Postural and anticonvulsant effects of inhibition of the rat subthalamic nucleus.

The subthalamic nucleus (STN) plays a crucial role as a regulator of basal ganglia outflow by providing excitatory glutamatergic input into the two output nuclei of the basal ganglia, substantia nigra pars reticulata (SNpr), and entopeduncular nucleus. This study examined the effects of suppressing activity in the STN of the awake, behaving rat. Specifically, we evaluated the effects of unilateral and bilateral focal inhibition of STN on posture, locomotion, and susceptibility to limbic motor seizures. Unilateral microinjection of a GABA(A) receptor agonist (muscimol, 200 pmol) into STN produced a site-dependent contralaterally directed postural asymmetry without locomotor activation. This effect differed from responses produced by the same dose of muscimol placed into SNpr, which included locomotor activation in addition to contralaterally directed postural asymmetry. Locomotor activation and postural asymmetry were obtained also after blockade of glutamate transmission in SNpr by the unilateral application of kynurenate (100 nmol). Our observation that STN inhibition did not induce the locomotor activation characteristic of SNpr inhibition suggests that there are glutamatergic inputs to SNpr, other than those from STN, that are responsible for controlling locomotion. Bilateral, but not unilateral, injection of muscimol (200 pmol) into STN protected against limbic motor seizures evoked either by intravenous bicuculline or by focal application of bicuculline into anterior piriform cortex (area tempestas). These results demonstrate that focal inhibition of STN reproduces the postural asymmetry and anticonvulsant actions that are obtained with the inhibition of SNpr. This provides behavioral support for the concept that STN contributes a crucial tonic excitatory (glutamatergic) drive to the rat SNpr.     

Acute monoaminergic depletion in the rat potentiates the excitatory effect of the subthalamic nucleus in the substantia nigra pars reticulata but not in the pallidal complex

Summary Recent neurochemical evidence suggests that chemical or electrial stimulation of the subthalamic nucleus (STH) increases dopamine release in the substantia nigra (SN) with a subsequent decrease in the striatum. In a previous paper, we reported that bicuculline-induced activation of the STH increases neuronal activity in the substantia nigra pars reticulata (SNpr) and in the pallidal complex. In order to investigate the role played by the dopaminergic system in the observed activation, the neuronal responses of subthalamic nucleus target structures were studied in amine depleted rats following subthalamic stimulation. Amine depletion was accomplished by pretreating the rats with reserpine (2 mg/kg; S.C.) and with alpha-methyl-para-tyrosine (-mpt; 50 mg/kg; I.P.).Following this treatment, dopamine levels were reduced by 94% in the striatum as measured by HPLC. Amine depletion significantly increased the spontaneous activity of subthalamic cells by 53%. In the SNpr, no significant changes in the spontaneous neuronal activity were observed, but the excitatory responses to bicuculline-induced stimulation of the STH were potentiated as compared to non-treated animals. In the pallidial complex (GP-EP), no potentiation was found. The data suggest that the spontaneous pattern of discharge of the STH is probably under monoaminergic control. They also suggest a reciprocal interaction between dopamine and glutamatergic afferent terminals from the STH within the SNpr, but not in the pallidal complex.     

Fatty acid incorporation depicts brain activity in a rat model of Parkinson's disease

Following pulse labeling with [ ]arachidonic acid ([ ]AA), its incorporation pattern in brain reflects regional changes in neurotransmitter signal transduction using phospholipase A₂, that is, functional activity. In a rat model of Parkinson's disease, unilateral 6-hydroxydopamine lesion in the substantia nigra, [ ]AA acid incorporation from blood was increased in cerebral cortex, caudate putamen, globus pallidus, entopeduncular nucleus, subthalamic nucleus and substantia nigra pars reticulata ipsilateral to the lesion. This increased [ ]AA incorporation likely reflects disinhibition of basal ganglia and cortical circuits secondary to absent inhibitory nigrostriatal dopaminergic input.     

