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 to further elucidate the functional role of the LDTg in modulating reward pathways, such as the mesocorticolimbic pathway, and particularly the VTA. Oxotremorine sesquifumarate (OxoSQ), a muscarinic agonist, acts preferentially on M2/4 type muscarinic autoreceptors (Fisher et al., 1983; Sanz et al., 1997), which are known to mediate an inhibitory effect on cholinergic neurons (for review see, Calabresi et al., 2000). However, Brauner-Osborne and Brann (1996) showed that, although OxoSQ has the highest affinity for M2 autoreceptors of all available drugs, it is not necessarily exclusively selective to this autoreceptor, and had low EC50 values for M4 and M5 receptors as well in a cell culture assay. It is not known however, whether these other muscarinic receptor subtypes are present in the neuronal populations of LDTg. Regardless, it is possible that OxoSQ could be used to alter cholinergic modulation of the VTA which, should be reflected in altered cocaine seeking behaviors in animals.
