Marcus Lira Brandão

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.

Antidepressant-like effects of medial prefrontal cortex deep brain stimulation in rats.

BACKGROUND Subcallosal cingulate gyrus (SCG) deep brain stimulation (DBS) is being investigated as a treatment for major depression. We report on the effects of ventromedial prefrontal cortex (vmPFC) DBS in rats, focusing on possible mechanisms involved in an antidepressant-like response in the forced swim test (FST). METHODS The outcome of vmPFC stimulation alone or combined with different types of lesions, including serotonin (5-HT) or norepineprhine (NE) depletion, was characterized in the FST. We also explored the effects of DBS on novelty-suppressed feeding, learned helplessness, and sucrose consumption in animals predisposed to helplessness. RESULTS Stimulation at parameters approximating those used in clinical practice induced a significant antidepressant-like response in the FST. Ventromedial PFC lesions or local muscimol injections did not lead to a similar outcome. However, animals treated with vmPFC ibotenic acid lesions still responded to DBS, suggesting that the modulation of fiber near the electrodes could play a role in the antidepressant-like effects of stimulation. Also important was the integrity of the serotonergic system, as the effects of DBS in the FST were completely abolished in animals bearing 5-HT, but not NE, depleting lesions. In addition, vmPFC stimulation induced a sustained increase in hippocampal 5-HT levels. Preliminary work with other models showed that DBS was also able to influence specific aspects of depressive-like states in rodents, including anxiety and anhedonia, but not helplessness. CONCLUSIONS Our study suggests that vmPFC DBS in rats may be useful to investigate mechanisms involved in the antidepressant effects of SCG DBS.

Neural substrate of defensive behavior in the midbrain tectum

It has been shown that the gradual increase in the intensity of electrical stimulation of the dorsal periaqueductal gray (DPAG), deep layers of the superior colliculus (DLSC) and inferior colliculus of rats induces, in a progressive manner, characteristic aversive responses such as arousal, freezing, and escape behavior. The DPAG-DLSC together with the periventricular gray substance of the diencephalon, amygdala and the inferior colliculus, constitute the neural substrate of aversion in the brain. In general, the behavioral responses induced by midbrain tectum stimulation are accompanied by increases in the mean arterial blood pressure, heart rate, and respiration. Both the behavioral and autonomic consequences of electrical stimulation of the mesencephalic tectum have been shown to be attenuated by minor tranquilizers, probably through enhancement of GABAergic neurotransmission. Besides GABAergic mechanisms several lines of evidence have clearly implicated opioid, serotonergic, and excitatory amino acids-mediated mechanisms in the control of the neural substrates commanding defensive behavior in the brain aversive system.

Different patterns of freezing behavior organized in the periaqueductal gray of rats: Association with different types of anxiety

Freezing defined as the complete absence of body movements is a normal response of animals to unavoidable fear stimuli. The present review presents a series of evidence relating different defensive patterns with specific anxiety disorders. There are at least four different kinds of freezing with specific neural substrates. The immobility induced by stimulation of the ventral column of the periaqueductal gray (vPAG) has been considered a quiescence characteristic of the recovery component of defense-recuperative processes. There is an isomorphism between freezing response to contextual stimuli paired with electrical shocks and generalized anxiety disorder. Besides, two types of freezing emerge with the electrical stimulation of the dorsal aspects of the periaqueductal gray (dPAG): the dPAG-evoked freezing and the dPAG post-stimulation freezing. Evidence is presented in support of the hypothesis that whereas dPAG-evoked freezing would serve as a model of panic attacks, the dPAG post-stimulation freezing appears to be a model of panic disorder. It is also proposed that conditioned freezing plus dPAG electrical stimulation might also mimic panic disorder with agoraphobia. A model of serotoninergic modulation through on- and off-cells of the defense reaction generated in the dPAG is also presented. The understanding of how the periaqueductal gray generates and elaborates different types of freezing is of relevance for our better knowledge of distinct types of anxiety such as panic disorder or generalized anxiety disorder.

Role of resocialization and of 5-HT1A receptor activation on the anxiogenic effects induced by isolation in the elevated plus-maze test

Rats were isolated for periods varying from 1 h to 2 weeks and the exploratory activity of these animals on the elevated plus-maze was studied. Rats isolated from periods of 2 h on displayed a significant reduction in the number of entries and time spent in the open arms of the plus-maze compared to socially housed controls. This effect was not correlated with the decrease in the total number of entries also produced by isolation. Acute treatment with midazolam or resocialization for a 24-h period clearly reversed these responses produced by prior 2-h isolation in the elevated plus-maze. It is suggested that exposure to a 2-h isolation period could be a useful nonpharmacological means of generating anxiety in laboratory rodents. Chronic treatment, but not acute treatment, with gepirone, a 5-HT1A agonist, inhibited the anxiogenic effects caused by a 2-week period of isolation. The reduction in aversiveness promoted by resocialization may be due to a recovery in the 5-HT activity depressed by isolation in a much faster way than observed with chronic gepirone administration.

The relevance of neuronal substrates of defense in the midbrain tectum to anxiety and stress: empirical and conceptual considerations.

