Pharmacological evidence for two kinds of GABA receptor on rat hippocampal pyramidal cells studied in vitro.

1. The rat hippocampal slice preparation has been used in conjunction with intracellular recording and ionophoresis to study the action of gamma-aminobutyric acid (GABA) on CA1 pyramidal cells.2. GABA elicits a hyperpolarizing (h.) response at the soma. The reversal potential of this h. response is the same as for inhibitory post-synaptic potentials (i.p.s.p.s) evoked by stimulating pyramidal cell axons.3. GABA elicits primarily depolarizing (d.) responses when applied to the apical dendrites, but h. responses can also be found.4. The GABA antagonists bicuculline methiodide, picrotoxin, penicillin, and pentylenetetrazole are all ten to one hundred times more potent on the d. response than on the h. response. Hyperpolarizing responses are uncovered in the dendrites when intermediate doses of these drugs block the d. response.5. The GABA analogue, 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP), which has been proposed to activate synaptic receptors preferentially in other systems, elicits h. responses in the dendrites. It is one seventh as potent as GABA in eliciting d. responses.6. Pentobarbitone enhances d. responses to a much greater extent than h. responses, while diazepam enhances h. responses to a greater extent.7. Nipecotic acid, low temperature, and low sodium media all increase the size of d. responses to ionophoretically applied GABA indicating that an active uptake process limits their size.8. We conclude that h. responses reflect the activation of synaptic receptors which are highly concentrated on the pyramidal cell soma-initial segment, but are also present on the dendrites. Depolarizing responses, which are evoked in the dendrites, reflect the activation of extrasynaptic receptors.9. We propose that an ordinarily undetectable amount of synaptically released GABA can ;spill' over onto extrasynaptic (d.) receptors. Depolarizing receptor activation can be detected in the presence of pentobarbitone. Spillover is markedly enhanced at subphysiological temperatures presumably due to enhanced release of GABA and impairment of the GABA uptake system.