Since cAMP blocks meiotic maturation of mammalian and amphibian oocytes in vitro and cyclic nucleotide phosphodiesterase 3A (PDE3A) is primarily responsible for oocyte cAMP hydrolysis, we generated PDE3A-deficient mice by homologous recombination. The Pde3a -/-females were viable and ovulated a normal number of oocytes but were completely infertile, because ovulated oocytes were arrested at the germinal vesicle stage and, therefore, could not be fertilized. Pde3a -/-oocytes lacked cAMP-specific PDE activity, contained increased cAMP levels, and failed to undergo spontaneous maturation in vitro (up to 48 hours). Meiotic maturation in Pde3a -/-oocytes was restored by inhibiting protein kinase A (PKA) with adenosine-3′,5′-cyclic monophosphorothioate, Rp-isomer (Rp-cAMPS) or by injection of protein kinase inhibitor peptide (PKI) or mRNA coding for phosphatase CDC25, which confirms that increased cAMP-PKA signaling is responsible for the meiotic blockade. Pde3a -/-oocytes that underwent germinal vesicle breakdown showed activation of MPF and MAPK, completed the first meiotic division extruding a polar body, and became competent for fertilization by spermatozoa. We believe that these findings provide the first genetic evidence indicating that resumption of meiosis in vivo and in vitro requires PDE3A activity. Pde3a -/-mice represent an in vivo model where meiotic maturation and ovulation are dissociated, which underscores inhibition of oocyte maturation as a potential strategy for contraception.

Salicylate, one of the most widely used drugs, produces at repetitive high doses reversible tinnitus and hearing loss. Neural correlates of hearing loss have long been established, whereas they remain elusive for tinnitus. The average spectrum of electrophysiological cochleoneural activity (ASECA), a measure of spontaneous auditory nerve activity, was monitored in guinea pigs over weeks of salicylate administration. Auditory nerve compound action potential (CAP) was also recorded to monitor acoustic sensitivity. In the first days of treatment, ASECA decreased acutely during hours after salicylate administration; after several days this decrease could be reduced. Over weeks of treatment the level of ASECA increased progressively. No change in CAP threshold was observed. The ASECA decrease induced by a contralateral broadband noise remained unchanged. At the end of treatment, acoustic tuning of ASECA showed a partially decreased sensitivity. After cessation of treatment the ASECA level returned progressively to initial values. In control animals delivery of an ipsilateral acoustic noise could reproduce the ASECA increase observed in long-term salicylate-treated animals. This white noise was of moderate sound pressure level and it elevated slightly CAP thresholds at high frequencies. These data provide evidence for salicylate-induced ASECA alterations without changes in CAP thresholds, in accord with clinical reports of tinnitus being the first subjective sign of salicylate ototoxicity. The similarities in occurrence, development, reversibility, frequency content, and acoustic level support the idea that ASECA changes, which indicates alterations of spontaneous eighth nerve activity and reflects the presence of salicylate-induced high-pitch tinnitus.

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Emotional stress is a phenomenon experienced by many people at some time in their lives. Some of its early manifestations, such as unbearable loudness of ambient sounds and sensations of dizziness, might be linked to inner ear dysfunction. Although the inner ear is supplied with a substantial sympathetic innervation, previous studies have failed to demonstrate any significant functional impact. We show here that in the awake guinea pig and following unilateral ablation of the superior cervical ganglion, the temporary threshold shift induced by a 1-min exposure to 8 kHz pure tone at 96 dB sound pressure level was reduced by as much as 40 dB. Of interest, the protective effect was bilateral suggesting an intimate relationship between the sympathetic and the olivocochlear efferent systems. The data presented here provide new evidence for a key role for the sympathetic system in modulating temporary threshold shifts following exposure to moderate sound stimulation. This opens new perspectives for investigation of sympathetic control in noise-induced permanent hearing losses.

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Our group (Horner KC, Guieu R, Magnan J, Chays A, Cazals Y. Neuropsychopharmacology 26: 135–138, 2002) has earlier described hyperprolactinemia in some patients presenting inner ear dysfunction. However, in that study, it was not possible to determine whether hyperprolactinemia was a cause or an effect of the symptoms. To investigate the effect of hyperprolactinemia on inner ear function, we first developed a model of hyperprolactinemia in estrogen-primed Fischer 344 rats and then performed functional studies on pigmented guinea pigs. Hyperprolactinemia induced, after 2 mo, a hearing loss of ∼30–40 dB across all frequencies, as indicated by the compound action potential audiogram. During the 3rd mo, the hearing loss continued to deteriorate. The threshold shifts were more substantial in males than in females. Observations under a dissection microscope revealed bone dysmorphology of the bulla and the cochlea. Light microscopy observations of cryostat sections confirmed bone-related pathology of the bony cochlear bulla and the cochlear wall and revealed morphopathology of the stria vascularis and spiral ligament. Scanning electron microscopy revealed loss of hair cells and stereocilia damage, in particular in the upper three cochlear turns and the two outermost hair cell rows. The data provide the first evidence of otic capsule and hair cell pathology associated with estrogen-induced prolonged hyperprolactinemia and suggest that conditions such as pregnancy, anti-psychotic drug treatment, aging, and/or stress might lead to similar ear dysfunctions.