Pharmacological manipulation of the LDTg may provide new insights about the role of ACh in cocaine seeking and self-administration. It is known that electrical stimulation of the LDTg leads to a three-component phasic pattern of changes in DA efflux in the NAc that reflects activation of glutamate, nicotinic and muscarinic receptors in the VTA (Forster and Blaha, 2000). The first and third components are likely associated with increased levels of ACh in the VTA, although this has not been directly shown. The second component is associated with hyperpolarization of cholinergic neurons in the LDTg that is mediated by M2 autoreceptors (Forster and Blaha, 2000; Buckley et al, 1988, Vilaro et al., 1992, 1994). In fact patch-clamp studies have shown that ACh hyperpolarizes cholinergic neurons in the LDTg via inwardly rectifying potassium channels (Leonard and Llinas, 1994). Inactivation of M2 autoreceptors in the LDTg with an M2 antagonist can block the hyperpolarizing effects of ACh (Leonard and Llinas, 1994), and increases the release of endogenous ACh (Baghdoyan et al, 1998). Thus, manipulation of M2 autoregulation of cholinergic activity provides a way
