neuromedin-n and neurotensin-(8-13)

Repeated episodes of spontaneous large-scale neuronal bursting and calcium influx in the developing brain can potentially affect such fundamental processes as circuit formation and gene expression. Between postnatal day 3 (P3) and P7, the immature cortex can express one such form of activation whereby a wave of neuronal activity propagates through cortical networks, generating massive calcium influx. We previously showed that this activity could be triggered by brief stimulation of muscarinic receptors. Here, we show, by monitoring large cortical areas at low magnification, that although all areas respond to muscarinic agonists to some extent, only some areas are likely to generate the coordinated wave-like activation. The waves can be triggered repeatedly in frontal areas where, as we also show, waves occur spontaneously at a low frequency. In parietal and occipital areas, no such waves are seen. This selectivity may be related in part to differences in the cortical distribution of dopaminergic signaling, because we find that activation of dopamine receptors enables the response. Because M1 muscarinic receptors are typically coupled with G-alpha(q)/11, we investigated whether other receptors known to couple with this G-protein (group I glutamate metabotropic receptors, neurotensin type 1) could similarly elicit wave-like activation in responsive cortical areas. Our results suggest that multiple neurotransmitter systems can enable this form of activation in the frontal cortex. The findings suggest that a poorly recognized, developmentally regulated form of strong network activation found predominantly in the frontal cortex could potentially exert a profound influence on brain development.

Topics: Acetylcholine; Action Potentials; Animals; Benzazepines; Calcium Signaling; Dopamine; Frontal Lobe; Glutamic Acid; GTP-Binding Protein alpha Subunits, Gq-G11; Indans; Muscarine; Nerve Tissue Proteins; Neurotensin; Occipital Lobe; Parietal Lobe; Peptide Fragments; Phenanthridines; Picrotoxin; Rats; Rats, Long-Evans; Rats, Wistar; Receptor, Metabotropic Glutamate 5; Receptor, Muscarinic M1; Receptor, Muscarinic M3; Receptors, Dopamine D1; Receptors, Metabotropic Glutamate

The effects of neurotensin (NT) on neurons in the central amygdaloid nucleus (ACe) were investigated in rat brain slice preparations by adding the peptide to the perfusing medium. Of 115 ACe neurons, 69 cells (60%) showed excitatory responses and 10 cells (9%) showed inhibitory responses to application of NT. The excitatory response to NT was observed in a dose-dependent manner and the threshold concentration was approximately 3 x 10(-9) M. The excitatory effects of NT persisted under blockade of synaptic transmission. The NT fragment neurotensin 8-13 and the NT analogue neuromedin N showed effects similar to those of NT, whereas the NT fragment neurotensin 1-8 had no effect on ACe neurons. Of 43 neurons in the septal nucleus, 8 cells (19%) and 3 cells (7%) showed excitatory and inhibitory responses, respectively, to NT. The results suggest that NT exerts a potent excitatory effect on ACe neurons through a direct action on specific receptors, in which NT may play a role in amygdala-relevant functions.

Topics: Amygdala; Animals; Brain Mapping; In Vitro Techniques; Male; Neurons; Neurotensin; Peptide Fragments; Pyrrolidonecarboxylic Acid; Rats; Rats, Wistar

Quantitative receptor autoradiography was performed to test the effects of neurotensin (NT)/neuromedin N (NN) peptides on dopamine (DA) D2 receptors in rat neostriatal sections. Competition experiments showed that 10 nM of NT, 10 nM of NN, and 1 nM of the C-terminal NT-(8-13) fragment produced a 2-fold increase in the IC50 value and a 20% decrease in the B0 value of DA for the D2 antagonist [125I]iodosulpride binding sites. The results demonstrate a stronger reduction in the affinity of DA for neostriatal D2 receptors by the NT/NN peptides in brain sections compared with membrane preparations indicating the possible involvement of cytoplasmic factors and/or a demand for a more intact membrane structure in these receptor-receptor interactions. Further evidence for the hypotheses that the C-terminal NT fragments may be among the major ligands for the neostriatal NT receptors and that the neostriatal NT receptors may be a new subtype of NT receptor has been obtained.

Topics: Animals; Autoradiography; Binding, Competitive; In Vitro Techniques; Male; Neostriatum; Neuropeptides; Neurotensin; Peptide Fragments; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Neurotensin

Neuromedin-N, a hexapeptide recently isolated and purified from porcine spinal cord, has close sequence homology with the C-terminal region of the tridecapeptide neurotensin. Both peptides have a remarkably similar peripheral distribution. Little is known of the biological activity of neuromedin-N. Neurotensin and peptide histidine methionine are known to stimulate net fluid secretion into rat small intestine. We have therefore tested the effect of neuromedin-N and the hexapeptide neurotensin-(8-13), the smallest fully active analogue of neurotensin in this system, compared with that of neurotensin and peptide histidine methionine. All four peptides reduced net absorption in low doses and caused net secretion in larger doses. However, whereas peptide histidine methionine was active in all areas of the small intestine, neurotensin, neurotensin-(8-13) and neuromedin-N were inactive in the duodenum. In the post-duodenal areas neurotensin was approximately 7 times more active than peptide histidine methionine, 21 times more potent than neuromedin-N and 33 times more potent than neurotensin-(8-13).

Topics: Amino Acid Sequence; Animals; Body Fluids; Drug Synergism; Female; In Vitro Techniques; Intestinal Absorption; Intestine, Small; Molecular Sequence Data; Neurotensin; Peptide Fragments; Rats; Rats, Inbred Strains