Intravenous self-administration of nomifensine in rats: implications for abuse potential in humans.

Rats acquired and maintained intravenous self-administration of nomifensine, a new antidepressant compound. Additional experiments implicated dopamine-containing neurons in this behavior. These findings, along with the marked pharmacological similarities between nomifensine and such drugs as cocaine and methylphenidate, indicate a potential for nomifensine abuse by humans.

On the specificity of kainic acid.

The specificity of the neurotoxic agent, kainic acid, for destroying cell bodies while sparing terminals and fibers of passage was examined by infusing this agent into the axons of the dorsal noradrenergic bundle and measuring the degree of depletion of noradrenaline concentrations and the reduction in noradrenaline uptake in cortex and hippocampus. Extensive neuronal loss and gliosis were observed around the injection site. In addition, a significant and consistent 25 percent depletion of hippocampal-cortical noradrenaline was also obtained. The results suggest that although kainic acid has its greatest destructive action on neuronal perikarya, a significant amount of damage to axons of passage may also occur.

Dopaminergic and noradrenergic substrates of positive reinforcement: differential effects of d- and l-amphetamine.

Intracranial self-stimulation was elicited from electrodes located in either the lateral hypothalamus or substantia nigra of the rat. Facilitatory effects of d- and l-isomers of amphetamine on self-stimulation were assessed. The d-isomer was seven to ten times more effective than the l-isomer at the hypothalamic placement, whereas the two isomers were equipotent for substantia nigra electrodes. These data support the hypothesis that both dopaminergic and noradrenergic systems subserve positive reinforcement.

Increased intracranial self-stimulation in rats after long-term administration of desipramine.

The effects of long- and short-term administration of the tricyclic antidepressant desipramine on intracranial self-stimulation in rats were studied with electrodes in the A10 region of the dopamine-containing cell bodies of the ventromedial tegmentum. Long-term desipramine administration resulted in a significant shift to the left in the ascending portion of the rate--current intensity function, indicating that the activity of the mesolimbic dopamine system was enhanced. These findings point to a possible dopaminergic mechanism of action of antidepressants and support speculations concerning the role of dopamine-containing neurons in the pathophysiology of depression.

Reversal by L-dopa of impaired learning due to destruction of the dopaminergic nigro-neostriatal projection.

Rats receiving bilateral stereotaxic injections of 6-hydroxydopamine into the zona compacta of the substantia nigra failed to learn a one-way active avoidance response. Small doses of L-dopa (1.5 milligrams per kilogram of body weight) in combination with a peripheral decarboxylase inhibitor reversed this impairment. Animals with lesions which acquired the avoidance response during L-dopa administration retained this response when drug treatment was discontinued. These experiments suggest that the dopaminergic nigro-neostriatal projection serves a critical function in the acquisition of learned instrumental responses.

Ontogeny of adrenergic arousal and cholinergic inhibitory mechanisms in the rat.

With spontaneous activity as a measure of arousal, dose response curves were established for scopolamine and amphetamine administered to 10-, 15-, 20-, 25-, and 100-day-old rats. Amphetamine always increased activity, but scopolamine had no efect on younger rats, which suggests that adrenergic excitatory areas in the brainstem mature more rapidly than cholinergic inhibitory areas in the forebrain.

Kainic acid lesions of the striatum dissociate amphetamine and apomorphine stereotypy: similarities to Huntingdon's chorea.

Kainic acid lesion of cell bodies in the dorsal striatum enhanced the stereotypy-producing effects of d-amphetamine without affecting the sterotypy produced by the direct receptor agonist apomorphine. This pattern of results parallels that found in patients suffering from Hungtington's chorea, thus strengthening the parallels between the kainic acid animal model and the human disease state initially suggested on biochemical gounds. The present results further suggest a dissociation of the mechanisms involved in the production of stereotypy by these two drugs, perhaps in terms of differential involvement of the striato-nigral negative feedback loop.

Cholinergic mechanisms in learning, memory and dementia: a review of recent evidence.