Excitatory influence of rat subthalamic nucleus to substantia nigra pars reticulata and the pallidal complex: electrophysiological data

By selective chemical stimulation of the subthalamic nucleus (STh) with the gamma-aminobutyric acid (GABA) antagonist bicuculline, we have studied the effect of its projections to the target nuclei. Results show that bicuculline (0.39 mM) produced a mean activation of 358% in subthalamic neurons. Most of the cells recorded in the substantia nigra pars reticulata (SNpr), the entopenduncular nucleus (EP), and the globus pallidus (GP) were also significantly activated. In the substantia nigra pars compacta (SNpc), slight and opposite changes were produced: half of the cells were activated and half were inhibited. In the striatum, 3 types of responses were recorded: activation, inhibition, and biphasic effect. Inhibition of subthalamic neurons by local microinjection of muscimol (0.95 mM), produced reductions in the neuronal activity of cells in the SNpr, the EP, and the GP. These results suggest that the STh conveys an important and permanent excitatory influence onto its target nuclei. In another set of experiments, in order to investigate whether or not the STh utilizes glutamate for neurotransmission in the SNpr, we injected the glutamate receptor antagonist kynurenic acid (2.6 mM) into the SNpr, later followed by an injection of bicuculline in the STh. Kynurenic acid alone produced a mean inhibition of 30% in non-dopaminergic nigral cells, and antagonized the subsequent bicuculline-induced activating effect of the STh. These results further confirm recent data showing that the STh exerts an excitatory action on its efferent structures, and provide new evidence for glutamatergic transmission in subthalamic projections.(ABSTRACT TRUNCATED AT 250 WORDS)     

Convergent Synaptic Input From the Neostriatum and the Subthalamus Onto Identified Nigrothalamic Neurons in the Rat

The two major afferents of the substantia nigra pars reticulata are the subthalamic nucleus and the striatum. Stimulation of these afferents has opposing physiological effects on the output neurons of the substantia nigra pars reticulata. In order to better understand the role of these afferents in the flow of information through the basal ganglia and to better understand the ways in which they might interact, experiments have been performed to test the possibility that single-output neurons of the substantia nigra pars reticulata receive convergent synaptic input from the subthalamic nucleus and the neostriatum. To address this, rats received iontophoretic deposits of the anterograde tracer Phaseolus vulgaris leucoagglutinin in the subthalamic nucleus, injections of the anterograde tracer biocytin in the neostriatum and injections of the retrograde tracer horseradish peroxidase conjugated to wheat-germ agglutinin in the ventral medial nucleus of the thalamus. Following appropriate survival times the animals were perfusion-fixed and sections of the substantia nigra were processed to reveal the transported tracers and prepared for electron microscopy. Light microscopic examination revealed that the substantia nigra contained rich plexuses of anterogradely labelled subthalamic and striatal terminals, as well as many retrogradely labelled nigrothalamic neurons. The anterogradely labelled terminals were often seen apposed to the retrogradely labelled neurons. In the electron microscope the subthalamic terminals were seen to form asymmetrical synaptic contacts (subthalamic type 1) with the identified nigrothalamic neurons as well as unlabelled perikarya and both proximal and distal dendrites. In confirmation of previous findings, the striatal terminals made symmetrical synaptic contact with the nigrothalamic neurons as well as unlabelled neurons. In areas of overlap between the two classes of terminals, identified nigrothalamic neurons and unlabelled nigral neurons were found to receive convergent synaptic input from the subthalamic nucleus and the neostriatum. In addition to the anterogradely labelled subthalamic terminals that formed asymmetrical synaptic specializations, a second, much rarer class was also observed (subthalamic type 2). These terminals were much larger and formed symmetrical synapses; several lines of evidence suggest that they originated not in the subthalamic nucleus but in the globus pallidus. These terminals were found to make synaptic contacts with identified nigrothalamic neurons and non-labelled neurons and to form convergent synaptic contacts with subthalamic type 1 terminals and striatal terminals. It is concluded that the topographical and synaptic organization of the so-called direct (striatum to substantia nigra pars reticulata) and indirect pathways (i.e. pathways involving the subthalamic nucleus andlor the globus pallidus) of information flow through the basal ganglia underlies the inhibition and excitation of the output neurons of the substantia nigra pars reticulata that occur following stimulation of the striatum.     

Projections of the pedunculopontine tegmental nucleus in the rat: evidence for additional extrapyramidal circuitry

The projections of the pedunulopontine tegmental nucleus (PPT) were studied in the rat using anterograde and retrograde transport methods. Ascending fibers to the substantia nigra, the subthalamic nucleus, the globus pallidus, the entopeduncular nucleus, the neostriatum, the ventral thalamus, and the medial and sulcal frontal cortical areas were identified. PPT has been reported to receive afferents from the substantia nigra, the subthalamic nucleus, the entopeduncular nucleus and the neostriatum. The connections of PPT provide an additional limb to extrapyramidal circuitry.     

