GABA mediation of the anti-aversive action of minor tranquilizers.

Earlier observations have shown that systematically injected minor tranquilizers decrease the aversive consequences of electrical stimulation of the dorsal periaqueductal gray (DPAG) matter of the rat brain. In order to verify if these drugs can act directly on the DPAG, chlordiazepoxide (CDP) and pentobarbital (PB) were locally injected into the dorsal midbrain of rats chronically implanted with chemitrodes, allowing electrical stimulation of the same brain area. Microinjection of doses of 0.16 and 0.32 mumol of CDP and 0.16 mumol of PB significantly increased the threshold electrical current including flight behavior by stimulating the dorsal midbrain. Flight behavior was measured by the number of times rats crossed dividing line while running from one compartment of a shuttle-box to the other. The same effect was caused by the intracerebral injection of 0.32 and 0.64 mumol of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). Conversely, local injection of the GABA antagonists. bicuculline (5-20) nmol) or picrotoxin (0.3 and 0.6 nmol), into the dorsal midbrain induced flight behavior, like the electrical stimulation. On the other hand, the glycine antagonist, strychnine (40 nmol) caused convulsive behavior only, while the intracerebral injection of the cholinergic agonist, carbachol (10-40 nmol), increased locomotion, sniffing and turning behavior, but did not induce flight. Pretreatment with locally injected GABA (0.64 mumol) antagonized the aversive effect of either bicuculline (10 nmol) or picrotoxin (0.3 nmol), whereas CDP (0.32 mumol) antagonised bicuculline only and PB (0.16 mumol) was ineffective against either bicuculline or picrotoxin. These results suggest that minor tranquilizers act directly upon the DPAG by enhancing the tonic inhibitory influence of endogenous GABA. This action may underly the antiaversive affects of these drugs.