Defense reaction mediated by NMDA mechanisms in the inferior colliculus is modulated by GABAergic nigro-collicular pathways

Abstract

Electrical stimulation of the inferior colliculus (IC) causes a behavioral activation together with autonomic responses similar to fear reactions to threatening situations. GABAergic mechanisms exert a tonic inhibitory control on the neural substrates of aversion in the IC insofar as local injections of GABA agonists or antagonists inhibit or mimic these defensive behaviors, respectively. Recently, we have shown that systemic injections of the GABA-A receptor agonist muscimol unexpectedly enhanced the freezing and escape responses provoked by gradual increases in the intensity of the electrical stimulation of the IC. Taking into account that the neural circuits mediated by excitatory amino acids (EAA) in the IC may be responsible for the integration of fear states, in the present study we examined whether the defensive behavior induced by local injections of NMDA into the IC is influenced by prior treatment with systemic muscimol and also whether this GABAergic control could be exerted by GABAergic fibers that project to the inferior colliculus from the substantia nigra pars reticulata (SNpr). Rats were implanted with two guide-cannulae aimed at the IC and SNpr through which drug microinfusions with glass micropipette could be made with reduced brain damage. One week after surgery, the animals received either NMDA (7 nmol/0.2 μl) or saline into the IC and were placed into the middle of an enclosure where behavioral responses such as freezing, crossings, jumping, rearing, and turnings could be measured as an indirect index of unconditioned fear. These animals were pretreated either with saline or muscimol (0.5 mg/kg, IP) or with brain injections of saline or muscimol (1 nmol/0.2 ı̀l into SNpr). NMDA applied into the IC produced a behavioral activation with significant increases in all behavioral measures. IP injections of muscimol or into the SNpr enhanced the defense reaction caused by microinjections of NMDA into the IC. These findings give support to the idea that unconditioned defensive responses generated in the IC may be mediated by NMDA mechanisms. Additionally, a reduction of the inhibitory control exerted by nigrocollicular GABAergic neurons seems to be responsible for the unexpected pro-aversive action of systemic injections of muscimol on the neural substrates of aversion mediated by NMDA in the IC.