Mechanisms of defense in the inferior colliculus

The inferior colliculus (IC) is a well known relay station for auditory pathways in the brainstem. In the present review we are suggesting that aversive states are also generated and elaborated in the inferior colliculus and that this structure may be part of a brain system commanding defensive behavior. The evidences presented in this review have been obtained from experiments carried out with the combined use of intracerebral microinjections and of electrical stimulation of the inferior colliculus. This electrical stimulation caused a behavioral activation together with autonomic reactions usually observed as part of the defense reaction. NMDA—an excitatory amino acid—, or bicuculline—a GABAA antagonist—injected into the IC mimicked the effects of its electrical stimulation. The IC electrical stimulation showed clear aversive properties as rats submitted to a switch-off paradigm quickly learned to interrupt it. Systemic administration as well as IC microinjections of the anxiolytic compound midazolam caused dose-dependent increases in the latency and reductions in the frequency of switch-off responses to the inferior colliculus electrical stimulation. Similar results were obtained following microinjections into this brainstem structure of the GABAA agonist muscimol. These results suggest that neural substrates responsible for defensive behavior in the inferior colliculus may be depressed by benzodiazepines as part of the anxiolytic action of these compounds. This anti-aversive action may be produced by the enhancement of GABAA mechanisms. Serotonergic mechanisms seem also to be involved in the modulation of these aversive states as IC microinjections of zimelidine, a 5-HT uptake blocker, caused a significant inhibition of the switch-off responses in the shuttle-box. Stepwise increases in the intensity of electrical stimulation of the IC of rats placed inside a circular arena allowed the determination of thresholds for freezing and escape behavior. In this context, morphine caused dose-dependent increases in both aversive thresholds. This antiaversive effect was attenuated by IC microinjection of naloxone suggesting that neural substrates commanding defensive behavior in this structure are under opioid inhibitory control. Higher doses of morphine induced a non-naloxone reversible ‘fearful’ hyper-reactivity. It is suggested that opioid mechanisms exert an inhibitory control on the neural substrates of aversion in the IC and that high doses of morphine microinjected into IC cause pro-aversive actions probably through receptors different from μ opioid receptors. In view of all these results showing a chemical mediation of the aversive states in the IC by GABA, excitatory amino acids, serotonin and opioid mechanisms we suggest that these mechanisms operate in the inferior colliculus modulating aversive states as they do in the dorsal periaqueductal gray as it has been consistently demonstrated by innumerable studies.