Small conductance Ca²⁺-activated K⁺ channels (SK channels) are known to underlie the medium duration afterhyperpolarization in various types of CNS neurons. Previous experiments demonstrated that local SK channel blockade increases bursting in dopaminergic and serotonergic, but not noradrenergic neurons in vivo in anaesthetized rats (Waroux et al., 2005; Rouchet et al., 2008). The present study was conducted in awake rats using telemetric recordings. Wistar rats were implanted with microelectrode arrays made of 8 platinum electrodes (Alpha Omega°) in the ventral tegmental area. Neural activity was recorded during four sessions: one baseline session, without any experimental manipulation, and three sessions in which the rats (n = 5) received intraperitoneal injections of saline, the D2 agonist quinpirole (100 mg/kg) or the novel tertiary SK blocker AG525E1 (10 mg/kg) (Graulich et al., 2008). In total, 14 neurons were recorded. Injection of saline did not lead to any significant change in firing rate or pattern in any of the recorded neurons. Seven neurons had a long-lasting action potential. Their firing was completely inhibited by quinpirole within 5–15 min after its injection, which suggests that these neurons were dopaminergic. Within 20 min after the injection of AG525E1, these neurons underwent an increase in firing rate from 2.5 1.3 to 5.6 1.5 Hz, and an increase in the % of spikes in bursts from 6 1 to 31 6%. The effects of AG525E1 disappeared 40–45 min after the injection. Neither quinpirole nor AG525E1 had any significant effect in the other 7 neurons. These results suggest that SK channel blockade could enhance dopamine transmission. Therefore, the development of drugs crossing the blood-brain barrier and reversibly affecting SK channels may be a promising approach for treating CNS diseases.

Supported by grant n° 9.4560.03 from the F.N.R.S. (VS, J-FL) and by a grant from the Belgian Science Policy (PAI 6/31) (VS, SK). J.-F. L. is Research Director of the FRS-F.N.R.S.