GABAergic regulation of auditory sensory gating in low- and high-anxiety rats submitted to a fear conditioning procedure.

The inferior colliculus (IC) is primarily involved in the processing of acoustic stimuli, being in a position to send auditory information to motor centers that participate in behaviors such as prey catching and predators' avoidance. The role of the central nucleus of the IC (CIC) on fear and anxiety has been suggested on the basis that rats are able to engage in tasks to decrease the aversiveness of CIC stimulation, increased Fos immunolabeling during diverse aversive states and increased CIC auditory evoked potentials (AEP) induced by conditioned fear stimuli. Additionally, it was shown that brainstem AEP, represented by wave V, for which the main generator is the IC, is increased during experimentally-induced anxiety. Rats segregated according to their low or high emotional reactivity have been used as an important tool in the study of fear and anxiety. The IC contains a high density of GABA receptors. Since the efficacy of an anxiolytic compound is a function of the animal's anxiety level, it is possible that GABA-benzodiazepine (Bzp) agents affect LA and HA animals differently. In this study we investigated the GABA-Bzp influence on the modulation of AEP in rats with low- (LA) or high-anxiety (HA) levels, as assessed by the elevated plus-maze test (EPM). GABA-Bzp modulation on the unconditioned AEP response was analyzed by using intra-CIC injections (0.2 µl) of the GABA-Bzp agonists muscimol (121 ng) and diazepam (30 µg), or the GABA inhibitors bicuculline (10 ng) and semicarbazide (7 µg). In a second experiment, we evaluate the effects of contextual aversive conditioning on AEP using foot-shocks as unconditioned stimuli. On the unconditioned fear paradigm GABA inhibition increased AEP in LA rats and decreases this measure in HA counterparts. Muscimol was effective in reducing AEP in both LA and HA rats. Contextual fear stimuli increased the magnitude of AEP. In spite of no effect obtained with diazepam in LA rats the drug inhibited AEP in HA animals. The specificity of the regulatory mechanisms mediated by GABA-Bzp for the ascending neurocircuits responsible for the acquisition of aversive information in LA and HA animals shed light on the processing of sensory information underlying the generation of defensive reactions.

Glutamate receptor antagonism in inferior colliculus attenuates elevated startle response of high anxiety diazepam-withdrawn rats.

Rats segregated according to low (LA) or high (HA) anxiety levels have been used as an important tool in the study of fear and anxiety. Since the efficacy of an anxiolytic compound is a function of the animal's basal anxiety level, it is possible that chronic treatment with a benzodiazepine (Bzp) affects LA and HA animals differently. Based on these assumptions, this study aimed to provide some additional information on the influence of acute, chronic (18 days) and withdrawal effects (48 h) from diazepam (10 mg/kg), in rats with LA or HA levels, on startle response amplitude. For this purpose, the elevated plus-maze (EPM) test was used. In addition, the role of glutamate receptors of the central nucleus of the inferior colliculus (cIC), the most important mesencephalic tectum integrative structure of the auditory pathways and a brain region that is linked to the processing of auditory information of aversive nature, was also evaluated. Our results showed that, contrary to the results obtained in LA rats, long-term treatment with diazepam promoted anxiolytic and aversive effects in HA animals that were tested under chronic effects or withdrawal from this drug, respectively. In addition, since Bzp withdrawal may function as an unconditioned stressor, the negative affective states observed in HA rats could be a by-product of GABA-glutamate imbalance in brain systems that modulate unconditioned fear and anxiety behaviors, since the blockade of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors in the cIC clearly reduced the aversion promoted by diazepam withdrawal.

Dopamine and nitric oxide interaction on the modulation of prepulse inhibition of the acoustic startle response in the Wistar rat.