The medial hypothalamus, amygdala, and dorsal periaqueductal gray constitute the main neural substrates for the integration of aversive states in the brain. More recently, some regions of the mesencephalon, such as the superior and inferior colliculi have also been proposed as part of this system. In fact, fear-like behaviors often result when these sites are electrically or chemically stimulated. Both the behavioral and autonomic consequences of electrical stimulation of the mesencephalic tectum have been shown to be attenuated by minor tranquilizers, probably through enhancement of gamma-aminobutyric acid (GABA)-mediated neurotransmission, which exerts a tonic inhibitory control on the neural circuits responsible for the so-called defense behavior repertoire. Besides GABA, also 5-hydroxy tryptamine serotonin (5-HT), opioids, neuropeptides, histaminergic and excitatory amino acids have all been implicated in the regulation of anxiety-related behaviors induced by stimulation of midbrain tectum. Efforts have been made to characterize how these neurotransmitters interact with each other in the organization of these reactions to aversive stimulation. In this review, we summarize the evidence linking the brains defense response systems to the concept of fear-anxiety. Furthermore, a case is made for the consideration of the relevance of this body of data to the search for the physiological underpinnings of depression and its consequences.

Defense reaction induced by microinjections of bicuculline into the inferior colliculus

Behavioral and autonomic effects of microinjections of bicuculline--a GABA receptor antagonist--into ventral aspects of the inferior colliculus (IC) produced a behavioral activation together with jumps. This activation was similar to escape behavior that has been induced from periventricular structures although it was neither as explosive as that observed from the dorsal periaqueductal gray matter (DPAG) nor as coordinated as that obtained from the medial hypothalamus (MH). In anesthetized rats, microinjection of bicuculline into the IC produced a clear rise in mean arterial blood pressure and in heart rate. These effects reached a maximum after 10 min and subsided within 20 min after injection. GABA receptor blockade in the IC of detelencephalated rats also resulted in escape behavior qualitatively similar to that observed in intact animals. These results suggest that in addition to the central gray and medial hypothalamus, GABA also exerts a tonic inhibitory action on neurons of the IC implicated in the generation or elaboration of aversive responses.

Anatomical connections of the periaqueductal gray: specific neural substrates for different kinds of fear

The periaqueductal gray (PAG) has been traditionally considered to be an exit relay for defensive responses. Functional mapping of its subdivisions has advanced our knowledge of this structure, but synthesis remains difficult mainly because results from lesion and stimulation studies have not correlated perfectly. After using a strategy that combined both techniques and a reevaluation of the available literature on PAG function and connections, we propose here that freezing could be mediated by different PAG subdivisions depending on the presence of immediate danger or exposure to related signaling cues. These subdivisions are separate functional entities with distinct descending and ascending connections that are likely to play a role in different defensive responses. The existence of ascending connections also suggests that the PAG is not simply a final common path for defensive responses. For example, the possibility that indirect ascending connections to the cingulate cortex could play a role in the expression of freezing evoked by activation of the neural substrate of fear in the dorsal PAG has been considered.

Effects of microinjections of the neuropeptide substance P in the dorsal periaqueductal gray on the behaviour of rats in the plus-maze test.

Currently, the participation of neuropeptides in the generation of aversive states in the dorsal periaqueductal gray matter (DPAG) is poorly understood. The elevated plus maze (EPM) is widely used for studying the neurobiological mechanisms of anxiety in the laboratory. One difficulty with this test has been to evaluate the involvement of GABA mechanisms in the DPAG substrates of aversion, because microinjections of GABA receptor blockers in this region cause an intense behavioral activation. In this study, we examined in the EPM the effects of semicarbazide, a drug that acts indirectly on GABA neurotransmission through inhibition of the glutamic acid decarboxylase, and substance P (SP) following microinjections into the dorsal periaqueductal gray. Semicarbazide caused a clear decrease in the number of entries and time spent in the open arms. These results confirm previous data showing that GABA has a modulatory role in the DPAG, probably through reduction of tonic inhibitory mechanisms on neural substrates of aversion. A similar pattern of behavioral responses was observed with SP. However, these effects were more pronounced with intermediate doses of SP (25 ng), confirming the characteristic bell-shaped dose-effect function of this neuropeptide. The proaversive effects observed with DPAG microinjections of SP in the present study gain further relevance when combined with previous reports that have shown unconditioned and conditioned aversive effects following DPAG microinjections of SP in other animal models of aversion.

Gabaergic regulation of the neural organization of fear in the midbrain tectum

In midbrain tectum (MT) structures, such as the dorsal periaqueductal gray (dPAG), the superior colliculus (SC) and the inferior colliculus (IC) GABAergic neurons exert a tonic control on the neural substrates involved in the expression of defensive reactions. In this review, we summarize behavioral, immunohistochemical (brain Fos distribution) and electrophysiological (auditory evoked potentials) data obtained with the reduction of GABA transmission by local injections of a GABA receptor blocker (bicuculline, BIC) or a glutamic acid decarboxylase inhibitor (semicarbazide, SMC) into the MT. Distinct patterns of Fos distribution were obtained following the freezing and escape reactions induced by MT injections of SMC and BIC, respectively. While only the laterodorsal nucleus of the thalamus was labeled after SMC-induced freezing, a widespread increase in Fos expression in the brain occurred after BIC-induced escape. Also, injections of SMC into the IC increased the auditory evoked potentials recorded from this structure. It is suggested that GABAergic mechanisms of MT are also called into play when sensory gating of the MT is activated during different emotional states.