Death of dopaminergic neurones in the rat substantia nigra can be induced by damage to globus pallidus

Parkinson's disease is a debilitating disorder that results from the death of dopaminergic neurones in the substantia nigra. Subthalamic nucleus neurones use glutamate as their neurotransmitter and send excitatory projections to the substantia nigra. Changes in both the mean firing rate and firing pattern of neurones of the subthalamic nucleus have been found in patients with this disease. This has led to the suggestion that hyperactivity of the subthalamic nucleus may be involved in the pathology of the dopaminergic neurones. Subthalamic nucleus lesions or treatment with glutamatergic antagonists can be neuroprotective in animal models of Parkinson's disease but until now there has been no direct evidence that hyperactivity of subthalamic nucleus neurones can lead to downstream cell death. Here we show that lesions of the rat globus pallidus (a treatment that has been shown to increase subthalamic nucleus neuronal activity) result in a significant reduction of the number of dopaminergic neurones in the substantia nigra.     

Superior colliculus firing changes after lesion or electrical stimulation of the subthalamic nucleus in the rat

Recent data have suggested a critical role for the basal ganglia in the remote control of epileptic seizures. In particular, it has been shown that inhibition of either substantia nigra pars reticulata or subthalamic nucleus as well as activation of the superior colliculus suppresses generalized seizures in several animal models. It was previously shown that high frequency stimulation of the subthalamic nucleus, thought to act as functional inhibition, stopped ongoing non-convulsive generalized seizures in rats. In order to determine whether high frequency stimulation of the subthalamic nucleus involved an activation of superior colliculus neurons, we examined the effects of subthalamic nucleus manipulation, by either high frequency stimulation or chemical lesion, on the spontaneous electrical activity of superior colliculus neurons. Acute high frequency stimulation of the subthalamic nucleus (frequency 130 Hz) induced an immediate increase of unitary activity in 70% of responding cells, mainly located within the deep layers, whereas a reduction was observed in the remaining 30%. The latter responses are dependent on the intensity and frequency of the stimulation. Unilateral excitotoxic lesion of the subthalamic nucleus induced a delayed and transient decrease of superior colliculus activity. Our data suggest that high frequency stimulation of the subthalamic nucleus suppresses generalised epileptic seizures through superior colliculus activation.     

Pedunculopontine-evoked excitation of substantia nigra neurons in the rat

The effects of electrical stimulation of the nucleus tegmenti pedunculopontinus on the unitary activity of identified neurons of the rat substantia nigra were studied. The experiments were carried out in intact rats as well as in animals bearing either chronic bilateral electrolytic lesions of the deep cerebellar nuclei or an acute lesion of the ipsilateral subthalamic nucleus. Excitation of both compacta and reticulata cells of the substantia nigra (many of the latter being output neurons since they are antidromically activated from the superior colliculus) was the predominant response recorded. Two types of excitations could be distinguished. The first was a direct orthodromic excitation (latency 2.9 ± 1.6ms; duration3.7 ± 1.9ms). The second was a sparse and less pronounced activation (latency 5.2 ± 1.8ms; duration13.0 ± 3.0ms). These two types of excitation were the only responses recorded in intact rats (10/51, 19.6%, orthodromic and 10/51, 19.6%, diffuse activation). When the cerebellar nuclei were destroyed 7–21 days prior to the recording, both excitations were still found (10/59, 16.9% and 15/59, 25.4%, respectively), whereas a minority (3/59, 5.0%) of neurons were inhibited. Conversely, when the subthalamic nucleus was lesioned the orthodromic response was still present (9/42, 21.4%) whereas the occurrence of the diffuse excitation greatly decreased (3/42, 7.1%) and a greater number of inhibitions (6/42, 14.2%) appeared. A small population of cells (12/85, 14.1%) were excited from the contralateral pedunculopontine nucleus either by the orthodromic or by the diffuse excitation. The total number of nigral neurons antidromically activated from the ipsilateral pedunculopontine nucleus was 9/152 (5.9%). The results provide evidence that the nucleus tegmenti pedunculopontinus gives a dual excitatory input to the substantia nigra either through a probable direct connection or through a polysynaptic pathway via the subthalamic nucleus. A few cells from both parts of the substantia nigra, in turn, project back to the nucleus tegmenti pedunculopontinus. In addition, our data give further support to the view that output fibers from the deep cerebellar nuclei do not synapse in the substantia nigra in the rat.     