The discovery in the late 1970s that cholinergic neurons in the basal forebrain degenerate in Alzheimer's disease (AD) greatly accelerated research on the role of cholinergic mechanisms in learning and memory. As is often the case in science, the early enthusiasm for the cholinergic hypothesis has been tempered by the results of subsequent research. Although there is substantial pharmacological evidence that unspecified cholinergic systems in the brain play important roles in some forms of learning and memory, recent findings in humans indicate that antimuscarinic drugs do not model the deficits seen in AD. In addition, the goal of elucidating the functions of these basal forebrain neurons in animals has proved to be difficult and is yet to be achieved. Despite substantial effort, therefore, the cognitive and behavioral consequences of cholinergic pathology in AD remain unknown. Under these circumstances, attempts to develop cholinergic pharmacotherapies for these deficits in AD are based on questionable assumptions.

Neurochemical correlates of brain-stimulation reward measured by ex vivo and in vivo analyses.

Evidence from ex vivo analyses of dopaminergic function following self-stimulation behavior is reviewed and compared to in vivo analyses of extracellular dopamine measured by chronoamperometry during self-stimulation. Both data bases provide strong support for a dopaminergic substrate for brain-stimulation reward obtained by electrical stimulation of the ventral tegmental area (VTA). Data obtained from in vivo measures of dopamine release are particularly compelling as a positive correlation was observed between the rate/intensity function for self-stimulation and increments in the oxidation current for dopamine. An examination of the effects of the dopamine uptake blockers, cocaine and GBR 12909 on self-stimulation and stimulated release of dopamine revealed a facilitation of both measures. In contrast, the noradrenaline uptake blocker desipramine had no effect on either self-stimulation or extracellular dopamine. These pharmacological experiments also are consistent with a dopaminergic substrate of brain-stimulation reward at electrode sites in the VTA.

ECS-induced dopamine release: effects of electrode placement, anticonvulsant treatment, and stimulus intensity.

Although electroconvulsive therapy (ECT) remains an important therapy for severe depression, its mechanism of action remains elusive. We previously demonstrated that there is a significant increase of interstitial dopamine of neuronal origin in the rat striatum after electroconvulsive shock (ECS) but not after chemically (flurothyl) induced seizures. The present studies examined how electrode placement, stimulus intensity, and the administration of an anticonvulsant affect ECS-induced dopamine release in the rat striatum. Bilateral electrode placement resulted in greater dopamine release than that produced by a unilaterally applied stimulus. Pretreatment with sodium pentobarbital markedly decreased seizure duration but had no effect on the magnitude of the increase in interstitial dopamine. Finally, a higher voltage applied longer resulted in greater dopamine release without a concomitant increase in seizure duration. These data suggest that the passage of current may be directly responsible for certain ECS-induced chemical changes. These findings are discussed in the context of clinical observations that challenge the traditional view that the production of generalized seizures of adequate duration is both necessary and sufficient for a therapeutic response to ECT.

Regional topography within noradrenergic locus coeruleus as revealed by retrograde transport of horseradish peroxidase.

A hitherto unsuspected degree of regional topographic organization in the noradrenergic nucleus, locus coeruleus, was revealed by the use of retrograde transport of horseradish peroxidase (HRP) from terminal areas receiving noradrenergic innervation. HRP was injected into hippocampus, hypothalamus, thalamus, caudate-putamen, septum, amygdala-piriform cortex, cerebellum and cortex. Successful transport was obtained from all areas, including the caudate-putamen and cerebral cortex. The pattern of HRP positive cells in the ipsilateral locus coeruleus was markedly different depending on the location of the HRP injection. Thus, hippocampal injections labeled cells in the dorsal locus coeruleus but not at all in the ventral tip. Injections of HRP into caudate-putamen or cerebellum labeled the ventral tip along with the rest of the dorsal portion. HRP injections into the septum labeled cells only in the dorsal half of the dorsal locus coeruleus. There thus exists a three tier division of locus coeruleus into the ventral one third, dorsal one third and intermediate one third. A further division was seen in the anterior-posterior plane with HRP injections into the thalamus labeling the posterior pole of locus very intensely but with little transport to more anterior levels; conversely HRP injection into the hypothalamus resulted in intense labeling only in the anterior pole of locus coeruleus. Amygdala-piriform cortex HRP injections revealed a further pattern with very intensely reactive cells scattered sparsely throughout the nucleus. Cortical HRP injections yielded weaker labeling also in occasional, scattered cells. All HRP transport to locus coeruleus was shown to be noradrenergic by degeneration with 6-hydroxydopamine and due to terminal, rather than fiber of passage, uptake by control injection into the dorsal NA bundle. It is concluded that the locus coeruleus is not an homogenous nucleus with respect to the origin of the noradrenergic projections to sundry forebrain, spinal and cerebellar areas but is comprised of distinct subdivisions of noradrenergic neurons.

