Gender influence on manganese induced depression-like behavior and Mn and Fe deposition in different regions of CNS and excretory organs in intraperitoneally exposed rats.

Manganese (Mn) is an essential metal for mammals. It can modulate the action of endogenous substances, as neurotransmitters, but in excess also can trigger known neurotoxic effects. Many studies have been conducted assessing Mn neurotoxicity. However, Mn bioaccumulation in different brain tissues and behavior effects involving gender-specific studies are conflicted in the literature. Therefore, the aim of this work was to compare Mn effects, after 30days of intraperitoneal treatment, in male and female rats, submitted to forced swim and open field tests. After that, were evaluated Mn and Fe tissue levels in CNS, liver, and kidneys. Wistar rats were divided into saline, Mn 1mg/kg, Mn 5mg/kg, and imipramine (as forced swim control). Then, animals were euthanized by anesthesia overdose followed by decapitation and the collected tissue were striatum, hippocampus, brainstem, cortex, cerebellum, hepatic tissue, and renal tissue. Mn and Fe were determined by ICP-MS. There was a dose-dependent effect on accumulation of Mn in the cerebellum and brainstem to the dosage of 5mg/kg. In hippocampus there were bioaccumulation differences between gender and dose, and an increase of Fe in the groups exposed to Mn. Excess metals in the brain dissected has a strong influence on memory and learning processes and suggests pro-depressive effects, possibly triggered by the reduction of monoamines due to excessive metal bioaccumulation. It was concluded that, under this experimental design, Mn exposure cause metal deposition on dissected CNS, liver and kidney. There an effect at lower doses that was gender-dependent and males had more pronounced behavioral damage compared to females, although with increasing dose, females had an indication of motor damage.

Prior electrical stimulation of the inferior colliculus sensitizes rats to the stress of the elevated plus-maze test.

Besides its primary function in the transmission of acoustic signals, the inferior colliculus (IC) is involved in conveying auditory information of aversive nature to higher cortical structures. In the field of anxiety research, one widely used animal model is the electrical stimulation of a given structure supposed to be involved in the neural circuitry underlying emotional behavior. Indeed, electrical stimulation of the inferior colliculus produces fear-like responses. Moreover, prior exposure to stressful events sensitizes rodents' responsivity to fearful stimuli when they are subsequently tested in the elevated plus-maze. Based on these evidence it seems to be important to know whether animals stimulated in the inferior colliculus would show a heightened behavioral responsivity to subsequent stressful events. To this end, we examined the temporal course of the effects of the electrical stimulation of this midbrain region (5, 10 and 15 min afterward) on the conventional and ethological measures of the behavior of rats exposed to the elevated plus-maze test. Prior electrical stimulation of the inferior colliculus produced an 'anxiogenic' profile in the elevated plus-maze, i.e. a significant reduction in the number of entries and time spent into the open arms. Still, previous electrical stimulation of the inferior colliculus caused a significant decrease in rearing, scanning, peeping out, head dipping and end-arm activity while increased immobility. All these changes occurred after 5 min of inferior colliculus electrical stimulation. Therefore, stimulation of the inferior colliculus causes a heightened responsivity to anxiogenic stimuli inherent to the elevated plus-maze test. These findings bring additional support to the proposed role of this midbrain structure in the elaboration of adaptive responses to stressful situations.

Neurochemical mechanisms of the defensive behavior in the dorsal midbrain.

Some regions in the mesencephalon, such as dorsal periaqueductal gray, inferior colliculus and deep layers of superior colliculus have been grouped together as a continuous strip of midbrain structures involved in the integration of the different components of aversive states in the brain. In fact, escape behavior and defensive, or fear-like behavior often result when these sites are electrically or chemically stimulated. Moreover, the behavioral responses induced by stimulation of these structures are, in general, accompanied by increases in mean arterial blood pressure, heart rate and respiration, and by analgesia. Both the behavioral and autonomic consequences of electrical stimulation of the mesencephalic tectum was shown to be attenuated by minor tranquilizers, probably through enhancement of GABAergic neurotransmission. Besides GABAergic interneurons which exert a tonic inhibitory control on neural circuits responsible for the behavioral correlates of the aversion in the above-mentioned structures, several other mechanisms such as opioid, neuropeptides, serotonergic and excitatory amino acids have also been implicated in the regulation of these processes. As to the analgesia that accompanies these aversive states it is mediated by non-opioid mechanisms, particularly by serotonergic ones through 5-HT2 receptors. Now, efforts have been made to characterize the mode of action of these neurotransmitters on their multiple receptors and how they interact with each other to produce or regulate the neural substrates of aversion in the midbrain.

Defensive reactions are counteracted by midazolam and muscimol and elicited by activation of glutamate receptors in the inferior colliculus of rats.

The inferior colliculus is involved in conveying auditory information of an aversive nature to higher cortical structures. Gradual increases in the electrical stimulation of this structure produce progressive aversive responses from vigilance, through freezing, until escape. Recently, we have shown that microinjections of NMDA into the inferior colliculus mimic these aversive effects and that the neural substrates responsible for learned escape behavior in the inferior colliculus are regulated by GABA-benzodiazepine mechanisms. In the present study, we extend these observations showing that unlearned aversive responses are also depressed by muscimol and midazolam, both GABA-benzodiazepine agonists, and that microinjection of glutamate, an excitatory amino acid, into the inferior colliculus can trigger freezing responses. Electrical stimulation of the inferior colliculus of rats placed inside an open field allowed the determination of thresholds for the aversive responses, alertness, freezing and escape. Systemic administration (3 and 5.6 mg/kg) as well as microinjections into the inferior colliculus of the anxiolytic compound midazolam (10, 20 and 40 nmol) caused increases in threshold for these aversive responses. Similar results were obtained following microinjections of the GABA-A agonist muscimol (0.1, 1 and 5 nmol) into this brainstem structure. Microinjections of low doses of glutamate (5 nmol), presumed to activate mainly AMPA/kainate receptors, into the ventrolateral division of the central nucleus of the inferior colliculus of rats placed inside a circular arena induced aversive reactions, characterized by freezing responses. However, higher doses of glutamate caused no apparent effects. GDEE, an AMPA/kainate receptor antagonist, inhibited, whereas AP7, a NMDA receptor antagonist, did not influence these responses. It is suggested that GABA-benzodiazepine processes modulate the expression of defensive reactions in the inferior colliculus and that activation of fast-acting excitatory amino acid receptors in this midbrain region can trigger the initial steps of the defense reaction without eliciting the motor explosive behavior usually seen following the activation of NMDA receptors.