Baclofen inhibits guinea pig magnocellular neurones via activation of an inwardly rectifying K+ conductance

The magnocellular neurones of the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) synthesize and secrete the peptides vasopressin (AVP) and oxytocin (OT) into the systemic circulation from terminals in the neurohypophysis. AVP plays a key role in controlling fluid balance and tissue osmolarity (Poulain & Wakerley, 1982; Renaud, 1987; Bourque & Renaud, 1990), while OT plays a key role in parturition, milk ejection and maternal behaviour (Wakerley & Lincoln, 1973; Poulain & Wakerley, 1982; Bourque & Renaud, 1990; Crowley & Armstrong, 1992; Luckman et al. 1994; Russell et al. 1995). The relationship between the firing pattern and peptide release has been extensively characterized in rodents (see Bourque & Renaud, 1990). Oxytocin neurones fire in a random, continuous pattern or in a continuous, high-frequency burst during the suckling response (Poulain & Wakerley, 1982). In contrast, AVP neurones fire phasically in response to hyperosmotic or hypovolaemic conditions in the systemic circulation, resulting in enhanced release of vasopressin into the circulation (see Renaud, 1987). Endogenous cellular mechanisms that utilize intrinsic currents have been proposed to explain phasic firing in magnocellular neurones (see Legendre & Poulain, 1992; Bourque, 1998). The two hypothalamic nuclei which contain the magnocellular neurones receive GABAergic input from several sources. The dorsomedial and the anterior hypothalamic nucleus, the suprachiasmatic nucleus, the organum vasculosum lamina terminalis and the bed nucleus of the stria terminalis send direct GABAergic projections to the PVN (Pumford et al. 1993; Roland & Sawchenko, 1993; Yang et al. 1994; Richard & Bourque, 1995; Boudaba et al. 1996). The suprachiasmatic nucleus also sends direct projections to the SON (Cui et al. 2000). The GABAergic cells control the magnocellular neurones directly through a post-synaptic GABAA receptor (Decavel & Van den Pol, 1992; Boudaba et al. 1996; Tasker et al. 1998; Mouginot et al. 1998), resulting in an increase in chloride conductance (Jhamandas & Renaud, 1987; Randle & Renaud, 1987; Gribkoff & Dudek, 1990). In the rat, GABAergic cells also indirectly control magnocellular neurones via GABAB receptors on pre-synaptic glutamatergic terminals in the SON (Kombian et al. 1996; Kabashima et al. 1997; Ibrahim et al. 1998; Tasker et al. 1998; Kolaj et al. 2000). Finally, these GABAergic cells are regulated by AVP through a post-synaptic V1a receptor as part of a negative feedback loop (Hermes et al. 2000). Since the GABAB receptor is G protein-coupled to an inwardly rectifying K+ channel (IK,ir) in other systems (Christie & North, 1988; Chieng & Christie, 1995; Lagrange et al. 1996; Wagner et al. 1999), we hypothesized that functional GABAB receptors would be present within and coupled to IK,ir in magnocellular neurones, and subsequently identified GABAB receptor transcripts in SON and PVN magnocellular neurones. Therefore, we utilized both sharp and whole-cell recordings from the SON and PVN of female and male guinea pigs to ascertain the effects of the selective GABAB receptor agonist baclofen on magnocellular neurones. Some of the results have been presented in abstract form (Slugg et al. 1999a, 2000).