Regulation Of Brain Energy Metabolism Research Articles

Transcranial near-infrared light in treatment of neurodegenerative diseases.

Light is a natural agent consisting of a range of visible and invisible electromagnetic spectrum travels in waves. Near-infrared (NIR) light refers to wavelengths from 800 to 2,500 nm. It is an invisible spectrum to naked eyes and can penetrate through soft and hard tissues into deep structures of the human body at specific wavelengths. NIR light may carry different energy levels depending on the intensity of emitted light and therapeutic spectrum (wavelength). Stimulation with NIR light can activate intracellular cascades of biochemical reactions with local short- and long-term positive effects. These properties of NIR light are employed in photobiomodulation (PBM) therapy, have been linked to treating several brain pathologies, and are attracting more scientific attention in biomedicine. Transcranial brain stimulations with NIR light PBM in recent animal and human studies revealed a positive impact of treatment on the progression and improvement of neurodegenerative processes, management of brain energy metabolism, and regulation of chronic brain inflammation associated with various conditions, including traumatic brain injury. This scientific overview incorporates the most recent cellular and functional findings in PBM with NIR light in treating neurodegenerative diseases, presents the discussion of the proposed mechanisms of action, and describes the benefits of this treatment in neuroprotection, cell preservation/detoxification, anti-inflammatory properties, and regulation of brain energy metabolism. This review will also discuss the novel aspects and pathophysiological role of the glymphatic and brain lymphatics system in treating neurodegenerative diseases with NIR light stimulations. Scientific evidence presented in this overview will support a combined effort in the scientific community to increase attention to the understudied NIR light area of research as a natural agent in the treatment of neurodegenerative diseases to promote more research and raise awareness of PBM in the treatment of brain disorders.

Можливості фармакологічної регуляції енергетичного метаболізму мозку в ранньому відновлювальному періоді інсульту

Статтю присвячено питанням лікування пацієнтів у відновлювальному періоді інсульту. Зокрема, приділяється увага поліпшенню енергозабезпечення нейронів. У зв’язку з цим обговорюється застосування регулятора енергетичного обміну мельдонію в комплексній терапії даної категорії пацієнтів.

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives.

Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.

An Overview on the Differential Interplay Among Neurons-Astrocytes-Microglia in CA1 and CA3 Hippocampus in Hypoxia/Ischemia.

Neurons have been long regarded as the basic functional cells of the brain, whereas astrocytes and microglia have been regarded only as elements of support. However, proper intercommunication among neurons–astrocytes–microglia is of fundamental importance for the functional organization of the brain. Perturbation in the regulation of brain energy metabolism not only in neurons but also in astrocytes and microglia may be one of the pathophysiological mechanisms of neurodegeneration, especially in hypoxia/ischemia. Glial activation has long been considered detrimental for survival of neurons, but recently it appears that glial responses to an insult are not equal but vary in different brain areas. In this review, we first take into consideration the modifications of the vascular unit of the glymphatic system and glial metabolism in hypoxic conditions. Using the method of triple-labeling fluorescent immunohistochemistry coupled with confocal microscopy (TIC), we recently studied the interplay among neurons, astrocytes, and microglia in chronic brain hypoperfusion. We evaluated the quantitative and morpho-functional alterations of the neuron–astrocyte–microglia triads comparing the hippocampal CA1 area, more vulnerable to ischemia, to the CA3 area, less vulnerable. In these contiguous and interconnected areas, in the same experimental hypoxic conditions, astrocytes and microglia show differential, finely regulated, region-specific reactivities. In both areas, astrocytes and microglia form triad clusters with apoptotic, degenerating neurons. In the neuron–astrocyte–microglia triads, the cell body of a damaged neuron is infiltrated and bisected by branches of astrocyte that create a microscar around it while a microglial cell phagocytoses the damaged neuron. These coordinated actions are consistent with the scavenging and protective activities of microglia. In hypoxia, the neuron–astrocyte–microglia triads are more numerous in CA3 than in CA1, further indicating their protective effects. These data, taken from contiguous and interconnected hippocampal areas, demonstrate that glial response to the same hypoxic insult is not equal but varies significantly. Understanding the differences of glial reactivity is of great interest to explain the differential susceptibility of hippocampal areas to hypoxia/ischemia. Further studies may evidence the differential reactivity of glia in different brain areas, explaining the higher or lower sensitivity of these areas to different insults and whether glia may represent a target for future therapeutic interventions.

