Quinolinic acid and glutamatergic neurodegeneration in Caenorhabditis elegans.

Quinolinic acid (QUIN) is an endogenous neurotoxin that acts as an N-methyl-D-aspartate receptor (NMDAR) agonist generating a toxic cascade, which can lead to neurodegeneration. The action of QUIN in Caenorhabditis elegans and the neurotoxins that allow the study of glutamatergic system disorders have not been carefully addressed. The effects of QUIN on toxicological and behavioral parameters in VM487 and VC2623 transgenic, as well as wild-type (WT) animals were performed to evaluate whether QUIN could be used as a neurotoxin in C. elegans. QUIN reduced survival of WT worms in a dose-dependent manner. A sublethal dose of QUIN (20 mM) increased reactive oxygen species (ROS) levels in an nmr-1/NMDAR-dependent manner, activated the DAF-16/FOXO transcription factor, and increased expression of the antioxidant enzymes, superoxide dismutase-3, glutathione S-transferase-4, and heat shock protein-16.2. QUIN did not change motor behavioral parameters, but altered the sensory behavior in N2 and VM487 worms. Notably, the effect of QUIN on the sensory behavioral parameters might occur, at least in part, secondary to increased ROS. However, the touch response behavior indicates a mechanism of action that is independent of ROS generation. In addition, non-lethal doses of QUIN triggered neurodegeneration in glutamatergic neurons. Our findings indicate that C. elegans might be useful as a model for studies of QUIN as a glutamatergic neurotoxin in rodent models.

Tickling in juvenile but not adult female rats conditions sexual partner preference.

Female rats display a conditioned partner preference for males that bear odors paired with different types of rewarding unconditioned stimuli (UCS). Here we examined whether tickling constitutes a rewarding UCS that supports the development of partner preferences. In Experiment 1, we tested the possibility that odors associated with a tickling UCS in prepubescent rats would induce a conditioned partner preference in adulthood. Two groups were formed with 31-day-old, single-housed females, tickled for 6 min daily for 10 days, by a hand that wore a scented glove (almond or lemon). At 47 days of age, females were ovariectomized (OVX), hormone-primed (EB+P), and tested for sexual partner preference with two scented stud males (one almond and one lemon). In each group, females displayed a sexual preference toward males bearing the odor paired with tickling, as observed with longer visits, more solicitations, hops & darts, and receiving more intromissions and ejaculations from the preferred male. In Experiment 2, we used 3-month old, OVX, hormone-primed rats conditioned every 4 days for 10 trials. In contrast to juvenile females, adult females failed to prefer males that bore the odor paired with tickling but instead preferred the novel male. These results suggest that tickling has opposite age-dependent effects in the conditioning of partner preference. Tickling in juvenile females appears to act as a rewarding UCS, whereas in adult females it may act as an aversive UCS. Further research is needed to understand brain mechanisms that might account for such differences.

Early exposure to caffeine affects gene expression of adenosine receptors, DARPP-32 and BDNF without affecting sensibility and morphology of developing zebrafish (Danio rerio).

Adenosine receptors are the most important biochemical targets of caffeine, a common trimethylxanthine found in food and beverages. Adenosine plays modulatory action during the development through adenosine receptors and their intracellular pathways activation. In this study, we aimed to evaluate if caffeine gave to zebrafish in the very first steps of development is able to affect its direct targets, through the adenosine receptors mRNA expression evaluation, and latter indirect targets, through evaluation of the pattern of dopamine and cAMP-regulated phosphoprotein and brain-derived neurotrophic factor (BDNF) mRNA expression. Here, we demonstrate that zebrafish express adenosine receptor subtypes (A1, A2A1, A2A2 and A2B) since 24h post-fertilization (hpf) and that caffeine exposure is able to affect the expression of these receptors. Caffeine exposure from 1 hpf is able to increase A1 expression at 72-96 hpf and A2A1 expression at 72 hpf. No alterations occurred in A2A2 and A2B expression after caffeine treatment. DARPP-32, a phosphoprotein involved in adenosine intracellular pathway is also expressed since 24 hpf and early exposure to caffeine increased DARPP-32 expression at 168 hpf. We also evaluate the expression of BDNF as one of the targets of adenosine intracellular pathway activation. BDNF was also expressed since 24 hpf and caffeine treatment increased its expression at 48 and 72 hpf. No morphological alterations induced by caffeine treatment were registered by the check of general body features and total body length. Assessment of tactile sensibility also demonstrated no alterations by caffeine treatment. Altogether, these results suggest that caffeine is able to affect expression of its cellular targets since early phases of development in zebrafish without affect visible features. The up-regulation of direct and indirect targets of caffeine presents as a compensatory mechanism of maintenance of adenosinergic modulation during the developmental phase.

Oral and spinal melatonin reduces tactile allodynia in rats via activation of MT2 and opioid receptors.

