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.

<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)