Evidence for 11[beta]-HSD1 regulation of brain energy metabolism following systemic inflammation

Evidence for 11[beta]-HSD1 regulation of brain energy metabolism following systemic inflammation

Brain Poster Session: Cerebral Metabolic Regulation

Aim: Aquaglyceroporin-9 (AQP9) is a member of the Aquaporin channel family involved in water flux through plasma membranes and exhibits the distinctive feature of also being permeable to glycerol and monocarboxylates. AQP9 is detected in astrocytes and catecholaminergic neurons.1 However, the presence of AQP9 in the brain is now debated after a recent publication claiming that AQP9 is not expressed in the brain.2 Based on our results,3 we have evidence of the presence of AQP9 in the brain and we further hypothesize that AQP9 plays a functional role in brain energy metabolism. Methods: The presence of AQP9 in brain of OF1 mice was studied by RT-PCR and immunohistochemistry. To address the role of AQP9 in brain, we used commercial siRNA against AQP9 to knockdown its expression in 2 cultures of astrocytes from two distinct sources (from differentiated stem cells4 and primary astrocyte cultures). After assessment of the decrease of AQP9, glycerol uptake was measured using [H3]-glycerol. Then, modifications of the astrocytic energy metabolism was evaluated by measurement of glucose consumption, lactate release5 and evaluation of the mitochondrial activity by MTT staining. Results: AQP9 is expressed in astrocytes of OF1 mouse brain (mRNA and protein levels). We also showed that AQP9 mRNA and protein are present in cultured astrocytes. Four days after AQP9 siRNA application, the level of expression is significantly decreased by 76% compared to control. Astrocytes with AQP9 knockdown exhibit a 23% decrease of glycerol uptake, showing that AQP9 is a glycerol channel in cultured astrocytes. In parallel, astrocytes with AQP9 knockdown have a 155% increase of their glucose consumption without modifications of lactate release. Moreover, considering the observed glucose consumption increase and the absence of proliferation induction, the significant MTT activity increase (113%) suggests an increase of oxidative metabolism in astrocytes with AQP9 knockdown. Discussion: The involvement of AQP9 in astrocyte energy metabolism adds a new function for this channel in the brain. The determination of the role of AQP9 in astrocytes provides a new perspective on the controversial expression of AQP9 in brain. We also suggest that AQP9 may have a complementary role to monocarboxylate transporters in the regulation of brain energy metabolism.

Epilepsy, Regulation of Brain Energy Metabolism and Neurotransmission

Seizures are the result of a sudden and temporary synchronization of neuronal activity, the reason for which is not clearly understood. Astrocytes participate in the control of neurotransmitter storage and neurotransmission efficacy. They provide fuel to neurons, which need a high level of energy to sustain normal and pathological neuronal activities, such as during epilepsy. Various genetic or induced animal models have been developed and used to study epileptogenic mechanisms. Methionine sulfoximine induces both seizures and the accumulation of brain glycogen, which might be considered as a putative energy store to neurons in various animals. Animals subjected to methionine sulfoximine develop seizures similar to the most striking form of human epilepsy, with a long pre-convulsive period of several hours, a long convulsive period during up to 48 hours and a post convulsive period during which they recover normal behavior. The accumulation of brain glycogen has been demonstrated in both the cortex and cerebellum as early as the pre-convulsive period, indicating that this accumulation is not a consequence of seizures. The accumulation results from an activation of gluconeogenesis specifically localized to astrocytes, both in vivo and in vitro. Both seizures and brain glycogen accumulation vary when using different inbred strains of mice. C57BL/6J is the most “resistant” strain to methionine sulfoximine, while CBA/J is the most “sensitive” one. The present review describes the data obtained on methionine sulfoximine dependent seizures and brain glycogen in the light of neurotransmission, highlighting the relevance of brain glycogen content in epilepsies.

