Regional alterations in neuronal activity in dystonic hamster brain determined by quantitative cytochrome oxidase histochemistry.

The neural mechanisms underlying idiopathic dystonia are currently unknown. Genetic animal models, such as the dt(sz) hamster, a model of idiopathic paroxysmal dystonia, may be helpful to providing insights into the pathophysiology of this common movement disorder. Recent metabolic mapping studies in the hamster model, using 2-deoxyglucose autoradiography, demonstrated altered 2-deoxyglucose uptake in motor areas such as the striatum, ventral thalamic nuclei, red nucleus, and deep cerebellar nuclei, during dystonic attacks. Whereas the 2-deoxyglucose method is thought to reflect mainly acute alterations of synaptic activity, determination of cytochrome oxidase activity has been suggested as a method of choice to examine sustained baseline changes in neuronal activity. Therefore, in the present study quantitative cytochrome oxidase histochemistry was used to identify chronic regional alterations in the absence of dystonic attacks in mutant hamsters. For comparison with recent 2-deoxyglucose studies, cytochrome oxidase activity was also determined during a dystonic attack, which was induced by mild stress. Cytochrome oxidase was determined in 109 brain regions of dystonic hamsters and non-dystonic, age-matched control hamsters. In the absence of a dystonic attack, a tendency to decreased cytochrome oxidase activity was found in most brain regions, possibly due to retarded brain development in mutant hamsters. Significant decreases in cytochrome oxidase activity were found in motor areas and limbic structures, such as hippocampus, piriform cortex, fundus striatum, globus pallidus, substantia nigra pars reticulata, mediodorsal nucleus of the thalamus, ventral pallidum, and interpositus nucleus of the cerebellum. After induction of a dystonic attack, the trend of decreased cytochrome oxidase activity disappeared, except in globus pallidus and interpositus nucleus of the cerebellum. Although the significant alterations in cytochrome oxidase activity in the absence of a dystonic attack were moderate, the data are in line with previous findings in the mutant hamsters, indicating that dysfunctions of the basal ganglia and their output nuclei are involved in the dystonic condition. Altered neural activity in limbic structures, found in the absence of dystonic attacks in mutant hamsters, may contribute to the stress-susceptibility of the animals.

Dopamine D2-like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline.

Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia.

Alterations in N-methyl-D-aspartate receptor binding in dystonic hamster brains.

The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Previous pharmacological studies have shown that competitive and non-competitive N-methyl-D-aspartate (NMDA) receptor antagonists exert potent antidystonic activity in this model, indicating that abnormal NMDA receptor function may be involved in the pathophysiology of this movement disorder. Autoradiographic analysis of NMDA receptor density in 67 brain regions, using the ligand [3H] N-(1-[2-thienyl]cyclohexyl)3,4-piperidine, which binds to the phencyclidine (PCP) site in the ion channel of the NMDA receptor channel complex, revealed that NMDA receptor binding is not substantially altered in dystonic hamster brains compared to age-matched controls. Nevertheless, there was a tendency towards enhanced binding during a dystonic attack in several regions, including a 25% increase in the ventrolateral thalamic nucleus (P < 0.05), which may be associated with altered basal ganglia output. While the data do not indicate widespread abnormalities in the PCP site of the NMDA complex, they do not exclude the possibility of more pronounced changes at other regulatory binding sites of the NMDA complex or other types of glutamate receptors in dystonia.

Quantitative autoradiography reveals regionally selective changes in dopamine D1 and D2 receptor binding in the genetically dystonic hamster.

Dystonia has been proposed to be caused by abnormal input from thalamus to premotor cortex due to altered activity of the striatum projecting by way of the globus pallidus and substantia nigra pars reticulata to the thalamus. However, in the case of idiopathic dystonia, i.e. the most common form of dystonia in humans, there is only limited evidence to support such a neuroanatomic concept. In view of the problems of studying the pathophysiology of idiopathic dystonia in patients, genetically determined animal models of idiopathic dystonia may be used as a practical means of studying brain dysfunctions involved in this movement disorder. The genetically dystonic hamster is an animal model of idiopathic dystonia that displays sustained abnormal movements and postures either spontaneously or in response to mild environmental stimuli. Autoradiographic analysis of dopamine D1 receptor density, using the ligand [3H]SCH 23390, revealed significant decreases of D1 binding in several parts of the striatum and substantia nigra pars reticulata of dystonic hamsters. Binding of the D2 ligand [3H]YM-09151-2 was decreased in the dorsomedial caudate-putamen, but increased in nucleus accumbens. In most other sites studied, no significant changes were found in either [3H]SCH 23390 or [3H]YM-09151-2 binding. By studying groups of dystonic hamsters in the absence and presence of dystonic attacks, it was shown that most changes in D1 and D2 binding were not secondary to abnormal movement but rather due to the dystonic condition of the animals. The study provides evidence of altered dopamine receptor binding in dystonia and confirms the concept that basal ganglia dysfunction may be a primary component of dystonia.

Synthesis and autoradiographic localization of the dopamine D-1 agonists [11C]SKF 75670 and [11C]SKF 82957 as potential PET radioligands.

The high affinity benzazepine D1 agonists SKF 75670 and SKF 82957 were labeled with 11C by N-[11C]methylation of SKF 38393 and SKF 81297, respectively, using [11C]methyl iodide in the presence of N-ethyldiisopropylamine. Both radiotracers were purified using a semi-preparative cation exchange HPLC column. Radiochemical yields of 20-75% were obtained (from [11C]methyl iodide, decay-corrected) with a synthesis time of 30-35 min from EOB. The specific activities were 700-2500 Ci/mmol (25.9-92.5 GBq/mumol) at EOS, and the radiochemical purities were > 99%. Autoradiographic studies showed selective binding for both tracers in rat brain regions rich in D1 receptors such as the caudate-putamen, nucleus accumbens, olfactory tubercles and substantia nigra. [11C]SKF 75670 and [11C]SKF 82957 are thus potential PET radioligands for the functional high-affinity state of D1 receptors.