Response characteristics in the apex of the gerbil cochlea studied through auditory nerve recordings

In this study, we analyze the processing of low-frequency sounds in the cochlear apex through responses of auditory nerve fibers (ANFs) that innervate the apex. Single tones and irregularly spaced tone complexes were used to evoke ANF responses in Mongolian gerbil. The spike arrival times were analyzed in terms of phase locking, peripheral frequency selectivity, group delays, and the nonlinear effects of sound pressure level (SPL). Phase locking to single tones was similar to that in cat. Vector strength was maximal for stimulus frequencies around 500 Hz, decreased above 1 kHz, and became insignificant above 4 to 5 kHz. We used the responses to tone complexes to determine amplitude and phase curves of ANFs having a characteristic frequency (CF) below 5 kHz. With increasing CF, amplitude curves gradually changed from broadly tuned and asymmetric with a steep low-frequency flank to more sharply tuned and asymmetric with a steep high-frequency flank. Over the same CF range, phase curves gradually changed from a concave-upward shape to a concave-downward shape. Phase curves consisted of two or three approximately straight segments. Group delay was analyzed separately for these segments. Generally, the largest group delay was observed near CF. With increasing SPL, most amplitude curves broadened, sometimes accompanied by a downward shift of best frequency, and group delay changed along the entire range of stimulus frequencies. We observed considerable across-ANF variation in the effects of SPL on both amplitude and phase. Overall, our data suggest that mechanical responses in the apex of the cochlea are considerably nonlinear and that these nonlinearities are of a different character than those known from the base of the cochlea

Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders

Effects of neonatal amygdala lesions on [I-125] neurotensin binding in specific brain areas of adult rat

Neurotensin has been implicated in the pathophysiology of schizophrenia. The neonatal amygdala lesion in rat has been proposed to be a neurodevelopmental model for some aspects of schizophrenia. [125I] Neurotensin binding was assessed in adult rats using in vitro autoradiography following a lesion of the basolateral amygdala at postnatal day 7 (Pd 7) or postnatal day 21 (Pd 21). The Pd 7 and Pd 21 lesions differentially affected neurotensin receptor densities in the hippocampal complex and (less pronounced) in the dopaminergic cell regions, implying a neurodevelopmental cause. These results may be of relevance for the involvement of neurotensin in the pathogenesis of schizophrenia

Differential regulation of the CXCR2 chemokine network in rat brain trauma: implications for neuroimmune interactions and neuronal survival

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Structure-activity studies on the corticotropin releasing factor antagonist astressin, leading to a minimal sequence necessary for antagonistic activity

Corticotropin Releasing Factor (CRF) antagonists are considered promising for treatment of stress-related illnesses such as major depression and anxiety-related disorders. We report here the design, synthesis and biological evaluation of 91 truncated astressin analogues in order to deduce the pharmacophoric amino acid residues. Such truncated peptides may serve as valuable lead structures for the development of new small, non-peptide-based CRF antagonists. N-Terminal truncation of astressin led to active CRF antagonists that are substantially reduced in size and are selectively active at the human CRF receptor type 1 in vitro and in vivo. Subsequently, an alanine scan in combination with further truncated derivatives led to the proposal of a new pharmacophoric model of peptide-based CRF antagonists. It was found that the astressin(27–41)C sequence is the shortest active CRF antagonist. The first eight N-terminal amino acid residues were found to be an important structural determinant and were replaceable by alanine residues, thus enhancing theα-helical propensity. A covalent structural constraint is of utmost importance for the preorganization of the C-terminal amino acid residues. The C-terminal heptapeptide sequence, however, was found to be crucial for the antagonistic activity, since substitution or deletion of any residue led to inactive compounds

Dopamine displays an identical apparent affinity towards functional dopamine D1 and D2 receptors in rat striatal slices: possible implications for the regulatory role of D2 receptors

In this study we examined the selectivity of dopamine (DA) for rat striatal DA D1 and D2 receptors. In a Krebs-HEPES buffer, the Ki values of DA for D1 binding sites (labelled with [3H]SCH23390) and D2 binding sites (labelled with [3H]spiroperidol) in striatal membranes amounted to about 30 and 0.3 microM, respectively. However, the EC50s of DA (3 microM) and the DA releasing drug amphetamine (1 microM) were identical considering D1 receptor-stimulated and D2 receptor-inhibited adenylate cyclase activity in superfused striatal slices. Moreover, these EC50 values were also obtained studying DA- and amphetamine-induced D2 receptor activation, resulting in inhibition of the electrically evoked release of [14C]acetylcholine from the slices. Therefore, with regard to the apparent affinity of exogenous and endogenous DA for D1 and D2 receptors in rat striatal slices, the ligand-receptor binding data appeared to be misleading. Thus, our data show that in rat striatal slices DA has an identical apparent affinity towards functional D1 and D2 receptors, which is particularly intriguing in view of the very high receptor selectivity of synthetic D1 and D2 receptor agonists for these functional receptors in superfused brain slices as predicted on the basis of binding assays. This may have important implications for our understanding of central DA neurotransmission. For instance, since the inhibitory effect of opioid and muscarinic receptor activation on adenylate cyclase activity has been shown to be inversely related to the degree of DA D2 receptor activation, the degree of activation of D1 and D2 receptors by released DA is suggested to act as a functional gate allowing distinct neurotransmitters to play a role in striatal neurotransmission

Patterns of c-fos expression induced by fluvoxamine are different after acute vs. chronic oral administration

Prevention, Population and Disease management (PrePoD

Acute effects of oxidized low density lipoprotein on metabolic responses in macrophages

The immediate effects of oxidized low density lipoprotein (OxLDL) on the metabolic activity of cultured macrophages (RAW 264.7) were studied using a microphysiometer. Administration of OxLDL acutely induced a concentration- dependent increase in metabolic activity, with an EC50 of 16 ±3 μg/ml OxLDL and a maximal effect of 35% ± 4% (mean ± SEM; n=5). A biphasic response was measured after administration of 75 or 100 μg/ml OxLDL consisting of an initial sharp increase, followed by the induction of a long- lasting hypoactivity of 80% of the control value. Incubation of cells with polyinosinic acid (polyI; 100 μg/ml) for 30 min prior to OxLDL administration could completely block the effect of 25 μg/ml OxLDL. In addition, polyI acted as a full antagonist on the decrease of the biphasic response of cells generated by 75 and 100 μg/ml OxLDL. Macrophages used in this study possessed a specific binding site for OxLDL, with a dissociation constant (K(D)) of 9 ± 2 μg/ml and a maximal binding of 610 ± 32 ng 125I-OxLDL/mg cell protein. Binding of 125I-OxLDL to macrophages could be completely competed for by unlabeled OxLDL, by polyI for 58%, and by AcLDL for 46%. In conclusion, OxLDL can acutely activate the metabolic state of macrophages by a receptor-mediated process in a concentration-dependent fashion, which could be antagonized by polyI. Metabolic responses to OxLDL may underlie the changes observed in macrophages in the early atherosclerotic plaque