Nmr spectroscopic analysis of regional brain energy metabolism in manganese neurotoxicity

A central question in manganese neurotoxicity concerns the focal neuronal damage in the globus pallidus. In the present study, we investigated specific pathways of [1-(13)C]glucose as well as of [2-(13)C]acetate in this brain region and the frontal cortex following 4-day manganese treatment by high-resolution NMR spectroscopy. Following administration of 50 mg/kg/day manganese, glutamine concentration in the globus pallidus was decreased to 67% of control values but increased in frontal cortex by 56%. Manganese treatment also caused pronounced changes in glutamine-glutamate-GABA interconversion in which region-selective differences were observed in the isotopomer pattern of GABA compared with that of glutamine when including the astrocyte-specific substrate [2-(13)C]acetate. In particular, decreased (13)C-labeled glutamine, synthesized from [1-(13)C]glucose, paralleled accumulation of (13)C-labeled GABA in globus pallidus but not in frontal cortex. On the other hand, increased synthesis of glutamine from [2-(13)C]acetate showed that GABA accumulation was not due to increased synthesis from astrocytic glutamine. Furthermore, treatment with manganese resulted in a selective decrease in N-acetyl-aspartate in the globus pallidus. These data illustrate the potential importance of alterations in neuronal metabolic function. In particular, neuronal metabolic derangements and regional differences in the ability of astrocytes to fulfill their contribution to the glutamine-glutamate-GABA cycle during the early phase of manganese neurotoxicity may be crucial in determining the severity of cellular injury.

Neuron–astrocyte interactions in the regulation of brain energy metabolism: a focus on NMR spectroscopy

An adequate and timely production of ATP by brain cells is of cardinal importance to support the major energetic cost of the rapid processing of information via synaptic and action potentials. Recently, evidence has been accumulated to support the view that the regulation of brain energy metabolism is under the control of an intimate dialogue between astrocytes and neurons. In vitro studies on cultured astrocytes and in vivo studies on rodents have provided evidence that glutamate and Na(+) uptake in astrocytes is a key triggering signal regulating glucose use in the brain. With the advent of NMR spectroscopy, it has been possible to provide experimental evidence to show that energy consumption is mainly devoted to glutamatergic neurotransmission and that glutamate-glutamine cycling is coupled in a approximately 1 : 1 molar stoichiometry to glucose oxidation, at least in the cerebral cortex. This improved understanding of neuron-astrocyte metabolic interactions offers the potential for developing novel therapeutic strategies for many neurological disorders that include a metabolic deficit.

New magnetic resonance spectroscopy biomarker for monitoring neurodegenerative diseases: animal models.

Creatine kinase (CK) plays a central role in energy transfer in cells with high-energy demands, and the enzyme is rather susceptible to oxidative inactivation. The aim of the present study was to investigate whether the rate constant of forward CK reaction (k(for)) is a suitable indicator of alterations in cerebral energy metabolism. We monitored k(for) in the rat brain non-invasively by in vivo phosphorus ((31)P) magnetic resonance spectroscopy (MRS). To alter energy metabolism, we applied following experimental models: Huntington's disease, diabetes mellitus, chronic alcohol intoxication and chronic cerebral hypoperfusion (vascular dementia model). Results of our (31)P MRS experiment confirm importance of creatine kinase/phosphocreatinine (CK/PCr) system in the regulation of brain energy metabolism in vivo because a kinetic parameter k(for) was significantly changed in all above animal models that simulate neurodegenerative diseases or commonly during oxidative stress. Using this method we distinguished vascular dementia (VD) and Huntington disease (HD), because in VD model a kinetic parameter k(for) decreased and in the case HD increased. Considering the importance of CK for the maintenance of energy homeostasis in the brain, it is conceivable that an alteration of this enzyme activity in the brain may be one of the mechanisms by which various neurodegenerative diseases might be monitored just by means saturation transfer method (31)P MRS.

