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1. We have studied the effects of the purportedly selective 5-HT1A receptor antagonist (+)-WAY 100135 on electrically stimulated 5-hydroxytryptamine (5-HT) efflux in the ventrolateral geniculate nucleus (vLGN), and its affinity at human 5-HT1B and 5-HT1D receptors stably expressed in Chinese hamster ovary (CHO) cells. 2. On short 'pseudo single pulse' stimulations (20 pulses at 100 Hz, 190 ms train duration), (+)-WAY 100135 (1.0 microM) decreased 5-HT efflux in the vLGN to 68 +/- 8% of pre-drug values (P < 0.01). This decrease could be blocked by the 5-HT1D/1B receptor antagonist GR 127935 (50 nM). Conversely, when long stimulations (20 pulses at 20 Hz, 950 ms train) were used, (+)-WAY 100135 had no effect on 5-HT efflux (84 +/- 8% of pre-drug values) although both methiothepin (200 nM) and GR 127935 (50 nM) caused significant increases (to 175 +/- 18 and 130 +/- 10% of pre-drug values, respectively). 3. Paroxetine (100 nM), the selective 5-HT reuptake inhibitor, increased stimulated 5-HT efflux and reuptake half-life (to 145 +/- 18% and 649 +/- 121%, respectively) on pseudo single pulse stimulations. When (+)-WAY 100135 was added in combination with the uptake blocker, the effect of paroxetine on stimulated 5-HT efflux was potentiated to 282 +/- 48% (P < 0.01) without further effect on the 5-HT reuptake half-life. 4. The affinity and intrinsic activity of (+)-WAY 100135 were determined at recombinant human 5-HT1B and 5-HT1D receptors expressed in CHO cells, by use of radioligand binding and [35S]-GTP gamma S binding (+)-WAY 100135 was a partial agonist at human 5-HT1B and 5-HT1D receptors with moderately high affinity for 5-HT1D receptors (pEC50 = 7.61). 5. In conclusion, (+)-WAY 100135 was found to be not a selective 5-HT1A autoreceptor antagonist but may act as a partial agonist at the 5-HT1B/1D receptor, displaying agonist or antagonist properties depending on the stimulation protocol used and the resultant 5-HT 'tone' at the receptor.

Electrically stimulated 5-hydroxytryptamine (5-HT) release was monitored in slices of rat dorsal raphé nucleus (DRN) by fast cyclic voltammetry. Pseudo-single pulse stimulations (5 pulses at 100 Hz) were used to enable the effect of various receptor agonists to be seen without competition from endogenously released transmitter. The selective 5-HT1A receptor agonist, (+)-8-OH-DPAT (1.0 microM) decreased stimulated 5-HT release to 31 +/- 3% of controls. This decrease was inhibited by the 5-HT1A receptor antagonists, (+)-WAY-100135 (1.0 microM) and WAY-100635 (0.1 microM) but not by the 5-HT1D/B antagonist, GR127935 (0.05 microM). The selective 5-HT1B receptor agonist, CP-93129 (0.3 microM) decreased stimulated 5-HT release to 61 +/- 4% of control. This effect was antagonized by the 5-HT1B receptor antagonist, isamoltane (0.5 microM) but not by (+)-WAY-100135. The 5-HT1D agonist, sumatriptan (0.5 microM) decreased stimulated 5-HT release to 52 +/- 2% of controls. This decrease was blocked by GR-127935 but not by WAY-100635. These results suggest that 5-HT release in the rat DRN is under the control of 5-HT1A, 5-HT1B and 5-HT1D autoreceptors.

1. Fast cyclic voltammetry at carbon fibre microelectrodes was used in rats anaesthetized with chloral hydrate to monitor dopamine release in the caudate and nucleus accumbens evoked by electrical stimulation of the median forebrain bundle. Stimulation trains (50 Hz sinusoidal current, 100 +/- 10 microA r.m.s., 2s duration) were repeated every 5 min throughout the experiment. 2. The actions of the dopamine agonists quinpirole, pergolide, SKF 38393, bromocriptine, (+)-3-(3-hydroxyphenyl)-N-n-propylpiperidine ((+)-3PPP) and (-)-3PPP were compared in the two nuclei. 3. Bromocriptine (10 mg kg-1, i.p.) did not affect release in either nucleus while SKF 38393 caused a fleeting decrease in limbic but not striatal dopamine release at a high dose (20 mg kg-1, i.p.). 4. Quinpirole and pergolide (both 1 mg kg-1, i.p.) decreased stimulated dopamine release in the nucleus accumbens while in the caudate the drugs each caused a transient, though not quite significant, elevation of stimulated dopamine release followed by decrease in release of the same magnitude as that seen in the nucleus accumbens. 5. The (-)-enantiomer of 3PPP (20 mg kg-1, i.p.), a partial agonist at the dopamine autoreceptor, increased stimulated dopamine release in both nuclei although the action in the caudate was larger and more prolonged. (+)-3PPP (20 mg kg-1, i.p.), a full agonist, decreased release in the nucleus accumbens. A small, transient and not significant increase in the caudate was followed by decreased release. 6. The results are interpreted as being evidence for differences in the dopamine autoreceptor in the two nuclei, possibly in the affinity state of the receptor in each nucleus.

1. Fast cyclic voltammetry at carbon fibre microelectrodes was used to study the effects of several dopamine antagonists upon stimulated dopamine release in the rat striatum and nucleus accumbens. 2. In both nuclei, stimulated dopamine release was increased by D2-receptor-selective and mixed D1/D2-receptor antagonists. The D1-selective antagonist SCH 23390 had no effect. 3. Striatal and limbic dopamine release were elevated by cis- but not trans-flupenthixol. 4. The 'atypical' neuroleptics (clozapine and thioridazine) did not cause a selective elevation of dopamine release in the limbic terminal region, whereas the non-antipsychotic drug metoclopramide increased dopamine release more in striatum than nucleus accumbens. 5. We conclude from this study that striatal and limbic dopamine release are under the control of a stereoselective dopamine D2-autoreceptor on the nerve terminal and that atypical neuroleptics do not show a limbic-selective effect at this receptor after acute administration.