RATIONALE: The nitric oxide (NO)-arginine pathway is intimately connected to the release of dopamine (DA), a neurotransmitter system that may be dysfunctional in schizophrenia. Both schizophrenic patients and rats treated with DA agonists present deficits in sensorimotor gating measured by prepulse inhibition (PPI). OBJECTIVE: Our aim was to investigate the interaction between a NO synthase inhibitor, N(G)-nitro-L-arginine (L-NOARG), and the DA agonists, amphetamine (Amph), apomorphine (Apo), bromocriptine (BRC), quinpirole (QNP) and SKF38393, on the modulation of the PPI. METHODS: Male Wistar rats received two injections of either L-NOARG (40 mg/kg, i.p.) or saline, 1 h before the test, and the DA agonists or vehicle. Testing began 5 min after treatment with Amph (2 mg/kg, i.p.), Apo (0.5 mg/kg, s.c.) or QNP (0.3 mg/kg and 1.0 mg/kg, s.c.), 120 min after BRC (1 and 40 mg/kg, i.p.) and 15 min after SKF38393 (10 mg/kg, s.c.). The PPI test consisted of 60 presentations divided into pulse (100 dB), prepulse (65, 70, 75 and/or 80 dB) and prepulse + pulse. RESULTS: L-NOARG prevented the PPI disruption caused by Amph (2 mg/kg). Apo, QNP and BRC disrupted PPI, but these effects were not significantly changed by L-NOARG. SKF38393 had no significant effect on PPI whether or not preceded by L-NOARG. CONCLUSIONS: Our findings show that L-NOARG interacted with Amph, an indirect DA agonist, but not with the direct DA agonists on PPI, suggesting that NO is involved on the dopaminergic modulation of sensorimotor gating, probably by a presynaptic mechanism.

Unilateral electrical stimulation of the inferior colliculus of rats modifies the prepulse modulation of the startle response (PPI): effects of ketamine and diazepam.

The magnitude of an acoustic startle response can be reduced by a weak stimulus presented immediately before the startle-eliciting noise. This phenomenon has been termed prepulse inhibition of the startle reaction (PPI). Previous studies indicated that the primary neural pathways mediating PPI belong to the brain stem and that the inferior colliculus (IC) was crucial. Its destruction reduced PPI. Stimulations applied to brain areas may be as deleterious as lesions. Therefore, we looked for the possibility of a brain stimulation applied to the IC during a PPI test to reduce also PPI. Rats were implanted with chronic electrodes, their tips being aimed at the IC. They were located within or close to the inter-colliculus nucleus. A train of stimulations was applied and PPI was tested alternately during and between periods of stimulation. As the most common method used to attenuate PPI consists in administrating drugs, for example ketamine, we also tested the effect of this drug. Another drug was also tested, diazepam, since it alters the functioning of the IC without any known effect on PPI. This allowed a comparative analysis of the neurobiological and the pharmacological effects. It appeared that the stimulation decreased PPI quantitatively as much as ketamine (6 mg/kg) without an effect of the basic startle reaction. These effects did not interfere with each other. Diazepam (1 mg/kg) did not modify PPI, neither under stimulation nor per se. Only for a very high dose (4 mg/kg), a sedative and myo-relaxant one the basic startle and PPI were altered.

Facilitation of learning and modulation of frontal cortex acetylcholine by ventral pallidal injection of heparin glucosaminoglycan.

We examined the effects of heparin on learning and frontal cortex acetylcholine parameters following injection of the glucosaminoglycan into the ventral pallidum. In Experiment 1, possible mnemoactive effects of intrapallidal heparin injection were assessed. Rats with chronically implanted cannulae were administered heparin (0.1, 1.0, 10 ng) or vehicle (0.5 microl) and were tested on a one-trial step-through avoidance task. Two retention tests were carried out in each animal, one at 1.5 h after training to measure short-term memory and another at 24 h to measure long-term memory. Post-trial intrapallidal injection of 1.0 ng heparin improved both short- and long-term retention of the task, whereas the lower and the higher dose of the glucosaminoglycan had no effect. When the effective dose of heparin was injected 5 h, rather than immediately after training, it no longer facilitated long-term retention of the conditioned avoidance response. In Experiment 2, the effects of ventral pallidal heparin injection on frontal cortex acetylcholine and choline concentrations were investigated with in vivo microdialysis in anaesthetized rats. Heparin, administered in the dose of 1.0 ng, which was effective in facilitating avoidance performance, produced a delayed increase in cortical acetylcholine levels ipsi- and contralaterally to the side of intrabasalis injection, resembling the known neurochemical effects obtained for another glycosaminoglycan, chondroitin sulfate, which recently was shown to facilitate inhibitory avoidance learning and to increase frontal cortex acetylcholine. The present findings indicate that heparin, like other extracellular matrix proteoglycans, can exert beneficial effects on memory and strengthen the presumptive relationship between such promnestic effects of proteoglycans and basal forebrain cholinergic mechanisms. The data are discussed with respect to the presumed roles of matrix molecules in extrasynaptic volume transmission and in the 'cross-talk' between synapses.

Signaled two-way avoidance learning using electrical stimulation of the inferior colliculus as negative reinforcement: effects of visual and auditory cues as warning stimuli.

