Noise trauma alters D-[3H]aspartate release and AMPA binding in chinchilla cochlear nucleus.

Exposure of adults to loud noise can overstimulate the auditory system, damage the cochlea, and destroy cochlear nerve axons and their synaptic endings in the brain. Cochlear nerve loss probably results from the death of cochlear inner hair cells (IHC). Additional degeneration in the cochlear nucleus (CN) is hypothesized to stem from overstimulation of the system, which may produce excitotoxicity. This study tested these predictions by exposing one ear of anesthetized adult chinchillas to a loud noise, which damaged the ipsilateral cochlea and induced degeneration in the glutamatergic cochlear nerve. During the first postexposure week, before cochlear nerve axons degenerated, glutamatergic synaptic release in the ipsilateral CN was elevated and uptake was depressed, consistent with hyperactivity of glutamatergic transmission and perhaps with the operation of an excitotoxic mechanism. By 14 days, when cochlear nerve fibers degenerated, glutamatergic synaptic release and uptake in the CN became deficient. By 90 days, a resurgence of transmitter release and an elevation of AMPA receptor binding suggested transmission upregulation through plasticity that resembled changes after mechanical cochlear damage. These changes may contribute to tinnitus and other pathologic symptoms that precede and accompany hearing loss. In contrast, the other ear, protected with a silicone plug during the noise exposure, exhibited virtually no damage in the cochlea or the cochlear nerve. Altered glutamatergic release and AMPA receptor binding activity in the CN suggested upregulatory plasticity driven by signals emanating from the CN on the noise-exposed side.

Synaptophysin in the cochlear nucleus following acoustic trauma.

Chinchillas are notable for a low-frequency hearing range similar to that of humans and a marked sensitivity to loud noise. A single noise exposure that produces cochlear damage may lead to progressive loss of synaptic endings in the cochlear nucleus, followed by new axonal growth. As an index of synaptic regulation during such changes, we have examined the expression of a synaptic vesicle protein, synaptophysin, in the cochlear nucleus following a damaging acoustic stimulus in adult chinchillas. With one ear protected by a plug, following a 3-h exposure to an octave-band noise of 108 dB sound pressure level, centered at 4 kHz, the unprotected cochlea and the cochlear nuclei exhibited degeneration of hair cells and axons over periods of 7, 14, 30, 90, and 150 days. Axonal degeneration, as revealed by a silver degeneration method, was heavy ipsilateral to the cochlear damage, but sparse degeneration also appeared on the contralateral, unexposed side. Synaptophysin immunostaining underwent a major, bilateral decline in the anteroventral and posteroventral cochlear nuclei, interrupted at intervening periods by transient increases in the numbers of stained structures. A distinction in staining between large perisomatic structures and smaller puncta in the neuropil and between the dorsal and the ventral zones of the ventral cochlear nuclei revealed some variations in the response and degree of recovery of synaptophysin staining. These findings could best be explained by degeneration of synaptic endings followed by new growth of terminals and by regulatory changes in the levels of synaptophysin expression and synaptic vesicle accumulation over time.

Ontogeny of gonadotrophin and inhibin secretion in normal girls through puberty based on overnight serial sampling and a comparison with normal boys.

We measured luteinizing hormone (LH) and follicle stimulating hormone (FSH) by immunofluorometric assays and alpha-inhibin by radioimmunoassay in serum sampled every 10 min throughout the night (2100-0500 h) from 44 normal girls. Mean overnight LH values rose log-linearly from a mean of 0.2 IU/l in prepubertal girls to 3.0 IU/l in late pubertal girls. Log2 mean overnight FSH rose rapidly through early puberty and then remained constant; mean FSH rose from 1.0 IU/l in prepubertal girls to approximately 2.8 IU/l in Tanner III-V girls. Mean overnight inhibin increased through puberty, rising from 151 ng/l in prepubertal girls to 432 ng/l in fully pubescent girls. Within each of the first three Tanner stages, LH differed approximately 100-fold between the smallest and largest mean concentrations but differed <10-fold within stages IV or V. Such within-pubertal stage variability was less pronounced for FSH, which differed approximately 16-fold among Tanner I subjects and 4-10-fold at later stages, and for inhibin, which varied approximately 4-fold within each Tanner stage. The frequency of LH pulses during overnight sampling increased significantly during puberty, but the frequency of FSH and inhibin pulses remained constant. We compared the results from girls to those from 50 normal boys [Manasco et al. (1995) J. Clin. Endocrinol. Metab., 80, 20462052]. At each pubertal stage, girls had approximately the same mean overnight LH values as boys; girls had higher mean overnight FSH, particularly during Tanner stages II-IV; and boys had mean overnight alpha-inhibin immunoreactivity approximately 1.5 times that of girls at each pubertal stage. Still, hormone concentrations for individuals of both sexes intergraded at each pubertal stage.

