Serotonergic modulation of neuronal activity in rat midbrain periaqueductal

25 Serotonin (5-HT) modulates pain and anxiety from within the midbrain periaqueductal grey (PAG). In the 26 present study, the effects of 5-HT and 5-HT1/2 subtype selective ligands on rat PAG neurons were 27 examined using whole-cell patch-clamp recordings in brain slices. In voltage clamp, 5-HT produced 28 outward and inward currents in distinct subpopulations of neurons which varied throughout different 29 subregions of the PAG. The 5-HT1A agonist R(+)-8-OH-DPAT (1 μM) produced outward currents in 30 subpopulations of PAG neurons. By contrast, sumatriptan (1 μM) and other 5-HT1B,D and F subtype 31 agonists had little, or no postsynaptic activity. The 5-HT2A/C agonists DOI (3 μM) and TCB-2 (1 μM) 32 produced inward currents in subpopulations of PAG neurons, and DOI enhanced evoked IPSCs (inhibitory 33 postsynaptic currents) via a presynaptic mechanism. In current clamp, both R(+)-8-OH-DPAT and 34 sumatriptan produced an excitatory increase in evoked mixed PSPs (postsynaptic potentials). In addition, 35 R(+)-8-OH-DPAT, but not sumatriptan directly hyperpolarised PAG neurons. By contrast, the 5-HT2 36 agonist DOI depolarised subpopulations of neurons and produced an inhibitory decrease in evoked mixed 37 PSPs. These findings indicate that 5-HT1A and 5-HT1B/D ligands have partly overlapping inhibitory 38 effects on membrane excitability and synaptic transmission within the PAG, which are functionally 39 opposed by 5-HT2A/C actions in specific PAG subregions. 40 41