Behavioral pharmacology and biochemistry of central cholinergic neurotransmission.
Systemically administered cholinergic (muscarinic) receptor antagonists can impair the acquisition and post-acquisition performance of a variety of learned behaviors. acquisition performance of a variety of learned behaviors. At present, there is no consensus about the psychological mechanisms underlying these deficits. Behavioral inhibition, working (short-term) memory, reference (long-term) memory, attention, movement and strategy selection, and stimulus processing are among the constructs that have been proposed as underlying the effects of muscarinic receptor blockade. On the basis of neuroanatomical and neuropharmacological considerations it is contended that debates about the nature of the mediating events are pointless because they are on an anatomy that does not exist. Specifically, given that cholinergic neurons innervate almost the entire neuraxis and that muscarinic cholinergic receptors are distributed throughout the central nervous system, it is virtually certain that systemically applied antimuscarinic drugs will influence a broad spectrum of brain functions. In addition, the nature of the deficits produced by scopolamine and atropine, which are competitive antagonists, will depend on the regional endogenous rate of acetylcholine release, which may in turn be influenced by the particular environment and/or level of training imposed on the animal. As the literature seems to indicate, therefore, the effects of competitive antagonists will vary as a function of both the behavioral test and the level of training. Accordingly, attempts at unitary formulations of central cholinergic function are ill-conceived and illusory. Another approach to understanding central cholinergic function has been based on the use of local injections of excitotoxins into brain regions such as the basal forebrain that contain cholinergic neurons. Recent published reports indicate, that many of the behavioral deficits observed after ibotenic acid lesions of the basal forebrain are due primarily to the loss of non-cholinergic neurons. The inherent limitations of the excitotoxin lesion approach for unravelling the functions of central cholinergic systems are such that they cannot produce definitive information and might best, therefore, be abandoned. At present, a reliable selective toxin for cholinergic neurons is not available and urgently required. Until such a compound is identified, local intracerebral applications of antimuscarinic agents may be the preferred procedure for studying the behavioral correlates of regional blockade of cholinergic activity. Brain microdialysis in freely moving animals also holds considerable promise with respect to defining the circumstances under which acetylcholine is released in discrete regions of the central nervous system. At present, the function of central cholinergic systems and the possible role of each in learning and memory remain poorly understood.
Fibiger
H C
HC
Department of Psychiatry, University of British Columbia, Vancouver, Canada.
Damsma
G
G
Day
J C
JC
D000109:Acetylcholine / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000502:physiology*; D007858:Learning / Q000187:drug effects / Q000502:physiology*; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology*; D012601:Scopolamine / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
D009498:Neurotoxins; D011976:Receptors, Muscarinic; D012601:Scopolamine; D000109:Acetylcholine