Tardive dyskinesia (TD), a movement disorder produced by long-term treatment with a classical antipsychotic drug, is generally considered to be a disorder of dopamine (DA) systems, since classical antipsychotics are potent DA D2 receptor blockers. Also, acute DA D1 agonist treatment of rats is known to produce vacuous chewing movements (VCMs), a behavioral feature resembling the oral dyskinesia that is so prominent in most instances of TD. In this paper we outline a series of studies in a new animal model of TD in which DA D1 receptor supersensitivity was produced by neonatal 6-hydroxydopamine (6-OHDA)-induced destruction of nigrostriatal DA fibers. In rats so-lesioned 5-HT receptor supersensitivity is additionally produced, and in fact 5-HT receptor antagonists attenuate enhanced DA D16-lesioned rats treated with haloperidol for one year, there is a 2-fold increase in numbers of VCMs (versus intact rats treated with haloperidol); and this high frequency of VCMs persists for more than 6 months after discontinuing haloperidol treatment. During this stage, 5-HT2 receptor antagonists, but not DA D1 receptor antagonists, attenuate the incidence of VCMs. This series of findings implicates the 5-HT neuronal phenotype in TD, and promotes 5-HT2 receptor antagonists, more specifically 5-HT2C receptor antagonists, as a rational treatment approach for TD in humans.

Tardive dyskinesia (TD), first appearing in humans after introduction of the phenothiazine class of antipsychotics in the 1950s, is now recognized as an abnormality resulting predominately by long-term block of dopamine (DA) D2 receptors (R). TD is thus reproduced in primates and rodents by chronic administration of D2-R antagonists. Through a series of studies predominately since the 1980s, it has been shown in rodent modeling of TD that when haloperidol or other D2-R antagonist is added to drinking water, rats develop spontaneous oral dyskinesias, vacuous chewing movements (VCMs), after ~3 months, and this TD is associated with an increase in the number of striatal D2-R. This TD persists for the duration of haloperidol administration and another ~2 months after haloperidol withdrawal. By neonatally lesioning dopaminergic nerves in brain in neonatal rats with 6-hydroxydopamine (6-OHDA), it has been found that TD develops sooner, at ~2 months, and also is accompanied by a much higher number of VCMs in these haloperidol-treated lesioned rats, and the TD persists lifelong after haloperidol withdrawal, but is not associated with an increased D2-R number in the haloperidol-withdrawn phase. TD apparently is related in part to supersensitization of both D1-R and serotoninergic 5-HT2-R, which is also a typical outcome of neonatal 6-OHDA (n6-OHDA) lesioning. Testing during the haloperidol-withdrawn phase in n6-OHDA rats displaying TD reveals that receptor agonists and antagonists of a host of neuronal phenotypic classes have virtually no effect on spontaneous VCM number, except for 5-HT2-R antagonists which acutely abate the incidence of VCMs in part. Extrapolating to human TD, it appears that (1)5-HT2-R supersensitization is the crucial alteration accounting for persistence of TD, (2) dopaminergic-perhaps age-related partial denervation-is a risk factor for the development of TD, and (3) 5-HT2-R antagonists have the therapeutic potential to alleviate TD, particularly if/when an antipsychotic D2-R blocker is withdrawn.

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D1/D5 receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D1 receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in l-dihydroxyphenylalanine (l-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D1 agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H3 receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H3 receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D1 agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D1/D5 receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.

