Dopaminergic modulation of the septohippocampal cholinergic system

The central cholinergic system is thought to be an integral component of the neural circuitry involved in mnemonic processes. The septohippocampal cholinergic pathway is considered crucial in this respect. In addition, however, other neurotransmitter systems are also likely involved in learning and memory either by interacting with the cholinergic system or on their own. Dopamine is postulated to be one such neurotransmitter. Accordingly, this thesis examines the possible interactions between dopamine and acetylcholine in the hippocampus, in particular in relation to cognitive processes.Using a fimbriaectomy/receptor autoradiography approach, we examined the location of hippocampal dopamine receptors and found that a proportion of dopamine D1-like receptors are likely located on cholinergic terminals in the hippocampus. Moreover, the stimulation of D1-like, but not D2-like, receptors enhanced in vivo hippocampal acetylcholine release, in a phasic manner. The loci for this action is apparently at the level of the cholinergic terminals within the hippocampus.There are at least two members of the D1-like family of dopamine receptors, namely D1 and D5 subtypes. Owing to the unavailability of selective ligands, we utilized a combined antisense-in vivo dialysis approach in order to ascertain which of these two receptors is involved in modulating hippocampal acetylcholine release. It appears that the D5 receptor subtype is responsible for this function. Interestingly, this is the first evidence of a possible function for the dopamine D5 receptor subtype in the mammalian brain.This dopaminergic modulation of hippocampal acetylcholine release is preserved as the animal ages. Interestingly, stimulation of D1-like receptors attenuated the memory deficits observed in aged rats in the Morris water maze task. Thus the hippocampal dopamine-acetylcholine interactions likely have a cognitive significance.Finally, dopamine D1-like receptors were also found in the hippocampal formation of monkey and human brains. It is conceivable, therefore, that dopamine acting via these receptors might serve similar functions in primates as those described above for the rat.Taken together, the results presented in this thesis provide information about the heteroregulation of the cholinergic synapses in the hippocampus. Most importantly, this work suggests a novel approach to alleviate age-associated memory deficits by stimulating D5 receptors