Neurochemical mechanisms of the defensive behavior in the dorsal midbrain
Introduction
The chemical nature of the defence reaction has been examined for decades and the enormous advances achieved in this area of research are now providing a more clear picture of what happens in the brain during these processes. It has been postulated that amygdala, medial hypothalamus and dorsal periaqueductal gray (DPAG) constitute the main neural substrates for the integration of aversive states in the brain [1], [2], [3], [4], [5], [6]. In this review we will focus on the neural substrate of defensive behavior, and by extension of fear and anxiety, in the midbrain tectum. We summarize literature studies, many from our own laboratory, showing that the superior and inferior colliculi act in concert with DPAG in the integration of aversive states in the brain. Indeed, reciprocal anatomical connections have been demonstrated among the inferior colliculus and superior colliculus and DPAG [7], [8], [9], [10], [11]. This is consistent with the demonstration of functional connections between the inferior colliculus and these structures [12], and in particular, with the aversion-related functions of these structures, i.e. those involved in the regulation of the behavioral expression of fear states and the changes in nociceptive processing that accompany these states [1]. Besides the reciprocal connections these midbrain structures have with each other there also exist two-way projections from DPAG and medial hypothalamus and amygdala [13], [14], [15]. A diagramatic representation of these anatomical connections is shown in Fig. 1. All evidence points to a multicomponent process for the defence reaction and this makes sense due to the complexity of defensive behavior expressed by animals when they face danger or predators. In this review, we will focus on the nature and chemical mediation of fear-related behavior induced by electrical and chemical stimulation of the dorsal midbrain.
Section snippets
Electrical stimulation of the neural substrates of aversion in the midbrain tectum
There are many reports showing that defence patterns are organized in a hierarchical series of responses [16], [17], [18]. In this line, evidence from this laboratory has shown that gradually increasing the intensity of electrical stimulation of the dorsal periaqueductal gray (DPAG), deep layers of the superior colliculus (DLSC) and of the inferior colliculus of rats induces, in a progressive manner, characteristic aversive responses such as arousal, freezing and escape behavior [19], [20], [21]
GABAergic restraint of the neural substrates of aversion
Local injections of benzodiazepines into the midbrain tectum depress both unlearned and learned escape behaviors induced by electrical stimulation of this region [19], [24], [52], [53]. That these effects are mediated by benzodiazepines receptors is supported by the fact that chlordiazepoxide or midazolam raise the aversive threshold of midbrain tectum electrical stimulation in a dose-dependent manner, producing parallel dose–effect curves and that the effects of both drugs were blocked by
Activation of excitatory amino acid receptors
Circumventing the main problem associated with the electrical stimulation procedure, which excites both neuronal cell bodies and axons of passage, intracerebral microinjections of excitatory amino acids (EAA) cause selective depolarization of somatodendrites. The excitatory amino acids, among many important physiological functions, also play a significant role in the expression of defensive behavior. Considerable evidence suggests that EAA play a critical function in integrating somatic and
Opioid modulation
A large body of evidence supports a modulatory role for opioids in the brain aversion system. As a matter of fact, it has been reported that microinjections of low doses of morphine into midbrain tectum (DPAG and inferior colliculus) attenuates in a dose-dependent manner the aversive consequences of tectal stimulation [87], [88], [89]. High doses of morphine, however, when locally injected into this region causes a behavioral activation together with jumps which is similar to the reaction
Neuropeptides
The involvement of neuropeptides in the processing of the defence reaction has not been well studied. Among them special attention has been given lately to the neurokinin, substance P, due to the possibility of the clinical use of neurokinin receptors antagonists (NK-1 receptors, particularly) as anxiolytic agents [108]. Animal studies supporting these clinical studies had already shown substance P to be present within circuits of the brain aversion system, such as amygdala and hypothalamus
Serotonergic mechanisms
Serotonergic mechanisms have been one of the main focus of attention in the search for the neural basis of fear in the brain. At the mesencephalic level the median raphe nucleus has been implicated in the control of conditioned fear, while the dorsal raphe nucleus regulates the unconditioned responses to aversive stimulation of the midbrain tectum [34], [120]. In this respect, many studies have shown that 5-HT exerts an inhibitory role on unconditioned fear in the DPAG. In fact, inhibition of
Acknowledgements
This work was supported by FAPESP (Proc no. 98/11187-2 and 98/11706-0). M.L. Brandão is a research fellow from CNPq (524011/94-0). J.E. Pandossio is a recipient of the doctoral scholarship from CAPES, J.E. Araújo is a recipient of the doctor scholarship from CNPq and V. Anseloni and V.M. Castilho from FAPESP.
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