Afferent connections of the laterodorsal and the pedunculopontine tegmental nuclei in the rat: a retro- and antero-grade transport and immunohistochemical study.

Increasingly strong evidence suggests that cholinergic neurons in the mesopontine tegmentum play important roles in the control of wakefulness and sleep. To understand better how the activity of these neurons is regulated, the potential afferent connections of the laterodorsal (LDT) and pedunculopontine tegmental nuclei (PPT) were investigated in the rat. This was accomplished by using retrograde and anterograde axonal transport methods and NADPH-diaphorase histochemistry. Immunohistochemistry was also used to identify the transmitter content of some of the retrogradely identified afferents. Following injections of the retrograde tracer wheatgerm agglutinin-conjugated horseradish peroxidase (WGA-HRP) into either the LDT or the PPT, labelled neurons were seen in a number of limbic forebrain structures. The medial prefrontal cortex and lateral habenula contained more retrogradely labelled neurons from the LDT, whereas in the bed nucleus of the stria terminalis and central nucleus of the amygdala, more cells were labelled from the PPT. Moderate numbers of neurons were seen in the magnocellular regions of the basal forebrain, and many labelled neurons were observed in the lateral hypothalamus, the zona incerta, and the midbrain central gray from both the LDT and the PPT. Accessory oculomotor nuclei in the midbrain as well as eye movement-related structures in the lower brainstem contained some neurons labelled from the LDT, and fewer neurons from the PPT. A few labelled neurons were seen in somatosensory and other sensory relay nuclei in the brainstem and the spinal cord. Retrograde labelling was seen in a number of extrapyramidal structures, including the globus pallidus, entopenduncular and subthalamic nuclei, and substantia nigra following PPT injections; with LDT injections, labelling was similar in density in the substantia nigra but virtually absent in the entopeduncular and subthalamic nuclei. Data with the fluorescent retrograde tracer fluorogold combined with immunofluorescence indicated that many neurons in the zona incerta-lateral hypothalamic region that were retrogradely labelled from the LDT contained alpha-melanocyte-stimulating hormone. Numerous neurons were labelled throughout the reticular formation of the brainstem following either LDT or PPT injections. Many neurons retrogradely labelled in the LDT and PPT, the dorsal and median raphe nuclei, and the locus ceruleus contained choline acetyltransferase, serotonin, and tyrosine hydroxylase, respectively. The anterograde tracers WGA-HRP and phaseolus vulgaris leucoagglutinin were used to confirm some of the projections indicated by the retrograde labelling data; anterograde labelling was seen in the LDT and PPT following injections of one of these tracers into the medial prefrontal cortex, lateral hypothalamus, and the contralateral LDT.(ABSTRACT TRUNCATED AT 400 WORDS)

Time of origin of cholinergic neurons in the rat basal forebrain.

The timing of the final mitotic division of basal forebrain cholinergic neurons was studied by injecting [3H]thymidine into timed pregnant rats and processing the brains of their progeny as young adults for immunohistochemistry with a monoclonal antibody to choline acetyltransferase (ChAT) followed by autoradiography. ChAT-positive neurons located caudally in the basal forebrain were found to become postmitotic mostly on embryonic (E) days 12 and 13, whereas the peak final mitosis of more rostrally located ChAT-positive neurons occurred increasingly later, with the most rostral ChAT-immunoreactive neurons leaving their final mitotic cycles on E15 and E16. In all basal forebrain regions, cholinergic neurogenesis was complete by E17. These results indicate that the cholinergic neurons in the basal forebrain become postmitotic in a caudal-to-rostral gradient over about 5 days. The continuity of the gradient suggests that these cholinergic neurons may derive from the same germinal source.

Distribution of central cholinergic neurons in the baboon (Papio papio). I. General morphology.