Role of astrocytes in coupling synaptic activity to glucose utilization

Recently, in vitro evidence has suggested that astrocytes might play an important role in coupling neuronal activity to glucose utilization. The mechanism proposed to explain such coupling involves the uptake of glutamate by astrocytes via specific transporters. Here, we have taken advantage of the existence of knockout (KO) mice for each glial glutamate transporter to further explore the underpinnings of this mechanism, both in vitro and in vivo. Experiments performed on cultured cortical astrocytes from these mice indicate that an increase in intracellular Na + concentration caused by glutamate transport via the glutamate transporter GLAST is necessary to induce an increase in glucose utilization and lactate production. In vivo, the role of glial glutamate transporters in coupling neuronal activity to energy metabolism was further explored using the whisker-to-barrel pathway. Specific stimulation of the whiskers caused an accumulation of 14C-2-deoxyglucose in related areas of the somatosensory cortex in wild type mice at the age of postnatal day 10. In both GLAST and GLT-1 transporter knockout mice, the metabolic response was strongly reduced. These data further emphasized the prominent role of astrocytes in the regulation of brain energy metabolism and identify glial glutamate transporters as key elements.

Delayed changes in regional brain energy metabolism following cerebral concussion in rats.

Traumatic brain injury (TBI) results in an acute altered metabolic profile of brain tissue which resolves within hours of initial insult and yet some of the functional deficits and cellular perturbations persist for days. It is hypothesized that a delayed change in energy status does occur and is a factor in the neural tissue's ability to survive and regain function. Regional metabolic profile and glucose consumption were determined at either 1 or 3 days following two different intensities of parasagittal fluid-percussion (F-P). A significant decrease in both 1CMRgluc and levels of ATP and P-creatine was evident in the hemisphere ipsilateral to the trauma at 1 day after the insult. The effect was greater in the cortical than the subcortical regions and was more pronounced at the higher trauma intensity. Normalization of glucose consumption and energy levels was essentially complete by 3 days. It would appear that the delayed metabolic changes at 1 day postinsult cannot be explained by a secondary ischemia since the changes in the metabolite profile do not elicit an increase in the consumption of glucose. These changes in energy metabolites may account for and contribute to the chronic neurological deficits following TBI.

Glycolysis in neurons, not astrocytes, delays oxidative metabolism of human visual cortex during sustained checkerboard stimulation in vivo.

The regulation of brain energy metabolism during neuronal activation is poorly understood. Specifically, the extent to which oxidative metabolism rather than glycolysis supplies the additional ATP necessary to sustain neuronal activation is in doubt. A recent hypothesis claims that astrocytes generate lactate with the muscle-type lactate dehydrogenase (LDH) isozyme LD 5. Lactate from astrocytes then undergoes oxidation in neurons after reconversion to pyruvate by the LDH subtype LD 1. On the basis of this hypothesis, the authors predicted that the time course of an excitatory increase of the oxidative metabolism of brain tissue must depend on the degree to which astrocytes provide neurons with pyruvate in the form of lactate. From the known properties of the LDH subtypes, the authors predicted two time courses for the changes of oxygen consumption in response to neuronal stimulation: one reflecting the properties of the neuronal LDH subtype LD 1, and the other reflecting the astrocytic LDH subtype LD 5. Measuring oxygen consumption (CMR O2 ) with positron emission tomography, the authors demonstrated increased CMR O2 during sustained stimulation of visual cortex with a complex stimulus. The CMR O2 increased 20.5% after 3 minutes and 27.5% after 8 minutes of stimulation, consistent with a steady-state oxygen-glucose metabolism ratio of 5.3, which is closest to the index predicted for the LD 1 subtype. The index is equal to the oxygen-glucose metabolism ratio of 5.5 calculated at baseline, indicating that pyruvate is converted to lactate in a cellular compartment with an LDH reaction closest to that of LD 1, whether at rest or during stimulation of the visual cortex with the current stimulus. The findings are consistent with a claim that neurons increase their oxidative metabolism in parallel with an increase of pyruvate, the latter generated by neuronal rather than astrocytic glycolysis.

