Neuroscience
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The existence of at least three opioid receptor types, referred to as mu, kappa, and delta, is well established. Complementary DNAs corresponding to the pharmacologically defined mu, kappa, and delta opioid receptors have been isolated in various species including man. The expression patterns of opioid receptor transcripts in human brain has not been established with a cellular resolution, in part because of the low apparent abundance of opioid receptor messenger RNAs in human brain. ⋯ A comparison of the distribution patterns of opioid receptor messenger RNAs in the human brain and that reported for the rat suggests a homologous expression pattern in many regions. However, in the human brain, kappa opioid receptor messenger RNA expression was more widely distributed than in rodents. The differential and region specific expression of opioid receptors may help to identify targets for receptor specific compounds in neuronal circuits involved in a variety of physiological functions including pain perception, neuroendocrine regulation, motor control and reward.
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Stimulation of murine primary mixed cortical neuron/glia cultures with lipopolysaccharide, an endotoxin, was used as a model for inflammatory disorders of the central nervous system. Lipopolysaccharide (20 microg/ml) increased the secretion of lactate dehydrogenase, a marker for cell injury, and nitric oxide into the culture medium. The lipopolysaccharide-induced release of lactate dehydrogenase into the culture medium was reduced by pituitary adenylate cyclase-activating polypeptide (PACAP) at 10(-14)-10(-12) M. ⋯ PACAP6-38 did not effect the reduction of the lipopolysaccharide-induced release of lactate dehydrogenase into the culture medium by 10(-12) M vasoactive intestinal polypeptide. These results indicate that stimulation of type I PACAP receptors by femtomolar concentrations of PACAP can prevent neuron death in a model for inflammatory disorders of the CNS. These results suggest that PACAP is also an extraordinarily potent inhibitor of some microglial functions.
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The prefrontal cortex receives dopaminergic inputs from the ventral tegmental area and excitatory inputs from the hippocampus. Both afferent pathways target in close proximity dendritic spines of pyramidal cells in layer V-VI of the prefrontal cortex. In view of the prominent role of dopamine in cognitive functions we examined the effects of ventral tegmental area stimulation on the induction of long-term potentiation in the hippocampal-prefrontal cortex pathway of anesthetized rats. ⋯ However, a recovery to normal long-term potentiation was observed 1 h after tetanic stimulation. In contrast to the effects on long-term potentiation, ventral tegmental area stimulation, when applied at low or high frequency, decreases the amplitude of the hippocampal-prefrontal cortex postsynaptic synaptic response. The present study demonstrates the importance of the integrity of the mesocortical dopaminergic system for long-term potentiation to occur in the hippocampal-prefrontal cortex pathway and suggests a frequency-dependent effect of dopamine on hippocampal-prefrontal cortex transmission.
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In primary cultures of rat cerebellar granule cells, transcripts of voltage-gated Ca2+ channels have been amplified by reverse transcription-polymerase chain reaction and identified by sequencing of subcloned polymerase chain reaction products. In these neurons cultured for six to eight days in vitro, fragments of the three major transcripts alpha1C, alpha1A, and alpha1E are detected using degenerated oligonucleotide primer pairs under highly stringent conditions. Whole-cell Ca2+ current recordings from six to eight days in vitro granule cells show that most of the current is due to L-type (25%), P-type (33%) and R-type (30%) Ca2+ channels. ⋯ These data show that: (i) alpha1E is expressed in rat brain as a structural homologue to the mouse and human alpha1E; and (ii) rat cerebellar granule cells in primary culture express a set of alpha1E isoforms, containing two different sized carboxy termini. Since no new transcripts of high-voltage-activated Ca2+ channels genes are identified using degenerate oligonucleotide primer pairs, the two isoforms differentiated by the 129 base pair insertion might correspond to the two R-type channels, G2 and G3, characterized in these neurons. Functional studies including recombinant cells with the different proposed isoforms should provide more evidence for this conclusion.
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Wobbler mice display forelimb weakness, altered paw positioning, reduced running speed, muscle atrophy and motor neuron loss; co-treatment with glycosaminoglycans and insulin-like growth factor-I counteracts the progression of the disease. Reportedly, treatment with glycosaminoglycans or insulin-like growth factor-I slows the early stages of progressive forelimb dysfunction in wobbler mice. Our aim was to study whether the combination of these two drugs would result in greater neuroprotective effects. ⋯ Moreover, the mouse phenotype itself was strikingly improved. The effect of the combination treatment was significantly higher than that of the single drugs, even at a dosage as high as 1 mg/kg insulin-like growth factor-I. The ability of the insulin-like growth factor-I/glycosaminoglycans pharmacological cocktail to arrest the progression of motor neuron disease in wobbler mice and the safety of the low dose of insulin-like growth factor-I used hold promise that this combination might represent a novel approach for the treatment of motor neuron disease and peripheral neuropathies.