Gap pre-pulse inhibition of the acoustic startle (GPIAS) is a behavioral paradigm used for inferring the presence of tinnitus in animal models as well as humans. In contrast to pre-pulse inhibition (PPI), the neural circuitry controlling GPIAS is poorly understood. To increase our knowledge on GPIAS, a comparative study with PPI was performed in mice combining these behavioral tests and c-Fos activity mapping in brain areas involved in the inhibition of the acoustic startle reflex (ASR). Both pre-pulses and gaps efficiently inhibited the ASR and abolished the induction of c-Fos in the pontine reticular nucleus. Differential c-Fos activation was found between PPI and GPIAS in the forebrain whereby PPI activated the lateral globus pallidus and GPIAS activated the primary auditory cortex. Thus, different neural maps are regulating the inhibition of the startle response by pre-pulses or gaps. To further investigate this differential response to PPI and GPIAS, we pharmacologically disrupted PPI and GPIAS with D-amphetamine or Dizocilpine (MK-801) to target dopamine efflux and to block NMDA receptors, respectively. Both D-amp and MK-801 efficiently decreased PPI and GPIAS. We administered Baclofen, an agonist GABAB receptor, but failed to detect any robust rescue of the effects of D-amp and MK-801 suggesting that PPI and GPIAS are GABAB-independent. These novel findings demonstrate that the inhibition of the ASR by pre-pulses or gaps is orchestrated by different neural pathways.

Repeated exposure to cocaine results in motor sensitization that, in the ventral tegmental area (VTA), is associated to enhanced glutamate release, which in turn leads to enhanced calcium levels in dopaminergic neurons. Calcium influx activates calcium-calmodulindependent protein kinases such as CaMKII. D-Serine could participate on these effects, and the objective was to discern the role of VTA D-serine after a sensitizing regimen of cocaine (10 mg/kg daily), and to discern consequent expression changes in CaMKII and its activated form. For this purpose, D-serine, sodium benzoate (inhibitor of D-amino acid oxidase, the degradating enzyme of D-serine), and 7-chlorokynurenate (inhibitor of the glycine site of NMDA receptors) were injected into the VTA (in either the induction or expression phase of sensitization), and activation state of CaMKII was assessed through blotting. The findings indicated that intra-VTA administration of D-serine (5 mM) and sodium benzoate (100 and 200 mg/ml) during the induction phase (not expression) reliably augmented the expression of behavioral sensitization to cocaine, providing evidence that D-serine in the VTA participates in the initiation of motor sensitization to this psychostimulant drug. Intra-VTA infusions of D-serine, sodium benzoate and 7-chlorokynurenate did not elicit a motor effect of their own. Confirming the important role of NMDA receptors and their activation at the glycine site, the employment of 7-chlorokynurenate (2 and 5 mg/ml) led to blocking of the development of sensitization to cocaine. CaMKII within the VTA was found to participate in D-serine's effects because this kinase, that is activated after repeated cocaine, was further activated after co-treatment with D-serine or sodium benzoate. Besides CaMKII activity was otherwise reduced by 7-chlorokynurenate.

The chemotherapeutic agent cisplatin is renowned for its ototoxic effects. While hair cells in the cochlea are established targets of cisplatin, less is known regarding the afferent synapse, which is an essential component in the faithful temporal transmission of sound. The glutamate aspartate transporter (GLAST) shields the auditory synapse from excessive glutamate release, and its loss of function increases the vulnerability to noise, salicylate, and aminoglycosides. Until now, the involvement of GLAST in cisplatin‐mediated ototoxicity remains unknown. Here, we test in mice lacking GLAST the effects of a low‐dose cisplatin known not to cause any detectable change in hearing thresholds. When administered at nighttime, a mild hearing loss in GLAST KO mice was found but not at daytime, revealing a potential circadian regulation of the vulnerability to cisplatin‐mediated ototoxicity. We show that the auditory synapse of GLAST KO mice is more vulnerable to cisplatin administration during the active phase (nighttime) when compared to WT mice and treatment during the inactive phase (daytime). This effect was not related to the abundance of platinum compounds in the cochlea, rather cisplatin had a dose‐dependent impact on cochlear clock rhythms only after treatment at nighttime suggesting that cisplatin can modulate the molecular clock. Our findings suggest that the current protocols of cisplatin administration in humans during daytime may cause a yet undetectable damage to the auditory synapse, more so in already damaged ears, and severely impact auditory sensitivity in cancer survivors.

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