We investigated the involvement of striatal dopamine release in electrographic and motor seizure activity evoked by kainic acid in the guinea pig. The involvement of the dopamine receptor subtypes was studied by systemic administration of the dopamine D(1) receptor antagonist, R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390; 0.5 mg kg(-1)), or the dopamine D(2) antagonist, (5-aminosulphonyl)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-methoxybenzamide (sulpiride, 30 mg kg(-1)). Microdialysis and high performance liquid chromatography were used to monitor changes in extracellular levels of striatal dopamine and its metabolites, glutamate, aspartate and gamma-amino-butyric acid (GABA). These data were correlated with changes in the striatal and cortical electroencephalographs and clinical signs. We found that, although neither dopamine receptor antagonist inhibited behavioural seizure activity, blockade of the dopamine D(1)-like receptor with SCH 23390 significantly reduced both the 'power' of the electrical seizure activity and the associated change in extracellular striatal concentration of glutamate, whilst increasing the extracellular striatal concentration of GABA. In contrast, blockade of the dopamine D(2)-like receptor with sulpiride significantly increased the extracellular, striatal content of glutamate and the dopamine metabolites. These results confirm previous evidence in other models of chemically-evoked seizures that antagonism of the dopamine D(1) receptor tends to reduce motor and electrographic seizure activity as well as excitatory amino-acid transmitter activity, while antagonism of the dopamine D(2) receptor has relatively less apparent effect.
[Show abstract][Hide abstract] ABSTRACT: SCH 23390, the halobenzazepine (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H–3-benzazepine, is a highly potent and selective dopamine D1-like receptor antagonist with a Ki of 0.2 and 0.3 nM for the D1 and D5 dopamine receptor subtypes, respectively. In vitro, it also binds with high affinity to the 5-HT2 and 5-HT1C serotonin receptor subtypes. However, the doses required to induce a similar response in vivo are greater than 10-fold higher than those required to induce a D1-mediated response.
Previous in vivo pharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman. These studies provide evidence of the potential importance of D1-like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures. The inference from a majority of studies is that the activation of dopamine D1 receptors facilitates seizure activity, whereas activation of D2 receptors may inhibit the development of seizures. SCH 23390 has also been used in studies of other neurological disorders in which the dopamine system has been implicated, such as psychosis and Parkinson's disease. Apart from the study of neurological disorders, SCH 23390 has been extensively used as a tool in the topographical determination of brain D1 receptors in rodents, nonhuman primates, and humans.
In summary, SCH 23390 has been a major tool in gaining a better understanding of the role of the dopamine system, more specifically the D1 receptor, in neurological function and dysfunction.
CNS Drug Reviews 02/2001; 7(4):399-414. DOI:10.1111/j.1527-3458.2001.tb00207.x · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1. Microdialysis is an established technique for studying physiological, pharmacological and pathological changes of a wide range of low molecular weight substances in the brain extracellular fluid. Many studies have proven its sensitivity in sampling the extracellular space in discrete brain locations, such as the striatum, and monitoring the action of exogenous substances.
2. The two main areas of application of microdialysis are the recovery of endogenous substances, primarily the neurotransmitters, and the infusion of drugs through the microdialysis cannula (retrodialysis).
3. Microdialysis in awake animals is the tool of choice for studying the relationship between changes in behaviour and neurotransmitters in certain brain areas. In addition, the concomitant recording of the electroencephalogram at the site of microdialysis has been shown to be extremely useful in determining the role of certain neurotransmitters in paroxysmal activity.
4. Clinical applications of microdialysis have included monitoring of ischaemic injury, subarachnoid haemorrhage, trauma and epilepsy. With the recent availability of standardized equipment, the use of microdialysis in the neurological clinic is likely to become more common.
Clinical and Experimental Pharmacology and Physiology 01/2003; 30(1-2):16-24. DOI:10.1046/j.1440-1681.2003.03789.x · 2.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Kainic acid induces seizures and neurotoxicity in rats, produces changes in brain serotonin (5-HT), dopamine and noradrenaline metabolites among other changes in neurotransmitters. In this work, we investigated the changes in 5-HT turnover in brain regions from 84 rats intraperitoneally injected with kainic acid and a specific behavioural change, the body and head shakes, exerted by this neurotoxin in the presence of 5-HT receptor antagonists. Kainic acid produced an increase in 5-hydroxyindoleacetic acid levels in frontal cortex (212%; 180%), striatum (177%; 116%), amygdala (202%; 337%) and hippocampus (43%; 70 %) at 2 and 24 hr as compared with controls, respectively. Serotonin turnover was increased in amygdala (157%) and frontal cortex (169%) at 2 hr; whereas 24 hr after kainic acid administration, increases were observed in amygdala (207%), and frontal cortex (178%). Kainic acid also produced an increase in the frequency of head and body shakes when administered alone or together with pargyline, a monoamine oxidase inhibitor; whereas the administration of 5-HT receptor antagonists such as ketanserin and methiothepin, decreased this behaviour 54% and 50% as compared with kainic acid alone, respectively. These results suggest an active participation of 5-HT neurotransmission on the excitotoxic action of kainic acid in the brain.
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