Behavior and brain uptake of fluorodeoxyglucose in mature and aged C57BL/6 mice

This paper describes regional brain energy metabolism, sensorimotor, and memory functions in mature (12 months) and old (24 months) C57BL/6 mice. Male mice were tested across a variety of sensorimotor procedures and in the Morris water maze before evaluating brain uptake of fluorodeoxyglucose (FDG) in the resting state. Mature mice outperformed older mice during the difficult sensorimotor and memory tasks, but not the easier tasks. This suggested that the greater sensorimotor and memory demands of a task compromised the performance of the older mice. This conclusion was consistent with the relative FDG uptake decreases found in regions mediating sensorimotor coordination (vestibular, cerebellar, ventral thalamic regions) and some limbic regions linked to memory (mammillary body, posterior cingulate, and piriform cortices). The inferior colliculus and flocculus had the greatest metabolism in mature mice, as shown by resting FDG uptake, and these regions showed the most marked hypometabolism in the older mice. The data also showed that the neurobehavioral correlative pattern in older mice was modified. In conclusion, brain regions with higher energy metabolism, and the behaviors to which they are related, were affected most greatly by aging in C57BL/6 mice—suggesting that these areas are more metabolically vulnerable to aging effects.

The effects of (+)-UH232 and (−)-DS121 on local cerebral glucose utilization in rats

Although (+)-UH232 (cis-(+)-5-methoxy-1-methyl-2-(n-dipropylamino)tetralin) and (-)-DS121 (S(-)-3-(3-(cyanophenyl)-N-n-propylpiperidine) are both preferential dopamine autoreceptor antagonists, (-)-DS121 is a more effective behavioral stimulant and dopamine releasing agent. To further compare these two agents, Sokoloff's 2-deoxyglucose autoradiography method was used to study the effects of (+)-UH232 and (-)-DS121 on regional brain energy metabolism. (+)-UH232, 30 mg/kg i.p., depressed metabolism in 37 of 65 brain regions and antagonized the stimulant effects of amphetamine. (-)-DS121, 30 mg/kg i.p., exhibited a strong, nonsignificant trend towards an increase in regional brain energy metabolism by itself and enhanced the stimulant effects of amphetamine. The data demonstrate dramatic differences in the effects of two autoreceptor antagonists on regional brain energy metabolism. It is concluded that, compared to (+)-UH232, (-)-DS121 is a more effective stimulant of brain energy metabolism and autoreceptor antagonist owing to its greater ability to increase DA release.

Creatine kinase-B mRNA levels in brain regions from male and female rats

The creatine kinase-B (CKB) enzyme is proposed to have a pivotal role in the regeneration of ATP in the nervous system. In the present study, the steady-state levels of CKB mRNA were determined by RNase protection assay in seventeen separate brain regions obtained from rats during the initial interval of the light period or period of inactivity in rats. The antisense probe used specifically hybridizes to CKB mRNA and discriminates CKB from CKM mRNA. The results show that brain regions from Wistar rats differ in CKB mRNA content. Highest levels of CKB mRNA were detected in the male and female cerebellum. High levels of CKB mRNA were observed in the spinal cord, brain stem and its structures (medulla, pons and midbrain) and olfactory bulb of the male rats. Female rats also contained high levels of CKB mRNA in the brain stem. In both male and female rats, the frontal cortex, occipital cortex, hippocampus and striatum exhibited lower levels of CKB mRNA relative to the complete brain. Statistical analyses demonstrated a significant difference between the male and female CKB mRNA profiles. However, CKB mRNA levels in brain regions with estrogen receptors (hypothalamus, hippocampus) were similar in male and female rats. Differential CKB mRNA levels in various brain regions may suggest diverse physiological significance of the CKB system in the regulation of brain energy metabolism.

Antagonism of cocaine's stimulant effects on local cerebral glucose utilization by the preferential autoreceptor antagonist (+)-AJ 76.