Tremor in Parkinson's disease

Rest tremor is a common feature of Parkinson's disease, but its underlying pathophysiology remains unknown. This review hypothesizes that tremor is related to selective loss of components of the substantia nigra. The relative scarcity of tremor in related Parkinsonian conditions may indicate a dissociation associated with different pathological involvement of the substantia nigra and its connections. Connections of the subthalamic nucleus with the pallidum, modified by cortical and nigral inputs, allow for the transfer of tremorogenic activity to the thalamus. Thalamo-cortical interactions, tempered by cerebellar input, generate the final common pathway for tremor production.     

Psychoactive drugs and regulation of the cAMP/PKA/DARPP-32 cascade in striatal medium spiny neurons

Changes in activity of the medium spiny neurons (MSNs) of dorsal and ventral striatum result in alterations of motor performance, ranging from rapid increases or decreases in locomotor activity, to long-term modifications of motor behaviours. In the dorsal striatum, MSNs can be distinguished based on the organization of their connectivity to substantia nigra pars reticulata (SNpr) and internal segment of the globus pallidus (GPi), which, in turn, control thalamocortical neurons. Approximately half of the MSNs project directly to SNpr and GPi, their activation leading to disinhibition of thalamocortical neurons and increased motor activity. The other subpopulation of MSNs connects to SNpr and GPi indirectly and when activated promotes inhibition of thalamocortical neurons, thereby reducing motor activity. The dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) is a modulator of the cAMP signalling pathway, highly expressed in MSNs. This review discusses the regulation of DARPP-32 exerted by psychoactive substances in specific populations of striatal projection neurons and its involvement in short- and long-term motor responses.     

Effects of high frequency stimulation of subthalamic nucleus on extracellular glutamate and GABA in substantia nigra and globus pallidus in the normal rat

High frequency stimulation (130 Hz) of the subthalamic nucleus has dramatic beneficial motor effects in severe parkinsonian patients. However, the mechanisms underlying these clinical results remain obscure. The objective of the present work was to study the neurochemical changes induced in rats by high frequency stimulation of the subthalamic nucleus by using intracerebral microdialysis within its target structures. Our results show that high frequency stimulation of the subthalamic nucleus induces a significant increase of extracellular glutamate levels in the ipsilateral globus pallidus and substantia nigra while GABA was augmented only in the substantia nigra. These data suggest that functional effects induced by high frequency stimulation of the subthalamic nucleus might imply distal mechanisms involving the synaptic relationships with the subthalamic efferences. They question the current view that the direct inhibition of the subthalamic neurons is induced by high frequency stimulation.     

l-DOPA produces regional changes in glucose utilization which form discrete anatomic patterns in motor nuclei and the hypothalamus of rats

Systemic injections of l-DOPA (200 mg/kg) combined with a peripheral decarboxylase inhibitor (Carbidopa) produced increased motor activity and changes in regional cerebral glucose utilization similar to and different from changes seen with other dopaminergic drugs in previous studies. Similarities were an increased glucose utilization (relative optical density measurement) in the subthalamic and entopeduncular nuclei and the substantia nigra. A major difference was a suggested decreased glucose utilization in the striatum with l-DOPA treatment rather than the increases observed with apomorphine in other studies. Also, glucose utilization in the paraventricular nucleus of the hypothalamus was decreased. Finally, specific, discrete patterns were visible in motor nuclei of the l-DOPA-treated rats which were not visible with other dopaminergic drugs: the ventral posterior striatum was increased compared with the dorsal striatum and the compacta region of the substantia nigra contained unusual round spots and patterns of high-normal density and low-normal density, especially in the lateral compacta region. In one case, the density pattern in the substantia nigra was similar to the field of dopamine cell bodies and their dendrites which extend into the reticulata region. The results confirm the importance of activity in the subthalamic nucleus, globus pallidus, and entopeduncular nucleus, as well as the substantia nigra for dopaminergic drug effects either through striatal dopamine receptors or through dopamine receptors in each of these nuclei. In addition, new “functional units” in the substantia nigra were revealed.     

l-DOPA produces regional changes in glucose utilization which form discrete anatomic patterns in motor nuclei and the hypothalamus of rats

