinical stages of PD, such insights may help to develop neuroprotective therapeutic approaches.

115 Upregulation of Dopamine Receptor 2 Expression in Gastric Neurons and Interstitial Cell of Cajal in Diabetic Rats Contribute to Tachygastria Evoked by Hyperglycemia

115 Upregulation of Dopamine Receptor 2 Expression in Gastric Neurons and Interstitial Cell of Cajal in Diabetic Rats Contribute to Tachygastria Evoked by Hyperglycemia

Amisulpride-Induced Tardive Dyskinesia and Possible Association of Dyskinesia with Hypothyroidism

Back to table of contents Previous article Next article LETTERFull AccessAmisulpride-Induced Tardive Dyskinesia and Possible Association of Dyskinesia with HypothyroidismDattatrya Namdeorao Mendhekar D.P.M., M.D.,Chittaranjan Andrade M.D.,Dattatrya Namdeorao Mendhekar D.P.M., M.D.Search for more papers by this author,Chittaranjan Andrade M.D.Search for more papers by this author,Published Online:1 Jan 2009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Amisulpride, a second generation antipsychotic, is a substituted benzamide derivative that preferentially binds to dopamine D2/D3 receptors in limbic rather than striatal structures. The literature is sparse, with only two case reports of tardive dyskinesia associated with amisulpride. 1 , 2 We report a similar case and also highlight possible interaction of thyroid hormone and dopamine receptors in the emergence of tardive dyskinesia. Case ReportMr. S, a 24-year-old single male engineer, was diagnosed with schizophrenia 3 years ago according to ICD-10 criteria. He had good premorbid functioning, with no significant family or personal history of psychiatric and neurological illness. He exhibited predominantly negative symptoms as well as periods of paranoid symptoms. Mr. S consulted a psychiatrist for the first time 6 months after the onset of his illness. He was stabilized on olanzapine, up to 20 mg/day for 2 years, and was later switched to aripiprazole due to significant weight gain. After 4 months of optimal dose of aripiprazole (30 mg/day), however, there was no further improvement in his positive or negative symptomatology. Subsequently, Mr. S was started on amisulpride, 50 mg/day, titrated up to 400 mg/day over 10 weeks. After 15 weeks of amisulpride therapy, he developed dyskinetic finger movements in both hands, predominately involving his right thumb. Although he was aware of the movements, he had no difficulty in carrying out his daily routine activities. When asked to control it, he could suppress these movements only for a few seconds. There were no abnormal movements noticed in other parts of the body. His Abnormal Involuntary Movements Scale (AIMS) score was 9. In view of persistent weight gain and marked negative symptoms, a metabolic panel was obtained, including thyroid function tests. These showed elevated thyroid-stimulating hormone (8.3 mU /liter; normal range =0.4–5.0 mU/liter). Amisulpride was discontinued and it was replaced by clozapine, which was gradually titrated to 75 mg/day along with levothyroxine, 25 mg/day. All dyskinetic movements subsided after 6 weeks of this combined therapy. Subsequent thyroid profile also became normal, and he was continued on clozapine and levothyroxine.Discussion The appearance of dyskinesia while on amisulpride and the prompt resolution of dyskinesia after discontinuing amisulpride strongly suggests a case of amisulpride-induced tardive dyskinesia. There has been no information associating tardive dyskinesia and hypothyroidism in patients receiving amisulpride. Hypothyroidism has been associated with subsensitivity of strial dopamine receptors and thyroid hormones potentiate dopaminergic behavior. 3 A study carried out in rats treated with haloperidol revealed significant upregulation of dopamine receptors in hypothyroid rats compared with hyperthyroid rats. 4 Furthermore those psychotropic drugs which generally do not show the tendency to develop tardive dyskinesia such as clozapine, supiride, and nomifensine also exhibited tardive dyskinesia and associated hypothyroidism. 5 – 7 It is possible that thyroid dysfunction interacts with or has some influence on the dopaminergic system as far as emergence of tardive dyskinesia is concerned. This case raises the possibility of underreporting the association of tardive dyskinesia and hypothyroidism and demonstrates a need for further research to answer the queries about the risk factors between hypothyroidism and the emergence of tardive dyskinesia. Neuropsychiatry and Headache Clinic, Pratap Nagar Metro, Delhi, IndiaDepartment of Psychopharmacology, National Institute of Mental Health and Neurosciences, Bengalooru, IndiaReferences1 . Masdrakis VG, Papadimitriou GN, Papageorgiou C, et al: Development of tardive dyskinesia in a patient taking amisulpride. Prog Neuropsychopharmacol Biol Psychiatry 2007; 31:586–587Google Scholar2 . Fountoulakis KN, Panagiotidis P, Siamouli M, et al: Amisulpride-induced tardive dyskinesia. Schizophr Res 2006; 88:232–234Google Scholar3 . Goetz CG, Wriner WJ, Klawans HL: Treatment of chorea, in Disorders of Movements. Edited by Bareau A. Lancaster, England, MTP Press, 1989, pp 29–43Google Scholar4 . Crocker AD, Overstreet DH: Modification of the behavioral effects of haloperidol and dopamine receptor regulation by altered thyroid status. Psychopharmol 1984; 82:102–106Google Scholar5 . Mendhekar DN, Duggal HS: Clozapine induced tardive dyskinesia and hypothyroidism. J Neuropsychiatry Clin Neurosci 2006; 18:2Google Scholar6 . Sandyk R: Tardive dyskinesia induced by sulpride in a patient with hypothyroidism. Clin Neuropharmacol 1986; 9:100–101Google Scholar7 . Sandyk R, Gilman MA: Nomifensive exacerbates orofacial dyskinesia in hypothyroidism. Neurology 1985; 35:282Google Scholar FiguresReferencesCited byDetailsCited byThyroid dysfunction in Down's syndrome secondary to risperidone8 November 2022 | Progress in Neurology and Psychiatry, Vol. 26, No. 4Asian Journal of Psychiatry, Vol. 41Clinical Psychopharmacology and Neuroscience, Vol. 16, No. 2 Volume 21Issue 1 Winter, 2009Pages 104-105 Metrics PDF download History Published online 1 January 2009 Published in print 1 January 2009

Agitation Associated with Aripiprazole Initiation

Aripiprazole is a novel antipsychotic with a mechanism of action different from those of traditional first- and second-generation antipsychotics. We describe three patients with long histories of treatment for schizophrenia or schizoaffective disorder in whom conversion to aripiprazole was being attempted. After they started aripiprazole, their psychosis, agitation, anxiety, or aggression worsened. Although the cause of the increased agitation was unclear, it may have been related to long-term use of dopamine-blocking antipsychotics and resultant upregulation of postsynaptic dopamine receptors. The mechanism of partial dopamine agonism observed with aripiprazole may increase dopaminergic activity and worsen positive dopamine-associated symptoms, such as paranoia, agitation, and aggression. The treatment of schizophrenia is often a clinical challenge, particularly when patients have a long history of noncompliance and poor response. Clinicians face difficult decisions in finding an effective and well-tolerated regimen. These cases magnify some of the challenges and provide insight into the clinical implications of converting to therapies with different pharmacodynamic effects.

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.