Ethanol attenuation of morphine dependence: comparison to dizocilpine.

Recent studies indicate that morphine dependence, assessed as the severity of naloxone-precipitated opiate withdrawal in rats, is attenuated by dizocipline, a non-competitive, excitatory amino acid antagonist. Because ethanol is a putative excitatory amino acid antagonist, the present study compared the effects of co-administration of ethanol to that of dizocilpine on morphine dependence. Rats were administered morphine (10 mg/kg) twice daily for 9 days. One group received ethanol (1 g/kg) co-administration, another received dizocilpine (0.05 mg/kg) co-administration, and a third served as vehicle controls. On day 10, all rats received naloxone (4 mg/kg) injections and ratings of several classic signs of opiate withdrawal were made. Both ethanol- and dizocilpine-treated rats showed significantly less severe precipitated opiate withdrawal overall, with the ethanol group showing reduced ratings of some specific signs. These results demonstrate that ethanol, like dizocilpine, attenuates the development of morphine dependence. The results are consistent with the action of ethanol at glutamate receptors.

Ontogeny of gonadotropin, testosterone, and inhibin secretion in normal boys through puberty based on overnight serial sampling.

To investigate hormonal changes occurring in male puberty, we measured LH, FSH, testosterone, and alpha-inhibin immunoactivity in serum samples drawn every 10 min for 8 h (2100-0500 h) from each of 50 normal prepubertal and pubertal boys, aged 8.4-18.8 yr. We measured gonadotropins with ultrasensitive immunofluorometric assays, and testosterone and alpha-inhibin with RIAs. Unlike previous studies, which indexed pubertal development with Tanner stages, we used testicular volume, a more finely graduated indicator of development, to reveal patterns that were obscured when subjects were grouped by Tanner stage. The overnight mean concentration of each hormone increased with testis volume, but the rate of increase on a logarithmic scale slowed as testes grew. Log LH rose precipitously in the late prepubertal and early pubertal periods and plateaued during mid- and late puberty. Based on fitted regression curves, LH increased about 20-fold (from 0.11 IU/L) between testis volumes of 1 and 10 mL, but only an additional 1.5-fold by 30 mL. The developmental trajectory of log testosterone was like that of log LH, but rose less steeply early in puberty. From 0.14 micrograms/L at a testis volume of 1 mL, testosterone increased about 8.5-fold by 10 mL and an additional 3-fold by 30 mL. In contrast, logarithms of overnight mean FSH and alpha-inhibin concentrations rose at a more nearly constant rate throughout puberty. From 0.62 IU/L at a testis volume of 1 mL, the FSH concentration doubled by 10 mL and increased an additional 1.7-fold by 30 mL. From 270 ng/L at a testis volume of 1 mL, inhibin increased 1.5-fold by 10 mL and an additional 1.3-fold by 30 mL. Overnight pulse amplitudes exhibited developmental trajectories similar to those of the corresponding overnight mean concentrations. The number of LH and testosterone pulses during the sampling period averaged 2.2 and 2.1, respectively, at Tanner stage 1 and increased to 4.5 and 3.2, respectively, at Tanner stage 5. The number of FSH and inhibin pulses remained constant throughout puberty, averaging 3.3 and 3.5, respectively. Pairwise correlations among hormone concentrations were strong, reflecting common increasing trends through puberty; however, after accounting for developmental trends, FSH, LH, and testosterone concentrations remained correlated, whereas inhibin was uncorrelated with each of the other three hormones. Measuring gonadotropins with ultrasensitive assays and analyzing the results on a logarithmic scale as a function of testis volume made clear the dramatic hormonal changes that begin before the clinical changes of puberty.

Potential corticotropin-releasing factor pathways in the rat brain as determined by bilateral electrolytic lesions of the central amygdaloid nucleus and the paraventricular nucleus of the hypothalamus.

The projection fields of corticotropin-releasing factor (CRF)-containing perikarya in the rat central nervous system were studied using a combination of electrolytic lesions, microdissection and radioimmunoassay. The effects of bilateral electrolytic lesions of the central nucleus of the amygdala (Ce) or the paraventricular nucleus (PVN) of the hypothalamus were measured by a sensitive and specific radioimmunoassay. Following lesions of the Ce, CRF concentrations in the locus ceruleus (LC) were significantly decreased. Following lesions of the PVN, CRF concentrations in the median eminence were markedly decreased (> 85%), with smaller but consistent reductions of CRF in the hippocampus as well. In contrast to the Ce lesions, PVN lesions resulted in increases in CRF concentrations in the LC. These results further confirm the projection of CRF-containing cells from the PVN to the median eminence, provide evidence for a PVN-hippocampal CRF pathway, and suggest that the PVN modulates CRF neurons innervating the LC. Moreover, the existence of a CRF-containing pathway from the Ce to the LC appears likely, and such a circuit may play a role in the behavioral and physiological responses to stress.