The morphological characteristics of cholinergic neurons in the central nervous system (CNS) of the baboon (Papio papio) were studied by choline acetyltransferase (ChAT) immunohistochemistry and acetylcholinesterase (AChE) pharmacohistochemistry. The distributions of central cholinergic neurons as visualized by these two histochemical techniques were similar in most, but not all regions of the brain and spinal cord. Based upon these observations, central cholinergic neurons that are immunoreactive to ChAT and intensely stained for AChE by the pharmacohistochemical procedure can be divided into four major groups: (1) those in the caudate nucleus, putamen, nucleus accumbens and anterior perforated substance. These ChAT-containing and AChE-intense neurons are large and multipolar, and are scattered throughout these structures. (2) The rostral cholinergic column, which consists of a continuous mass of cholinergic perikarya situated in the medial septal nucleus, nucleus of the diagonal band, and nucleus basalis (Meynert). The ChAT-immunoreactive and AChE-intense cell bodies of the nucleus basalis are a prominent feature in the basal forebrain of the baboon. The labeled neurons are large, multipolar, and hyperchromic and show a tendency to aggregate in cell clusters. These cells are distributed within the full extent of the substantia innominata, often being associated with subcortical fiber networks such as the medullary laminae of the globus pallidus. (3) The caudal cholinergic column, which consists of a continuous group of cholinergic neurons in the caudal midbrain and pontine tegmentum. The rostral component of this group of cells is the nucleus tegmenti pedunculopontinus (subnucleus compacta) and it extends caudally to include the laterodorsal tegmental nucleus. Compared to that in other species the nucleus tegmenti pedunculopontinus in the baboon appears to occupy a relatively greater volume and is composed of a greater number of cholinergic neurons. The cells of the caudal column are large and hyperchromic. (4) Nuclei of origin of somatic and visceral efferents of the cranial nerves (III, IV, V, VI, VII, IX, X, XI, XII) and spinal nerves. In addition to these major cholinergic cell groups, a small population of ChAT-positive and AChE-intense cell bodies can be observed at the floor of the fourth ventricle and in lamina VII and X of the cervical cord. The present findings indicate that although some differences exist, the overall distribution and morphological features of cholinergic cell bodies identified in the baboon brain and spinal cord are similar to those demonstrated previously in investigations of the rhesus monkey and nonprimates.

Distribution of central cholinergic neurons in the baboon (Papio papio). II. A topographic atlas correlated with catecholamine neurons.

The topographic distribution of central cholinergic and catecholaminergic neurons has been investigated in the baboon (Papio papio). The perikarya were mapped on an atlas through the brain and spinal cord employing sections processed for acetylcholinesterase (AChE) pharmacohistochemistry coupled with choline acetyltransferase (ChAT) immunohistochemistry or aqueous catecholamine-fluorescence histochemistry. Compared with subprimates, there is a remarkable increase in the volume occupied by and the number of cholinergic cells contained in the nucleus basalis and nucleus tegmenti pedunculopontinus (subnucleus compacta). The elaboration of these parts of the cholinergic system is accompanied by a large extension of catecholaminergic cell groups in the midbrain (groups A8-A10), particularly the substantia nigra (pars compacta), and in the dorsolateral pontine tegmentum (A5-A7 complex). Although cholinergic and catecholaminergic soma generally occupy distinctly different regions of the brain, a close apposition of cholinergic and noradrenergic neurons occurs in the dorsolateral pontine tegmentum. In the peripeduncular region ChAT-positive cells and green fluorescent neurons of the A6-A7 complex form parallel lines and do not intermingle as has previously been demonstrated in the cat. Two distribution patterns, aggregated or disseminated, are another common feature of central cholinergic and catecholaminergic perikarya. The cholinergic neurons in the nucleus tegmenti pedunculopontinus and the catecholaminergic neurons in A6-A7 complex display both patterns. This comparative study of three transmitter systems in the baboon suggests that the cholinergic as well as the catecholaminergic neurons that give rise to ascending telencephalic and dorsal diencephalic projections undergo phylogenetic development in terms of cell number and nuclear volume.

Cholinergic neurons of the laterodorsal tegmental nucleus: efferent and afferent connections.