The inferior colliculus is a primary relay for the processing of auditory information in the brainstem. The inferior colliculus is also part of the so-called brain aversion system as animals learn to switch off the electrical stimulation of this structure. The purpose of the present study was to determine whether associative learning occurs between aversion induced by electrical stimulation of the inferior colliculus and visual and auditory warning stimuli. Rats implanted with electrodes into the central nucleus of the inferior colliculus were placed inside an open-field and thresholds for the escape response to electrical stimulation of the inferior colliculus were determined. The rats were then placed inside a shuttle-box and submitted to a two-way avoidance paradigm. Electrical stimulation of the inferior colliculus at the escape threshold (98.12 +/- 6.15 (A, peak-to-peak) was used as negative reinforcement and light or tone as the warning stimulus. Each session consisted of 50 trials and was divided into two segments of 25 trials in order to determine the learning rate of the animals during the sessions. The rats learned to avoid the inferior colliculus stimulation when light was used as the warning stimulus (13.25 +/- 0.60 s and 8.63 +/- 0.93 s for latencies and 12.5 +/- 2.04 and 19.62 +/- 1.65 for frequencies in the first and second halves of the sessions, respectively, P < 0.01 in both cases). No significant changes in latencies (14.75 +/- 1.63 and 12.75 +/- 1.44 s) or frequencies of responses (8.75 +/- 1.20 and 11.25 +/- 1.13) were seen when tone was used as the warning stimulus (P > 0.05 in both cases). Taken together, the present results suggest that rats learn to avoid the inferior colliculus stimulation when light is used as the warning stimulus. However, this learning process does not occur when the neutral stimulus used is an acoustic one. Electrical stimulation of the inferior colliculus may disturb the signal transmission of the stimulus to be conditioned from the inferior colliculus to higher brain structures such as amygdala.

Signaled two-way avoidance learning using eletrical stimulation of the inferior colliculus as negative reinforcement: effects of visual and auditory cues as warning stimuli

The inferior colliculus is a primary relay for the processing of auditory information in the brainstem. The inferior colluculus is also part of the so-called brain aversion system as animals learn to switch off the electrical stimulation of this structure. The purpose of the present study was to determine whether associative learning occurs between aversion induced by electrical stimulation of the inferior colliculus and visual and auditory warning stimuli. Rats implanted with electrodes into the central nucleus of the inferior colliculus were placed inside an open-field and thresholds for the escape response to electrical stimulation of the inferior colliculus were determined. The rats were then placed inside a shuttle-box and submitted to a two-way avoidance pardigm. Electrical stimulation of the inferior colliculus at the escape threshold (98.12 + 6.15 (A, peak-to-peak) was used as negative reinforcement and light or tone as the warning stimulus. Each session consisted of 50 trials and was divided into two segments of 25 trials in order to determine the learning rate of the animals during the sessions. The rats learned to avoid the inferior colliculus stimulation when light was used as the warning stimulus (13.25 + 0.60 s and 8.63 + 0.93 for lactencies and 12.5 + 2.04 and 19.62 + 1.65 frequencies in the first and second halves of the sessions, respectively, P<0.01 in both cases). No significant changes in latencies (14.75 + 1.63 and 12.75 + 1.44 s) or frequencies of responses (8.75 + 1.20 and 11.25 + 1.13) were seen when tone was used as the warning stimulus (P>0.05 in both cases). Taken together, the present results suggest that rats learn to avoid the inferior colliculus stimulation when light is used as the warning stimulus. However, this learning process does not occur when the neutral stimulus used is an acoustic one. Electrical stimulation of the inferior colliculus may disturb the signal transmission of the stimulus to be conditioned from the inferior colliculus to higher brain structures such as amygdala.

Bilateral ablation of the auditory cortex in the rat alters conditioned emotional suppression to a sound as appraised through a latent inhibition study.

Latent inhibition consists of a retardation of conditioning seen when the to be conditioned stimulus is presented a number of times with no other consequence. This phenomenon likely reflects processes of selective attention whereby irrelevant stimuli come to be ignored. Using physiological models for auditory attention, some investigators have suggested that selective attention acts as a filtering mechanism capable of inhibiting or gating unattended stimuli relative to attended ones in the auditory cortex. In the present work, an on-baseline conditioned suppression response procedure was used to study the effects of stimulus preexposure in rats submitted to bilateral auditory cortex ablation. Our results indicate that both auditory cortex lesioned and control animals exhibit latent inhibition to a sound. However, learning after preexposure to that sound was particularly slow in animals with bilateral auditory cortex lesion, i.e. in these animals, the latent inhibition effect appeared to be enhanced. Conditioning from one day to the next also varied slightly. Thus, the auditory cortex appears to modulate learning when the conditioned stimulus is a sound.