Tardive dyskinesia (TD), marked by abnormal involuntary movements and frequently expressed as perioral activity, represents an adverse outcome of prolonged antipsychotic therapy, occurring in approximately 5 % of patients per treatment year. Although neuronal mechanisms underlying TD are largely unknown, more recent experimental studies in animal models of TD are providing insight into the neuronal mechanisms associated with TD and implicating newer treatment approaches. It is now evident that a predominance in the ratio of dopamine (DA) D1:D2 receptor (R) activation accounts for induction of perioral movements in rodent models of TD, in nonhuman primate models of TD, and in humans with TD. Experimentally, TD is produced in animal models of TD, in a manner analogous to that by which TD is produced in humans - by continuous and prolonged administration of a DA D2R antagonist (i.e., an antipsychotic drug). More recently, in a rodent model of TD, it has been shown that a lesion of dopaminergic - mainly nigroneostriatal - neurons reduces the time latency for occurrence of TD, also increases the severity of perioral activity, and results in permanence of TD after complete removal of D2R antagonist treatment. The induction of perioral activity is related to DAR supersensitivity but unrelated to numbers of D2R and D2R in the neostriatum, a brain region associated with perioral activity. More apropos, serotoninergic systems are now recognized as having a greater role in effecting perioral activity, and it appears that 5-HT2C receptor antagonists are most effective in abating perioral activity in a rodent model of TD. These processes and mechanisms, topics addressed in this chapter, highlight a newer understanding of mechanisms underlying TD and provide insight into new approaches towards treatment of TD in humans.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Considering the hypothesis that GABA and oxidative stress are involved in the development of oral movements associated with important neuropathologies, the present study investigated the possible ability of V. officinalis in the prevention of vacuous chewing movements (VCMs) induced by reserpine in rats. Adult male rats were treated with reserpine (1 mg/kg, s.c.) and/or with V. officinalis (in the drinking water). VCMs, locomotor activity and oxidative stress measurements were evaluated. The neuroprotective effect of V. officinalis against iron-induced cell toxicity was investigated in brain cortical slices. Furthermore, we carried out the identification of valeric acid and gallic acid by HPLC in the V. officinalis tincture. Our findings demonstrate that reserpine caused a marked increase on VCMs and the co-treatment with V. officinalis was able to reduce the intensity of VCM. Reserpine did not induce oxidative stress in cerebral structures (cortex, hippocampus, striatum and substantia nigra). However, a significant positive correlation between DCF-oxidation (an estimation of oxidative stress) in the cortex and VCMs (p<0.05) was observed. Moreover, a tendency for a negative correlation between Na+K+- ATPase activity in substantia nigra and the number of VCMs was observed (p= 0.06). In vitro, V. officinalis protected brain cortical slices viability against Fe(II)-induced neurotoxicity. In conclusion, V. officinalis had in vitro and in vivo neuroprotective effects in rats, i.e., reduced Fe(II) neurotoxicity and reserpine-induced VCMs, probably via modulation of oxidative stress in specific brain nucleus and its GABA-mimetic action. However, the mechanisms involved in this protective activity needs to further investigated to better understand the action of V. officinalis. / Considerando as hipóteses do papel da neurotransmissão gabaérgica e do estresse oxidativo no desenvolvimento de movimentos orais associados a neuropatologias importantes, o presente estudo investigou a possível habilidade da tintura de V. officinalis na prevenção dos movimentos de mascar no vazio (MMV) induzidos por reserpina em ratos. Os animais foram tratados com reserpina (1 mg/Kg, s.c.) e/ou com V. officinalis (na água de beber). MMV, atividade locomotora e medidas de estresse oxidativo foram avaliadas. O efeito neuroprotetor da V. officinalis contra a toxicidade celular induzida por ferro foi investigada em fatias de córtex cerebral. Além disso, fez-se a identificação do ácido valérico e do ácido gálico por HPLC na tintura de V. officinalis. Os resultados demonstram que a reserpina causou um aumento nos MMV quando comparado com o seu veículo e o co-tratamento com V. officinalis foi capaz de reduzir a intensidade dos MMV. A reserpina não alterou de forma significativa alguns parâmetros de estresse oxidativo analisados nas estruturas do cérebro (córtex, hipocampo, estriado e substantia nigra). Porém, uma correlação positiva entre os níveis de oxidação da DCF (uma estimativa do estresse oxidativo) no cortex e o número de MMV (p<0.05) foi observada. Além disso, foi observada uma tendência a haver uma correlação negativa entre a atividade da Na+/K+- ATPase na substantia nigra e o número de MMV (p= 0.055). In vitro, V. officinalis protegeu as fatias de córtex cerebral contra a neurotoxicidade induzida por ferro. Desta forma, pode-se concluir que a V. officinalis apresentou efeitos neuroprotetores em ratos tanto in vitro quanto in vivo, ou seja, reduziu a neurotoxicidade induzida por ferro e os MMV induzidos por reserpina, provavelmente via modulação do estresse oxidativo em núcleos específicos do cérebro e sua ação gabamimética. Porém, os mecanismos envolvidos nesta atividade protetora necessitam de mais investigações para melhor entender a ação da V. officinalis.

<p>Anti-psychotic drug (APD) administration can induce movement disorders including tardive dyskinesia (TD), characterized by abnormal movements of the oro-facial region and occasionally the trunk and limbs. The most widely accepted model of TD is the APD-induced vacuous chewing movement (VCM). While the mechanism of induction of TD remains unclear, there are two prevailing hypothesis: oxidative stress and dopamine supersensitivity. Currently available APDs antagonize dopamine D2 receptors (D2R) which can result in excessive dopamine accumulation and oxidation which was demonstrated to induce striatal neurodegeneration and increased oxidative stress. The dopamine supersensitivity hypothesis proposes that APD treatment causes an up-regulation of high affinity D2Rs to compensate for D2R antagonism. Curcumin, a derivative of turmeric, has been demonstrated to affect dopamine levels and hold significant anti-apoptotic potential. Thus, the goal of this study was to investigate curcumin’s potential to prevent haloperidol-induced behavioural and biochemical abnormalities. Four groups of rats were treated daily: control; haloperidol (at 2mg/kg intra-peritoneally); curcumin (at 200mg/kg orally in jello) and curcumin plus haloperidol. VCMs, catalepsy and locomotor activity were assessed. Animals were sacrificed and tissues removed for qPCR, immunoblot, receptor binding, and UPLC assessments. At day14 there was a significant increase in VCMs and catalepsy following haloperidol treatment, which was prevented by curcumin treatment. However, curcumin did not alter locomotor activity. Curcumin was demonstrated to increase the expression of the anti-apoptotic molecule BclXL and to increase striatal D2Rs. These investigations support the potential of curcumin in the prevention of TD and provide insight into the complex pathophysiology of this disorder.</p> / Doctor of Philosophy (Medical Science)