Dopamine selectively reduces GABA(B) transmission onto dopaminergic neurones by an unconventional presynaptic action

Abstract

The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement. In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine (DA) release in the brain. Here, we report a concentration-dependent depressant action of dopamine on the GABA(B) IPSPs intracellularly recorded from dopaminergic neurones. Such effect was observed in spite of the presence of D(1)/D(2) dopamine receptor antagonists. A reduction of the GABA(B) IPSPs was also caused by noradrenaline (norepinephrine) and by L-beta-3,4-dihydroxyphenylalanine (L-DOPA), which is metabolically transformed into DA. The DA-induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine. DA did not change the postsynaptic effects of the GABA(B) agonist baclofen, suggesting a presynaptic site of action. Furthermore, DA did not modulate the GABA(A)-mediated IPSP. The DA-induced depression of the GABA(B) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists. The DA- and 5-HT-induced depression of the GABA(B) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals. These results describe an unconventional presynaptic, D(1) and D(2) independent action of DA on the GABA(B) IPSP. This might have a principal role in determining therapeutic/side effects of L-DOPA and antipsychotics and could be also involved in drug abuse.

Figure 1. Dopamine inhibits the GABA_B IPSP

A, example of the concentration-dependent and reversible inhibition caused by DA in the slow IPSP which was subsequently reduced by the GABA_B receptor antagonist CGP (300 nm). B, time course of DA effects. Here and in subsequent graphs, the amplitudes of the IPSPs were normalized to the control amplitude determined for at least 5 min before application of DA. Each data point in this graph represents the mean ± s.e.m. of 7 cells. C, concentration-dependent curve of the reducing effects of DA on the GABA_B-mediated IPSP. Each point represents the mean ± s.e.m. of 25 cells.

Figure 2. Dopaminergic antagonists do not change the DA-mediated reduction of the GABA_B IPSP, NA mimics DA action while several noradrenergic antagonists are ineffective

A, the bars show that haloperidol (10 μm), clozapine (10 μm), chlorpromazine (Chlorpromaz, 10 μm) and spiperone (10 μm) had no significant antagonizing effect (P > 0.05 for each compound) on the DA-induced (100 μm) depression of the GABA_B potentials. Each column shows the average of three to four experiments. B, reversible inhibition of an IPSP by noradrenaline (100 μm). C, time course of NA-induced depression of the IPSP. Each data point represents the mean ± s.e.m. of four cells. D, the graph shows the lack of antagonizing effect (P > 0.05) of several NA antagonists, propanolol (20 μm), pindolol (300 nm), prazosin (300 nm), on the DA-induced depression (100 μm) of the IPSP. Note that yohimbine (10 μm) and phentolamine (Phentol, 30 μm) caused an incomplete but significant (P < 0.05) reduction in the DA effect. Each column shows an average of four to five cells. Asterisks indicate significant reduction of the DA-induced effect.

Figure 3. l-DOPA suppresses the GABA_B IPSP through its metabolic transformation

A, reversible inhibition of the IPSP caused by l-DOPA and DA. Only the attenuation caused by l-DOPA but not that caused by DA is blocked by pretreatment of the slices with carbidopa (300 μm). B, time course of l-DOPA (100 μm) and DA (100 μm) effects and modification of l-DOPA action by carbidopa (300 μm). Each data point in this figure represents the mean ± s.e.m. of four cells.

Figure 4. Dopamine selectively decreases the GABA_B-mediated IPSP by a presynaptic mechanism leaving the GABA_A IPSP unaffected

A, dopamine (100 μm) reduces the GABA_B IPSP without changing the membrane hyperpolarization caused by puffer applications of the GABA_B agonist baclofen (300 μm, 10–20 p.s.i., 8–10 ms). B, lack of DA effects on the GABA_A IPSP.

Figure 5. Activation of 5-HT_1B presynaptic receptors occludes the effects of DA on the GABA_B IPSP

Examples of IPSP inhibition caused by 5-HT and DA. Only the 5-HT but not the DA effects are antagonized by the 5-HT_1B receptor antagonist cyanopindolol (A). The inhibition of the IPSP caused by 5-HT is very similar to that induced by DA (B). The graph shows that the inhibition of the GABA_B IPSP caused by DA and 5HT is not additive. Each column shows the average of four to eight cells (C).

Figure 6. The superfusion of calcium and potassium blockers did not prevent DA and 5HT presynaptic actions

Dopamine (A) and serotonin (B) presynaptic actions in control and drug-treated slices (Nife, nifedipine; Tolb, tolbutamide). Columns show means of three experiments Note that either the DA- or the 5-HT-mediated inhibition of neurotransmitter release are not significantly different from control during the different experimental conditions (P > 0.05).