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Pharmacologic studies have indicated that accurate performance on the radial-arm maze depends upon the integrity of both nicotinic and muscarinic cholinergic neurotransmitter systems and that these systems interact in a complex fashion. Although numerous studies have suggested that pathways deriving from the basal nuclear complex of the forebrain are critical for the cholinergic modulation of learning and memory, most have focussed on the septohippocampal projection, and none have specifically targeted the medial or lateral systems. In Experiment 1, cortical knife cuts interrupting the medial cholinergic pathway were made at the level of the caudate-putamen nucleus. Such transections produced a robust but temporary disruption of choice accuracy performance in the radial-arm maze. Recovery of this behavior occurred within 10 days and before cholinergic fiber regeneration, suggesting that compensatory changes could have taken place in non-ablated neuronal circuits. In Experiment 2, daily postsurgical administration of arecoline, an agonist with predominantly muscarinic actions, was found to virtually eliminate the adverse behavioral effects of medial pathway transections, indicating that the deficit could be attributable, in part, to disruption of cholinergic projections. In Experiment 3, the effects of scopolamine, a muscarinic antagonist, and mecamylamine, a nicotinic antagonist, were examined in rats with medial cholinergic pathway transections after behavior had returned postsurgically to control levels. Although both drugs attenuated radial-arm maze performance before knife cuts, only scopolamine reduced choice accuracy following surgery. We conclude that the medial cholinergic pathway, particularly its nicotinic actions, plays an important role in cognitive function, at least as exemplified by radial-arm maze performance. Muscarinic mechanisms associated with other telencephalically projecting cholinergic networks, as well as possibly with the medial pathway itself, appear to operate interactively with nicotinic influences.

In an attempt to determine whether or not acetylcholinesterase (AChE)-containing neurons of the caudate-putamen proper were the source of striatal efferent fibers, we infused Evans Blue, a retrogradely transported fluorescent label, into the globus pallidus, entopeduncular nucleus, substantia nigra, or retrorubral area. Following microscopic analysis of the striatum for Evans Blue-labelled somata, the same brain sections were processed for AChE according to the pharmacohistochemical regimen and, after additional microscopic evaluation, were counterstained with cresyl violet. Histology for Nissl substance revealed that the areal density of cell bodies in the caudate-putamen complex proper was about 1510 somata/mm2. Striatal neurons labelled with Evans Blue, those considered to be projection cells, were medium-sized (approximate minor and major dimensions: 11 X 14 microns), had a density of roughly 833 cells/mm2, and were predominantly oval with lesser proportions being fusiform, triangular, or round. Each of the target structures received input from approximately 55% (range = 26-78%) of the total population of striatal neurons in regions where the projection cellsions: 11 X 14 microns), had a density of roughly 833 cells/mm2, and were predominantly oval with lesser proportions being fusiform, triangular, or round. Each of the target structures received input from approximately 55% (range = 26-78%) of the total population of striatal neurons in regions where the projection cellsions: 11 X 14 microns), had a density of roughly 833 cells/mm2, and were predominantly oval with lesser proportions being fusiform, triangular, or round. Each of the target structures received input from approximately 55% (range = 26-78%) of the total population of striatal neurons in regions where the projection cells were located. The two types of AChE-containing somata in the caudate-putamen complex proper--the medium-sized, lightly staining Type A and the large, intensely staining Type B cell--had densities of 14 and 15 somata/mm2, respectively. None of the AChE neurons contained Evans Blue, indicating that they were not the source of striatal efferent fibers but rather interneurons that could be categorized best as the aspiny or sparsely spined cells described in Golgi studies.

The postnatal development of acetylcholinesterase (AChE, EC 3.1.1.7) and NADH-diaphorase was examined in the caudate-putamen nucleus and substantia nigra of rats ranging from 3 to 90 days in age. From 3 to 15 days post partum islands of AChE and NADH-diaphorase activity were observed in the caudate-putamen nucleus. Individual neuronal somata could also be seen in AChE-stained sections up to 15 days. At later ages neuropil staining became increasingly dense, and this presumably accounted for the infrequent visualization of cell bodies in the brains of older animals. During development AChE appeared in the caudate-putamen nucleus in a lateral to medial topographic order; analogously, enzyme staining in the neostriatum reappeared in the same lateral to medial topographic order in adult rats following irreversible AChE inhibition by intramuscularly injected bis-(1-methylethyl)phosphorofluoridate (di-isopropylfluorophosphate: DFP). Furthermore, DFP treatment in mature animals revealed the presence of AChE in striatal neurons having morphologies similar to those observed in newborn rats. A similar time-course of postnatal AChE development was observed in the substantia nigra. In both the pars compacta and pars reticulata individual cell bodies, which were visible at early ages (3-10 days), became increasingly obscured at later times after birth by extra-somata staining. Between the 6th and 15th postnatal days AChE-containing fibers were seen projecting apparently from pars compacta into pars reticulata. Comparison of the present results with histochemical data of other investigators on the postnatal development of monoamines indicated the likelihood of cholinergicmonoaminergic interactions in the neostriatum and substantia nigra.

Infusion of 1 mul arachis oil containing 1.5 mug bis-(1 -methylethyl)phosphorofluoridate (di-isopropylfluorophosphate: DFP) into the caudate--putamen nucleus and substantia nigra of rats produced a considerable reduction of histochemical staining for acetylcholinesterase (AChE) in these two brain regions 30--120 min after injection. Thereafter, regeneration of AChE occurred within the zone of DFP effect. These new stores of AChE were associated with discrete neuronal perikarya and their processes. Intracerebral DFP administration had little or no histochemically detectable effect on NADH-diaphorase. Thionin staining was similarly unaffected. The results with punctate intracerebral application of DFP were replicated by intramuscular injection of 1.5 mg/kg DFP. Although the significance of dopaminergic--cholinergic interactions in the neostriatum could not be elucidated on the basis of these histochemical data, the thesis was advanced that dopamine neurons in the pars compacta of the substantia nigra also contained AChE, possibly to inactivate acetylcholine released from cholinergic fibers afferent to this neural structure.

The dorsolateral precommissural caudate-putamen complex has been characterized recently as a 'non-limbic' region of the neostriatum. In the present study, however, it was found that numerous neurons in the basolateral amygdala were labeled retrogradely following infusions of Evans Blue into that neostriatal region. Control infusions demonstrated that such labeling could not be attributed to the spread of the red fluorescent tracer into surrounding neocortical areas. On the basis of these data, it is proposed that: (1) the amygdalo-neostriatal pathway may be more extensive than previously believed, and (2) the basolateral amygdala may serve as an important link between the limbic and extrapyramidal motor systems.

A method employing the use of ion-exchange resin beads is described for the punctate introduction of discrete amounts of various anions, cations, or zwitterions into given brain regions. A series of experiments utilizing the method to introduce ionic copper into the caudate nucleus with the resulting motor manifestations are discussed.