The antiallodynic effect of melatonin after intrathecal (it) and oral administration as well as the possible participation of MT(2) and opioid receptors in melatonin-induced antiallodynia in neuropathic rats were assessed. Ligation of the L5/L6 spinal nerves produced a clear-cut tactile allodynia in the rats. Intrathecal (3-100 microg) and oral (37.5-300 mg/kg) administration of melatonin decreased tactile allodynia induced by spinal nerve ligation. Intrathecal administration of the preferential MT(2) receptor antagonist luzindole (1-100 microg), but not vehicle, significantly diminished in a dose-dependent manner the antiallodynic effect induced by melatonin (100 microg, it). Oral (0.01-1mg/kg) or intrathecal (0.1-10 microg) administration of the highly selective MT(2) receptor antagonist 4P-PDOT diminished the antiallodynic activity induced by oral (150 mg/kg) or intrathecal (100 microg) administration of melatonin, respectively. Subcutaneous (1mg/kg) or intrathecal (0.5-50 microg) treatment with naltrexone, but not vehicle, significantly diminished the antiallodynic effect induced by oral (150 mg/kg) or intrathecal (100 microg) administration of melatonin. Oral melatonin (150 mg/kg)-induced antiallodynia was partially reduced by the spinal administration of 4P-PDOT (10 microg). Moreover, the spinal effect of melatonin (100 microg) was significantly reduced by the combination 4P-PDOT (0.1 microg)-naltrexone (0.5 microg). At the greatest tested doses, the antagonist drugs did not modify tactile allodynia in neuropathic rats. Melatonin (100 microg or 300 mg/kg) did not affect motor co-ordination in the rotarod test. Results indicate that melatonin reduces tactile allodynia in neuropathic rats after intrathecal and oral administration. Moreover, data suggest the participation of spinal MT(2) and opioid receptors in the melatonin-induced antiallodynic effect in this model.

Blockage of vibrissae afferents: II. Footshock threshold increments.

Because of their dense innervation rat vibrissae have been regarded as a very important sensory system. Many behavioral deficits have been reported by other authors after rat vibrissal afferent blockades. In the present work we found significant threshold increments to footshock following either reversible nerve block (procaine or nerve pressure) or section of the vibrissal afferent nerves, but not following vibrissae trimming. These results are discussed in reference to the tonic or level-setting function of afferent systems.

Blockage of vibrissal afferents: III. Electrocorticographic effects.

We have shown signs of behavioral depression after vibrissal deafferentation. Locomotor slowing, motor impairments and footshock thresholds increment were demonstrated after vibrissal afferent blockages. Here, we study the electrocortical (ECoG) effects of vibrissal pad anaesthesia, also replicated by bilateral brachial plexus blockage. We found in both cases, that this acute and massive deafferentation produces synchronization over the entire neocortex accompanied by an important loss of muscular electrical activity. Slow waves observed in this condition were similar to those recorded in the sleeping rat without any treatment, but in our case, there were no behavioral signs of sleep. Thus a clear behavioral electroencephalographic dissociation was obtained by acute deafferentation. These results would seem to support the sleep deafferentation hypothesis.

Intraoral tactile sensitivity in adults with diabetes.

OBJECTIVE: The intraoral tactile sensitivity (ITS) of diabetic and nondiabetic subjects was compared. The effects of age, ethnicity, sex, and intraoral site were considered. RESEARCH DESIGN AND METHODS: The sample comprised 589 participants of the Oral Health: San Antonio Longitudinal Study of Aging. A total of 107 subjects (61.8 +/- 10.0 years; 48 women, 59 men) met American Diabetes Association diagnostic criteria for diabetes and 482 subjects (58.8 +/- 11.1 years; 274 women, 208 men) did not. ITS was assessed with an oral microaesthesiometer with a cross-modality matching procedure. The dependent variable was the slope of the psychophysical function relating physical stimulus intensity (air pressure) and subjects' judgments of stimulus intensity. Data were analyzed using ANOVA for repeated measures with between-subject factors of age, sex, ethnicity, and diabetes and the within-subject factor of intraoral site. RESULTS: Diabetic and nondiabetic subjects showed no significant differences in ITS at any of the three test sites. European Americans demonstrated greater soft-palate sensitivity (mean +/- SD 0.26 +/- 0.15) compared with Mexican Americans (0.24 +/- 0.16; P = 0.046). The three intraoral test sites differed in tactile sensitivity (P < 0.001); posterior tongue (0.33 +/- 0.22) was most sensitive, followed by the soft palate (0.25 +/- 0.15) and the anterior tongue (0.23 +/- 0.13). Potentially confounding factors were not associated with ITS. CONCLUSIONS: Our results suggest that diabetes per se may not influence ITS.

Tactile vibration thresholds after acute poisonings with organophosphate insecticides.

This study evaluated the association between acute poisoning with organophosphate pesticides (OPs) and quantitative tactile vibration thresholds. Thresholds of the dominant index fingers and big toes of 56 men hospitalized for acute poisoning with OPs were measured at hospital discharge (1-24 days after poisoning) and around seven weeks later (24-176 days after poisoning), and compared with those of controls. Thresholds of the big toes of men with severe intentional poisonings due to neuropathic OPs (metamidophos and chlorpyrifos) increased between the first and second examinations. Threshold impairment was not detected in the index finger regardless of poisoning agent or severity. The development of threshold impairment as a consequence of severe intentional poisonings with neuropathic OPs is consistent with other reports indicating that only severe OP poisonings produce sensory peripheral nerve effects.

The effect of oral-gustatory, tactile-bucal, and tactile-manual stimulation on the behavior of the hands in newborns.

The effect of stimulation (oral-gustatory with sucrose, tactile-bucal, and tactile-manual) on the frequency of hand contact with the oral (hand-mouth and hand sucking) and perioral (hands near the mouth) regions was compared in 24 full-term newborns. The 16-minute evaluation was divided into four equal periods, without intervals: (A) Baseline, no stimulation applied; (B) tactile-bucal, the newborn was allowed to suck the distal phalange of the researcher's little finger; (C) tactile-manual, the newborn was allowed to grasp the researcher's index finger; (D) 0.3 ml sucrose solution was administered orally to the newborns. After every three newborns were tested, the sequence of stimulation application was changed. The frequencies of the hand behaviors were calculated. It was observed that the sucrose significantly increased the frequency of hand sucking (p<0.05). Sucrose was, therefore, the most effective stimulus for eliciting the behavior of hand sucking.