The ascending projections of cholinergic neurons in the laterodorsal tegmental nucleus (TLD) were investigated in the rat by using Phaseolus vulgaris leucoagglutinin (PHA-L) and wheat germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) anterograde tracing techniques. Two ascending pathways were identified after iontophoretic injections of PHA-L into the TLD. A long projection system courses through the dorsomedial tegmentum, caudal diencephalon, medial forebrain bundle, and diagonal band. Different branches of this system innervate the midbrain (superior colliculus, interstitial magnocellular nucleus of the posterior commissure, and anterior pretectal nucleus), the diencephalon (lateral habenular nucleus, parafascicular, anteroventral, anterodorsal, mediodorsal, and intralaminar thalamic nuclei), and the telencephalon (lateral septum and medial prefrontal cortex). The second system is shorter and more diffuse and innervates the median raphe, interpeduncular, and lateral mammillary nuclei. Retrograde tracing with WGA-HRP, combined with choline acetyltransferase immunohistochemistry, revealed that most of the TLD projections to the tectum, pretectum, thalamus, lateral septum, and medial prefrontal cortex are cholinergic. Afferents to the TLD were studied by anterograde and retrograde tracing techniques. Injection of tracers into the TLD retrogradely labelled neurons bilaterally in the midbrain reticular formation, the periaqueductal gray, the medial preoptic nucleus, the anterior hypothalamic nucleus, and the perifornical and lateral hypothalamic areas. Retrogradely labelled cells were also located bilaterally in the premammillary nucleus, paraventricular hypothalamic nucleus, zona incerta, and lateral habenular nucleus. In the telencephalon, the nucleus of the diagonal band and the medial prefrontal cortex contained retrogradely labelled neurons ipsilateral to the TLD injection site. The projections of the medial prefrontal cortex, the bed nucleus of the stria terminalis, and the lateral habenular nucleus to the TLD were confirmed in anterograde tracing studies. These findings indicate that the TLD gives rise to several ascending cholinergic projections that innervate diverse regions of the forebrain. Afferents to the TLD arise in hypothalamic and limbic forebrain regions, some of which appear to have reciprocal connections with the TLD. The latter include the lateral habenular nucleus and medial prefrontal cortex.

Demonstration of a pallido-nigral projection innervating dopaminergic neurons.

Afferents to the substantia nigra from the neostriatum and globus pallidus were studied in the rat by means of the autoradiographic tracing technique. 3H-leucine was injected stereotaxically into either the globus pallidus or neostriatum. Twenty-four hours later the axoplasmic transport of labelled proteins to the substantia nigra was studied by light and electron microscopic autoradiography. In animals used for electron microscopy, degeneration of dopaminergic cells in the substantia nigra was induced by intraventricular injection of 6-hydroxydopamine 72 hours before sacrifice. After neostriatal injections, light microscopic analysis revealed heavy labelling of the globus pallidus and entopeduncular nucleus, but only background labelling of the subthalamic nucleus. There was preferential labelling of the zone reticulata of the substantia nigra, with significantly less labelling of the zone compacta. After pallidal injections, light microscopic analysis showed very light labelling of those parts of the caudate-putamen in the vicinity of the injection site. There was intense labelling of the subthalamic nucleus and heavy labelling of the entopeduncular nucleus. The zona compacta of the substantia nigra was also heavily labelled. There was considerably less labelling of the zona reticulata. The electron microscopic analyses showed that after neostriatal injections, autoradiographic grains in the substantia nigra were located preferentially over boutons which terminated on normal dendritic processes. After pallidal injections, however, grains were preferentially located over boutons synapsing with degenerating dendritic processes. The degeneration produced in these dopaminergic processes by 6-hydroxydopamine was invariably of the dark type. Except for the different association with degenerating vs. non-degenerating dendrites, the subcellular distribution of autoradiographic grains in the substantia nigra was the same after injection into either the globus pallidue or caudate-putamen. Approximately 80 percent of the grains were over axons or boutons which invariably made symmetrical synaptic contacts. These observations demonstrate the existence of a pallido-nigral projection which terminates preferentially on dopaminergic cells in the pars compacta of the substantia nigra. They also confirm previous studies indicating that the strionigral projection terminates mainly in the pars reticulata. These terminations appear to be principally to non-dopaminergic cells.

Ontogeny of histidine-decarboxylase-immunoreactive neurons in the tuberomammillary nucleus of the rat hypothalamus: time of origin and development of transmitter phenotype.

The ontogeny of the histidine decarboxylase (HDC)-immunoreactive neurons of the tuberomammillary (TM) nucleus was studied in the rat brain. The time of origin of TM neurons was studied by counting the percentage of HDC-immunopositive neurons double labelled by autoradiography in adult progeny of dams injected with [3H]-thymidine at various times during gestation. Neurogenesis began on embryonic day (E) 13, peaked on E16, and was complete by E18. HDC immunoreactivity was first detected in the fetal rat brain on E16. Experiments utilizing short-survival [3H]-thymidine autoradiography combined with HDC immunohistochemistry demonstrated that TM neurons undergo their final mitotic division prior to expression of their transmitter phenotype.

