Neuroscience
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The mechanism underlying the therapeutic effect of antidepressants is not known but neuroadaptive processes akin to long-term potentiation have been postulated. Arc (Activity-regulated, cytoskeletal-associated protein) is an effector immediate early gene implicated in LTP and other forms of neuroplasticity. Recent data show that Arc expression is regulated by brain 5-hydroxytryptamine neurones, a target of many antidepressants. ⋯ Acute antidepressant injection, and repeated administration of the antipsychotic drug chlorpromazine, produced either limited or no changes in Arc mRNA. The data suggest that chronic treatment with antidepressant drugs induces Arc gene expression in specific regions across the rat forebrain. Up-regulation of Arc expression may be part of the process by which antidepressant drugs achieve long-term changes in synaptic function in the brain.
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Accumulating evidence suggests that tuberoinfundibular peptide of 39 residues (TIP39) may be the endogenous ligand of the parathyroid hormone 2 receptor. The vast majority of TIP39-containing neurons are localized in two regions, the subparafascicular area at the thalamic-midbrain junction, and the medial paralemniscal nucleus in the rostral pons. In contrast to the restricted localization of TIP39-containing cell bodies, TIP39-containing fibers have a widespread distribution. ⋯ Unilateral lesions of the medial and the lateral subparafascicular area demonstrated that the projections are ipsilateral and that medial lesions produce higher reductions in the density of TIP39 fibers except in the amygdala and the hypothalamus. Following lesions of the medial paralemniscal nucleus, TIP39-immunoreactive fibers disappeared from the medial geniculate body, the periaqueductal gray, the deep layers of the superior colliculus, the external cortex of the inferior colliculus, the cuneiform nucleus, the nuclei of the lateral lemniscus, the lateral parabrachial nucleus, the locus coeruleus, the subcoeruleus area, the medial nucleus of the trapezoid body, the periolivary nuclei, and the spinal cord, suggesting that these regions receive TIP39-containing fibers from the medial paralemniscal nucleus, and unilateral lesions demonstrated that the projections are ipsilateral. The projections of the TIP39-containing cells in the subparafascicular area suggest their involvement in limbic and endocrine functions, while the projections of the TIP39-containing cells in the medial paralemniscal nucleus suggest their involvement in auditory and nociceptive functions.
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The neurochemistry of aggression and rage has largely focused on the roles played by neurotransmitters and their receptor mechanisms. In contrast, little attention has been given to the possible functions of other substances. Interleukin-1beta is an immune and brain-derived cytokine that is present in the hypothalamus. ⋯ In the third experiment, pretreatment with a selective 5-HT2 receptor antagonist, LY-53857, blocked the facilitating effects of interleukin-1beta upon defensive rage. These findings reveal for the first time that brain cytokines can dramatically alter aggressive behavior. In particular, interleukin-1beta in the medial hypothalamus potentiates defensive rage behavior elicited from the periaqueductal gray in the cat, and the potentiating effects of interleukin-1beta on this form of emotional behavior are mediated via a 5-HT2 receptor mechanism.
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Focal traumatic injury to the cerebral cortex is associated with early activation of the neuronal isoform of nitric oxide synthase (nNOS), where high concentrations of nitric oxide-derived free radicals elicit extensive DNA damage. Subsequent activation of the nuclear repair enzyme poly(ADP-ribose) polymerase (PARP) causes a severe energy deficit leading to the ultimate demise of affected neurons. Little is known about the temporal relationship of nNOS and PARP activation and the neuroprotective efficacy of their selective blockade in traumatic brain injury. ⋯ In contrast, i.p. AB treatment remained largely ineffective. In conclusion, our data indicate early activation of PARP after cold lesion that is, at least in part, related to nNOS induction and supports the relevance of nNOS and/or PARP inhibition to therapeutic approaches of traumatic brain injury.
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Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. ⋯ A GABAA antagonist, bicuculline, did not modify the inhibitory effects of thiopental and the GABAA agonist, muscimol, did not inhibit norepinephrine release. In addition there was no interaction of barbiturates with either OX1 or OX2 receptors. Collectively our data suggest that orexinergic neurons may be an important target for barbiturates, and GABAA, OX1 and OX2 receptors may not be involved in this interaction.