Systemic injections of l-DOPA (200 mg/kg) combined with a peripheral decarboxylase inhibitor (Carbidopa) produced increased motor activity and changes in regional cerebral glucose utilization similar to and different from changes seen with other dopaminergic drugs in previous studies. Similarities were an increased glucose utilization (relative optical density measurement) in the subthalamic and entopeduncular nuclei and the substantia nigra. A major difference was a suggested decreased glucose utilization in the striatum with l-DOPA treatment rather than the increases observed with apomorphine in other studies. Also, glucose utilization in the paraventricular nucleus of the hypothalamus was decreased. Finally, specific, discrete patterns were visible in motor nuclei of the l-DOPA-treated rats which were not visible with other dopaminergic drugs: the ventral posterior striatum was increased compared with the dorsal striatum and the compacta region of the substantia nigra contained unusual round spots and patterns of high-normal density and low-normal density, especially in the lateral compacta region. In one case, the density pattern in the substantia nigra was similar to the field of dopamine cell bodies and their dendrites which extend into the reticulata region. The results confirm the importance of activity in the subthalamic nucleus, globus pallidus, and entopeduncular nucleus, as well as the substantia nigra for dopaminergic drug effects either through striatal dopamine receptors or through dopamine receptors in each of these nuclei. In addition, new “functional units” in the substantia nigra were revealed.     

Suppression of cell firing in the substantia nigra by caudate nucleus stimulation

Cats anesthetized with barbiturates show a unique 8–12/sec continuous rhythmic activity in the subthalamic nucleus and ventral tegmental region which may be correlated with the “barbiturate tremor.” Pallidal stimulation inhibits subthalamic nucleus slow-wave and single-unit activity, while nigral stimulation produces a phasic discharge in subthalamic neurons. In contrast to pallidal stimulation, caudate stimulation does not inhibit the firing of subthalamic nucleus cells. In view of this and the action of the substantia nigra upon the subthalamic nucleus, we studied the effects of caudate activation upon extracellularly recorded single unit responses in the nigra of barbiturate-anesthetized cats. Fifty-one units were analyzed. Of these, 24 were localized to the tegmentum just above the substantia nigra, 25 in the nigra, and two in the cerebral peduncle. The predominant effect of single caudate stimuli was suppression of firing of nigral (95%) or tegmental (58%) cells for either 70 or 140 msec, or more. These effects were seen in both medial and lateral portions of the nigra, and at rostral and caudal levels of the nucleus. No short-latency spikes were seen in nigral cells following caudate stimulation, and only a few in units localized to the tegmentum. In the barbiturate anesthetized cat, caudate stimulation leads to a suppression of firing of cells throughout the substantia nigra.     

Projections of the feline globus pallidus

The organization of globus pallidus (GP) projections was studied in cats using autoradiographic and horseradish peroxidase (HRP) techniques. Both methods confirmed the existence of a topographically organized projection to subthalamic nucleus (STN). Although all but the most caudal GP projects to STN, the heaviest projection is to the lateral two-thirds. In addition, HRP studies showed that the GP projection to the medial part of substantia nigra, pars reticulata receives projections from the rostral lateral GP, while lateral substantia nigra receives input from caudal GP. There is in addition a small projection from caudal GP to the caudal lateral mesencephalon. This most caudal projection of GP arises from the portion of GP which projects the least to the subthalamic nucleus. Mesencephalic and pontine cells labeled after injection of horseradish peroxidase into STN were in areas receiving projections from GP and entopeduncular nucleus, suggesting there may be reciprocal relationships between these areas. Labeled cells were located in the lateral part of subthalamic nucleus after injection into the lateral portion of substantia nigra pars reticulata, but cells were not labeled after medial injection. Pontine injections of HRP also revealed that cells in fields of Forel and zona incerta project to pons but very few subthalamic nucleus cells project there.     

Two separate neuronal populations of the rat subthalamic nucleus project to the basal ganglia and pedunculopontine tegmental region

Employing a retrograde fluorescent double labeling technique, we compared the localization of subthalamic nucleus (STN) cells projecting to the striatum and nucleus tegmenti pedunculopontinus pars compacta (TPC), with that of STN cells sending axon collaterals to both the globus pallidus and substantia nigra in the rat. The STN-striatal projections were mostly the third branches of massive STN-pallidal and STN-nigral collateral projection neurons, whereas only very rarely did the STN-TPC projections contribute to these collateral projections. The TPC projecting STN cells, giving rise to an independent output of the nucleus, were located mainly in its thin lateral strip region. The STN may integrate the somatic motor information from various cortical/subcortical brain areas (including the motor cortex, striatum, globus pallidus, thalamus and TPC), and disperse it predominantly to the pallidal complex, substantia nigra and striatum by way of axon collaterals, and to a lesser degree to the TPC through separate fibers. Thus, the STN might be in a strategic position to exert a prominent control over the basal ganglia-related somatic motor functions.     