(+)-AJ 76 is a stimulant dopamine (DA) antagonist, which has a putative preferential action at DA nerve terminal autoreceptors. Because it is both a mild stimulant and a DA antagonist, it has previously been suggested that (+)-AJ 76 might antagonize both the euphoria and craving associated with cocaine abuse and withdrawal, respectively. To evaluate this hypothesis further, (+)-AJ 76 was evaluated for its ability to affect cocaine-induced changes in regional brain energy metabolism. Using Sokoloff's 2-deoxyglucose autoradiographic technique, (+)-AJ 76 antagonized the stimulant effect of cocaine. Although classical DA antagonists are known to depress regional brain energy metabolism, (+)-AJ 76 by itself had no effect. It is concluded that the results are consistent with the previously stated hypothesis that (+)-AJ 76 might be useful as a pharmacotherapy for treatment of cocaine abuse.

Chapter 12 Vasoactive intestinal peptide and noradrenaline regulate energy metabolism in astrocytes: a physiological function in the control of local homeostasis within the CNS

Publisher Summary Neurotransmitters that are released from neurons can interact in a receptor-mediated manner with nonneuronal cells, such as astrocytes, choroid plexus cells, or cells of the vasculature. Nonneuronal cells—in particular, astrocytes and the microglia—can release molecules, such as interleukins and prostanoids, known to play a role in cell–cell communication in the immune system and in inflammatory processes, respectively. This chapter focuses on the evidence indicating that the neurotransmitters vasoactive intestinal peptide (VIP) and noradrenaline (NA) act on astrocytes to regulate energy metabolism in the cerebral cortex. Observations reviewed in the chapter show that VIP and NA participate in the regulation of brain energy metabolism by tightly regulating the glycogen content and the glucose uptake in astrocytes for NA. In addition, cytological and pharmacological evidence strongly suggest that VIP- and NA-containing neurons interact with intraparenchymal blood vessels. The demonstration of homeostatic functions regulated by the neurotransmitters contained in discrete neuronal circuits supports the concept that such circuits may represent, within the brain, the counterpart of the autonomic nervous system that regulates, among other functions, blood flow, energy metabolism, and local homeostasis in peripheral tissues.

Comparison of cholinergic drug effects on regional brain glucose consumption in rats and humans by means of autoradiography and positron emission tomography

Cholinergic mechanisms have been extensively studied in animals and have been implicated in the pathogenesis of human disorders such as Alzheimer's disease. However, few investigations have directly evaluated the validity of extrapolating the results of animal studies to humans. As a component of a continuing examination of the contribution of cholinergic deficits to the alterations in brain metabolism that occur in Alzeimer's disease, we have compared the effects of scopolamine and physostigmine on regional brain energy metabolism in both rats and humans, using a common region of interest atlas. In Alzheimer's patients and in rodents, physostigmine increased glucose metabolism in several regions (e.g. thalamus) and decreased it in others. Overall, there was a significant positive correlation for the effects of physostigmine in the nineteen brain regions etudied in both species (r = 0.51, P < 0.05). In normal humans, scopolamine induced a metabolic increase in most brain regions except in the thalamus. Outside this structure, the regional effects of scopolamine were significantlly and negatively correlated (r = −0.58, P < 0.01) between rat and human. These resuts suggest that: (1) cholinergic mechanisms have a similar anatomic distribution in both species, (2) muscarinic receptor-mediated cholinergic effects could predominate outside the thalamus, (3) muscarinic mechanisms are inhibitory in humans but are more complex and possibly excitatory in rats, (4) nicotinic stimulatory effects are found in the thalamus of both species, and (5) physostigmine, but not scopolamine, alters glucose consumption similarly in both species.

Effects of cholinergic agonists on regional brain energy metabolism in the scopolamine-treated rat.

The effects of scopolamine, physostigmine, RS86 and U-80816B on regional energy metabolism were studied in rodents by means of the 2-deoxyglucose autoradiographic technique. Scopolamine depressed metabolism in an area of cerebral cortex, focused around the parietal region. Rats treated with cholinergic direct agonists (U-80816B, RS86) as well as with the indirect agonist (physostigmine) all showed decreases in cortical energy metabolism, similar to scopolamine. They also induced an increase in thalamic metabolism. When these drugs were given in conjunction with scopolamine, metabolism tended to change in the opposite direction from the values obtained with the drug alone. These results suggest that there are complex interactions between pre- and post-synaptic muscarinic receptors. Additionally, nicotinic receptors could also be involved in some of the effects of physostigmine.