Participation of vertebrate forebrain activating systems in organization of the wakefulness-sleep cycle

The article considers mechanisms of diencephalic-telencephalic interactions in regulation of the wakefulness-sleep cycle in various classes of vertebrates. In such interactions a special role is played by the dopaminergic systems that perform neurosecretory function at the level of diencephalon and neurotransmitter function at the level of telencephalon. Concepts of A.I. Karamyan and A.L. Polenov about the stage pattern of development of CNS and neurosecretory systems are presented, as well as the interconnection of dopaminergic and glutamatergic neurotransmitter systems in the mammalian neostriatum in the wakefulness-sleep cycle is considered. Comparison of dynamics of expression of the dopamine metabotropic receptors and of the glutamate ionotropic receptors in neostriatum showed unidirectional changes of D₁ and AMPA on the background of the 6-h sleep deprivation as well as of D₂ and NMDA on the background of postdeprivative sleep. The corticofugal direction of glutamate impulsation and its relatively fast actions allow admitting its triggering action on generation of the sleep-inducing processes in the underlying brain parts.     

Dopaminergic system in the telencephalic and diencephalic brain regions in vertebrates in the sleep-wakefulness cycle organisation

The aim of our study was to investigate the role of dopaminergic system in telencephalic and diencephalic brain regions of vertebrates in sleep-wakefulness cycle. The level of thyrosine-hydroxylase--the main enzyme in dopamine synthesis--was measured in striatum, zona inserta supraoptic and arcuate nuclea of hypothalamus in fish (Acipenceridae) and in mammals (rats) in ontogenesis (14-, 30-day old rats and adult animals) under tactile and sleep deprivation stresses. The thyrosine-hydroxylase-immunoreactive cells were revealed in all brain regions of fishes after a short-term stress. In the group after longtime stress, the thyrosine-hydroxylase-immunoreactive cells and fibers were almost absent in anterior brain but were found in hypothalamic nuclea. At 14-day old rats, 2-hour sleep deprivation caused increasing of thyrosine-hydroxylase-immunoreactivity both in fibers of caudate nucleus as well as in cells of the zona inserta. A 6-hour deprivation caused increasing of thyrosine-hydroxylase-immunoreactive material level in cells of zona inserta and decreasing it in fibers of 30-day old rats. In adult rats, the level of thyrosine-hydroxylase-immunoreactive material decreased in nucleus arcuatus and zona inserta after sleep deprivation and increased after sleep. Data obtained are discussed in terms ofphylo- and ontogenetic development of neurosecretory and neurotransmitter functions of dopaminergic system in evolutionary old diencephalic and evolutionary young telencephalic brain regions of vertebrates, which are the important systems of starting and maintenance of some functional conditions of the organism in sleep-wakefulness cycle.     

Wakefulness-sleep cycle and hypothalamo-pituitary system of young rat pups on the background of photostimulation

Effects of multiple photostimulations (PS) on behavioral reactions of the 30-day old rats were studied in the “open field” test, on the dynamics of the time EEG parameters of the wakefulness-sleep cycle, and on morpho-functional characteristics of the hypothalamo-pituitary neuroendocrine system. It has been revealed that PS promotes the gradual inhibition of the locomotor activity and exploratory behavior (p < 0.05) and an enhancement of autonomic reactions (p < 0.05) as well as an initial increase of intensity of orientation reactions with a subsequent decrease of their number (in connection with adaptation to a light stimulus), A comparative analysis of time parameters of the wakefulness-sleep cycle (WSC) shows a decrease of the part of wakefulness, the slow-wave and rapid-wave sleep phases with a simultaneous increase of the cataleptic stage and the sleep stage transient to the rapid-wave stage, as well as of the number of microactivations appearing on the sleep background at once after the several first PS. By the 4–5th photostimulations the CWS parameters on the whole are restored, except for the cataleptic stage, whose value remains statistically significantly high. The obtained data indicate the initial total CNS excitation and a decrease of the CWS stability. This conclusion is confirmed by the data of analysis of spectral characteristics of electrograms of cortical, hippocampal, hypothalamic brain parts and of caudate nucleus, which revealed only a brief small increase of δ-waves in the slow-wave sleep phase, but a statistically significant long decrease of power of the EEG δ-and ?-oscillations with a simultaneous power increase of α-components in the rapid-wave sleep. The quantitative parameters of changes of the morpho-functional state of neurosecretory cells of the hypothalamus supraoptic and paraventricular nuclei indicate the stress effect of this performed stimulation. The aspects of interaction of the hypothalamic-cortical and thalamo-cortical levels of the CWS integration on the background of chronic stress are discussed.     