Brainstem afferents to the magnocellular basal forebrain studied by axonal transport, immunohistochemistry, and electrophysiology in the rat.

Brainstem afferents to the magnocellular basal forebrain were studied by using tract tracing, immunohistochemistry and extracellular recordings in the rat. WGA-HRP injections into the horizontal limb of the diagonal band (HDB) and the magnocellular preoptic area (MgPA) retrogradely labelled many neurons in the pedunculopontine and laterodorsal tegmental nuclei, dorsal raphe nucleus, and ventral tegmental area. Areas with moderate numbers of retrogradely labelled neurons included the median raphe nucleus, and area lateral to the medial longitudinal fasciculus in the pons, the locus ceruleus, and the medial parabrachial nucleus. A few labelled neurons were seen in the substantia nigra pars compacta, mesencephalic and pontine reticular formation, a midline area in the pontine central gray, lateral parabrachial nucleus, raphe magnus, prepositus hypoglossal nucleus, nucleus of the solitary tract, and ventrolateral medulla. A similar but not identical distribution of labelled neurons was seen following WGA-HRP injections into the nucleus basalis magnocellularis. The possible neurotransmitter content of some of these afferents to the HDB/MgPA was examined by combining retrograde Fluoro-Gold labelling and immunofluorescence. In the mesopontine tegmentum, many retrogradely labelled neurons were immunoreactive for choline acetyltransferase. In the dorsal raphe nucleus, some retrogradely labelled neurons were positive for serotonin and some for tyrosine hydroxylase (TH); however, the majority of retrogradely labelled neurons in this region were not immunoreactive for either marker. The ventral tegmental area, substantia nigra pars compacta, and locus ceruleus contained retrogradely labelled neurons which were also immunoreactive for TH. Of the retrogradely labelled neurons occasionally observed in the nucleus of the solitary tract, prepositus hypoglossal nucleus, and ventrolateral medulla, some were immunoreactive for either TH or phenylethanolamine-N-methyltransferase. To characterize functionally some of these brainstem afferents, extracellular recordings were made from antidromically identified cortically projecting neurons, mostly located in the HDB and MgPA. In agreement with most previous studies, about half (48%) of these neurons were spontaneously active. Electrical stimulation in the vicinity of the pedunculopontine tegmental and dorsal raphe nuclei elicited either excitatory or inhibitory responses in 21% (13/62) of the cortically projecting neurons.(ABSTRACT TRUNCATED AT 400 WORDS)

Distribution and organization of cholinergic neurons in the rat forebrain demonstrated by computer-aided data acquisition and three-dimensional reconstruction.

An understanding of the organization of cholinergic neurons in the central nervous system has been an important objective for many years. By developing and applying a new electronic method for mapping tissue sections, we have generated original graphic and quantitative findings on forebrain cholinergic neurons that provide new insight into their distribution and organization. Satoh, Armstrong, and Fibiger (Brain Res. Bull. 11:693-720, 1983) have proposed that in the basal forebrain cholinergic neurons with long axons form a continuum rather than being arranged as a series of discrete nuclear groups. It has been difficult, however, by conventional methods of data analysis and display, to test this hypothesis. By using a digital microscopy system, the position of every cholinergic neuron was marked with 1-micron resolution in tissue sections taken at 90-microns or 180-microns intervals through the entire distribution of these neurons in the forebrain. The three-dimensional reconstruction of these neurons in context shows them to be distributed as a continuous cell column. The column twists and changes position as it is deformed by adjacent neuronal structures, such that its shape and continuity would not be apparent without reconstruction into a computer graphics model. Complementary analyses of the distribution of cholinergic interneurons in dopamine-rich regions of the forebrain indicated that there are regional differences between striatal and olfactory tubercle neurons. Cellular morphometry analyses show the population of cholinergic neurons in the rat to be surprisingly homogenous in size, but not in shape. Graphic and quantitative analyses indicated that there is a striking relationship between the distributions of projection and interneuronal cell groups. We conclude that the basal forebrain cholinergic neurons form a continuum. The chemoarchitecture of this cell group does not conform to the usual cytoarchitectural divisions. The present results, however, taken together with the findings based on Nissl-stained sections and connectional and biochemical data, suggest that the region of this neurochemically defined continuum should be reexamined for consideration as a single functional entity or nucleus: a cholinergic basal nuclear complex.