Descending efferent connections of the sub-pallidal areas in the cat: Projections to the subthalamic nucleus,the hypothalamus,and the midbrain

The efferent connections of the sub-pallidal regions to the mediodorsal thalamic nucleus, the subthalamic nucleus, the lateral hypothalamic area, and the midbrain were investigated in the cat, using Phaseolus vulgaris—leucoagglutinin (PHA-L) as an anterograde label. The results indicate that the sub-pallidal regions of the cat project to the (dorso)medial tip of the subthalamic nucleus and the adjoining lateral hypotha-lamic area as well as to the ventral tegmental area and the greater extent of the dorsolateral tier of the substantia nigra pars compacta. Extensive projections were also found to the peripeduncular nucleus. The central gray as well as the mesencephalic locomotor region receive some input from the basal forebrain too. In contrast only very limited projections were found to the mediodorsal thalamic nucleus. The results are discussed in view of the possible role of these output regions in oro-facial dyskinesia. © 1993 Wiley-Liss, Inc.     

Differential expression of kainate receptors in the basal ganglia of the developing and adult rat brain

Glutamate is the principal excitatory transmitter of the mammalian brain and plays a particularly important role in the physiology of the basal ganglia structures responsible for movement regulation. Using in situ hybridization with oligonucleotide probes, we examined the expression patterns of the five known kainate type glutamate receptor subunit genes, KA1, KA2 and GluR5–7, in the basal ganglia of adult and developing rat brain. In the adult rat, a highly organized and selective pattern of expression of the kainate subunits was observed in the basal ganglia and associated structures as well as in other regions of the brain. KA2 mRNA was abundant in the striatum, nucleus accumbens, subthalamic nucleus and substantia nigra pars compacta, and was present at lower levels in the globus pallidus and substantia nigra pars reticulata. Neither KA1 nor GluR5 expression was observed in the basal ganglia of adult rats, although these messages were present in other regions. GluR6 was highly expressed in the striatum and subthalamic nucleus and to a lesser extent in the substantia nigra pars reticulata, while no hybridization signal was detectable in the large, presumably dopaminergic neurons of the substantia nigra pars compacta. In contrast, GluR7 was strongly expressed in the substantia nigra pars compacta, was present at lower levels in the striatum, globus pallidus and substantia nigra pars reticulata, and was not detectable in the subthalamic nucleus. During postnatal development, expression of the kainate receptor subunits was characteristically highest on postnatal day 1 and declined to adult levels by day 20; however, in the globus pallidus we did observe the transient expression of KA1 and GluR5 between day 1 and day 10. These results demonstrate that the neuronal structures comprising the basal ganglia express a distinct combination of kainate receptor subunit genes, suggesting that the pharmacological properties of the resultant glutamate receptors are likely to be regionally specific. The organization of expression of these genes is established early in life, which is consistent with the important role they may play in establishing the functions of the motor system.     

The cerebral metabolic effects of manipulating glutamatergic systems within the basal forebrain in conscious rats

N-methyl-d -aspartate (NMDA) and non-NMDA receptor-mediated manipulations of the cortical cholinergic input arising from the basal forebrain differentially affect cognitive function. We used [¹⁴C]-2-deoxyglucose autoradiography in conscious rats to map the effects of excitatory amino acid agonist infusions into the nucleus basalis magnocellularis (NBM) on cerebral functional activity, as reflected by local rates of glucose utilization. Acute stimulation of NBM neurones by local infusion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), 15 min before glucose use measurement, resulted in glucose use reductions in nine cortical regions innervated by NBM efferents including prefrontal, frontal, sensorimotor and cingulate cortices. NMDA infusions altered glucose use in two cortical areas. Both AMPA and NMDA markedly increased glucose use in the striatum and globus pallidus, with concomitant perturbations in striato-pallidal projection targets including the substantia nigra, entopeduncular nucleus, subthalamic nucleus and lateral habenular nucleus. In contrast, the GABA_A agonist muscimol did not affect glucose use in the NBM or neocortical regions, but induced glucose use increases in several subcortical nuclei including the substantia nigra and entopeduncular nucleus. The delayed effects of excitotoxic lesions were assessed 3 weeks after basal forebrain infusions of AMPA, NMDA, ibotenate or quisqualate. Statistically significant glucose use changes only occurred in the hypothalamus after NMDA, and the NBM after ibotenate infusions, although reduced cortical metabolism was apparent following AMPA-induced lesions of the NBM. Results support a dissociation between the functional sequelae of NMDA and non-NMDA receptor-mediated events in the basal forebrain, and long-term compensatory functional adaptation following cortical denervation.