Interruption of the ascending dopamine neurons of the nigrostriatal pathway, by 6-hydroxydopamine (6-OHDA) lesion in rats, produced a significant loss of the dopamine transport complexes labeled with ...the phencyclidine derivative 3HBTCP. This loss of dopamine innervation in the striatum was present at least 12 to 14 months after lesioning and was functionally manifested by ipsilateral rotation of the animals in response to amphetamine. In these same animals, in comparison to controls, there was a significant increase in the number (Bmax) of 3HSCH 23390-labeled D-1 receptors in the striatum (36.7%) and the substantia nigra (35.1%) and a 54.4% increase in the number (Bmax) of 3Hsulpiride-labeled striatal D-2 receptors without an apparent change in affinity (Kd). Ten to twelve months after the transplantation of homologous fetal substantia nigra into the denervated striatum, there was a significant decrease in amphetamine-induced turning behavior. In these animals, there was an ingrowth of dopamine nerve terminals in the striatum as demonstrated by a return of 3HBTCP binding. Accompanying this reinnervation was the normalization of D-1 and D-2 receptors to control values in the striatum as well as the return of D-1 receptors to prelesion densities in the substantia nigra. In a subgroup of transplanted rats, amphetamine continued to induce ipsilateral turning. In these animals both D-1 and D-2 receptors remained supersensitive. These results support the hypothesis that the functional recovery of transplanted animals is due, in part, to reinnervation of the striatum. In addition, long-term alterations in receptor density may be related to the behavioral deficits that are associated with the 6-OHDA-lesioned rat. Furthermore, dopamine receptor plasticity may play a role in the functional recovery of substantia nigra transplanted animals and graft viability seems to be a prerequisite for behavioral recovery as well as receptor normalization.
In the dementia associated with acquired immunodeficiency syndrome (AIDS), indirect pathomechanisms are important mediators of progressive neuronal injury and variable candidate molecules of ...potential pathogenetic importance have been identified.
In an attempt to characterize additional mediators of human immunodeficiency virus type 1 (HIV-1)-induced neurotoxicity in vivo we have adapted the mRNA differential display technique to monitor the gene expression pattern in postmortem cortical tissue from AIDS patients with (n = 7) and without (n = 8) cognitive impairment as well as from HIV-1 seronegative controls (n = 4).
Out of 29 differentially expressed cDNAs, two cDNA clones had confirmed variation of transcriptional regulation as assessed by reverse Northern analysis and gene-specific reverse transcription polymerase chain reaction (RT-PCR) and were up-regulated in the cortex of patients with AIDS dementia. Nucleotide sequence analysis of the two cDNAs identified known genes not previously associated with the pathogenesis of AIDS dementia, including the neurotrophin receptor tyrosine kinase receptor B (TrkB) and the potassium channel human open rectifyer K+ channel (ORK) homologous open reading frame (HOHO1).
The altered expression of these transcripts may contribute to AIDS dementia through the enhancement of microglial activation and immunologic nitric oxide synthase (iNOS) activity by abnormal neurotrophic regulation and interference with membrane excitability through disturbance of local ion homeostasis.
The aziridinium ion of ethylcholine (AF64A) is a neurotoxin that has demonstrated selectivity for cholinergic neurons. Unilateral stereotaxic injection of AF64A into the caudate-putamen of rats, ...resulted in a decrease in dopamine D-2 receptors as evidenced by a decrease in 3H-sulpiride binding. Dopamine D-1 receptors, labeled with 3H-SCH 23390, were unchanged. The efficacy of the lesion was demonstrated by the reduction of Na+-dependent high affinity choline uptake sites labeled with 3H-hemicholinium-3. These data indicate that a population of D-2 receptors are postsynaptic on cholinergic interneurons within the striatum of rat brain.
Ischemic damage to the prefrontal, motor, and somatosensory cortex induces alterations in the receptor systems of the caudate putamen and some subcortical brain regions. These alterations may ...represent an attempt of various neuronal systems to compensate for the reduction in innervation caused by the cortical infarction. Assessment of the receptor changes induced by cortical infarction define neuropharmacologic correlates of cortical damage, indicate possible neurotransmitters associated with neuroanatomically defined subcortical pathways, and suggest possible pharmacologic interventions to counteract the consequences of stroke. Bilateral cortical infarction, induced by ligation of both middle cerebral arteries and temporary occlusion of both common carotid arteries, was investigated in the rat. The infarction resulted in dramatic alterations in subcortical receptor populations as determined by autoradiography. Sodium-dependent, high-affinity, choline-uptake (SDHACU) sites and D1-dopamine receptors in the caudate putamen were unaffected by the infarction, whereas muscarinic and glutamate receptors were increased and D2 receptors were decreased in this structure. A reduction in SDHACU sites caused by the lesion was found in regions including the medial septum, vertical nucleus of the diagonal band, thalamus, nucleus basalis magnocellularis, and basolateral amygdala. M1 receptors were increased in the basolateral and central amygdaloid nuclei whereas non-M1 receptors were increased in the basolateral and central amygdaloid nuclei, but were diminished in the medial septum, vertical nucleus of the diagonal band, thalamus, and nucleus basalis magnocellularis. No significant alterations in muscarinic binding were observed in the various laminae of the hippocampus and dentate gyrus.
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