Baclofen reduces post-synaptic potentials of rat cortical neurones by an action other than its hyperpolarizing action.
1. Intracellular recordings were obtained from neurones in layers 2 and 3 of the rat frontal neocortex in an in vitro slice preparation. Three distinct types of stimulation-evoked post-synaptic potentials were recorded in these neurones: excitatory post-synaptic potentials (e.p.s.p.s); bicuculline-sensitive, chloride-dependent inhibitory post-synaptic potentials (i.p.s.p.s) with times to peak of 20-25 ms (fast(f)-i.p.s.p.s); bicuculline-insensitive, potassium-dependent i.p.s.p.s with bicuculline-insensitive, potassium-dependent i.p.s.p.s with times to peak of 150-250 ms (long(l)-i.p.s.p.s). 2. The effects of baclofen were investigated on seventy-one neurones. Baclofen was applied by ionophoresis or pressure ejection from micropipettes or was added to the superfusion medium. 3. Baclofen depressed stimulation-evoked e.p.s.p.s in fifty-seven of the sixty neurones tested. This effect was associated with an increase in the stimulation intensity required to produce a synaptically evoked action potential for thirty-nine of forty-four neurones. 4. Baclofen depressed f-i.p.s.p.s in thirty-seven of the thirty-nine neurones tested and l-i.p.s.p.s in each one of the seventeen neurones tested. Reversal potential values for each type of i.p.s.p. were not changed by baclofen and its depressions of each were independent of membrane potential (Em). Baclofen reduced the magnitude and the duration of the conductance increases that were associated with f- and l-i.p.s.p.s. 5. Baclofen hyperpolarized forty of seventy-one neurones and produced outward currents in three of four neurones recorded in voltage clamp at holding potentials between -55 and -65 mV. These actions were associated with 10-58% reductions of neuronal input resistance (RN) and 10-20% increases in neuronal input conductance (gN), respectively. Baclofen decreased the direct excitability of twenty-three of twenty-seven neurones tested. Determinations of the reversal potential for baclofen-induced changes of Em indicate that baclofen increases the conductance of rat neocortical neurones to potassium ions. 6. The EC50 for each action of DL-baclofen was approximately 1 microM. L-Baclofen was greater than 100 times more potent than D-baclofen. 7. Concentrations of bicuculline that blocked f-i.p.s.p.s and responses to ionophoretically applied gamma-aminobutyric acid (GABA) had no effect on the depressions of e.p.s.p.s or the hyperpolarizations and decreases in RN that baclofen produced. 8. Baclofen did not reduce the duration of action potentials that were prolonged with intracellular injections of caesium ions or by superfusions with medium that contained 10 mM-tetraethylammonium (TEA).(ABSTRACT TRUNCATED AT 400 WORDS)
Howe
J R
JR
Clinical Neuropharmacology, Max Planck Institute for Psychiatry, Munich, F.R.G.
Sutor
B
B
Zieglgänsberger
W
W
D000200:Action Potentials / Q000187:drug effects; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects*; D066298:In Vitro Techniques; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D011188:Potassium / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D019789:Tetraethylammonium; D013757:Tetraethylammonium Compounds / Q000494:pharmacology; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000596:Amino Acids; D013757:Tetraethylammonium Compounds; D001224:Aspartic Acid; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D019789:Tetraethylammonium; D001418:Baclofen; D011188:Potassium; D001640:Bicuculline