Evolutionary aspects of interaction of sleep and stress: Phylo- and ontogenetic approach

This work considers comparative behavioral, somatoautonomic, and neurophysiological characteristics of three forms of passive defensive behavior included in the amphibian wakefulness-sleep cycle and their dynamics in the ascending vertebrate series. Considered in parallel is sleep formation in early postnatal ontogenesis of mature-and immature-born mammals-from undifferentiated sleep to the mature sleep divided into two phases as well as of stress-reaction. Comparative phylo-and ontogenetic analysis of several aspects of stress-reactions, sleep, and immobility phenomenon of the catalepsy type allows concluding that the immobility state of the catalepsy type in amphibians and reptiles can be considered the preadaptive behavior type that underlies the homoiothermal stress-reaction. It is the genetically programmed to the poikilothermal state characterized by a relatively high animal alertness, a freezing of the animal in the immobile, but active posture, with a possibility of a fast exit into the wakefulness state, which, alongside with other somatoautonomic and neurophysiological characteristics, which determines the entire subsequent complex of evolutionary morphofunctional changes of neuroregulatory and hormonal changes in the homoiothermal organism. In poikilothermal animals, this in many aspects unspecific behavioral adaptive reaction is realized at the corresponding hormonal and neurological levels of development of the organism and promotes fast mobilization and stabilization of constancy of the internal medium. At the higher evolutionary ladder levels, on the background of maturation of most neurotransmitter systems of brain and the hypothalamo-pituitary-adrenal system, the leading role in the stress-reaction regulation begins to be played predominantly by hormones, and only in the phase of the stress-reaction alertness, there are observed elements of activation of extrapyramidal systems of regulation of locomotor activity, which is manifested as the cataleptic freezing reaction. Thus, stress as the general adaptational syndrome reflects evolutionary regularities of development of specific functions supporting the total homeostasis. A scheme of evolutionary development of the wakefulness-sleep cycle in the vertebrate subtype is presented; according to it, the immobility state of the catalepsy type, on one hand, is considered as a part of wakefulness providing mainly specific elements of the stress-reaction, while, on the other hand,—as a certain step of the process of inhibition in CNS for subsequent involvement of the sleep-regulatory systems of compensation and maintenance of recovery reactions.     

Diencephalo-telencephalic changes of tyrosine hydroxylase in rats and grass frogs after sleep deprivation

Based on sleep deprivation-produced changes of electrographic parameters of the wakefulness-sleep cycle (WSC) in rats and frogs (Rana temporaria), dynamics of activity of tyrosine hydroxylase, the key enzyme of dopamine synthesis, was studied immunohistochemically in substantia nigra and nigrostriatal pathway in rats and in striatum, paraventricular organ, and extrahypothalamic pathways in frogs. Changes in dynamics of tyrosine hydroxylase in rats and in frogs are revealed after the 6-h sleep deprivation and after 2 h of postdeprivation sleep. This allows determining the degree of participation of corticostriatal neuroregulatory and hypothalamo-pituitary neurosecretory systems and their role in regulation of WSC. Possible evolutionary peculiarities of morphofunctional differences in homoiothermal and poikilothermal animals are discussed.     

Effect of apomorphine on the wakefulness-sleep cycle of the common frog <Emphasis Type="Italic">Rana temporaria</Emphasis>

This work considers effects of introduction into spinal lymphatic sac of dopamine agonist-apomorphine (APO)-at doses of 0.1, 1.0, 2.0, and 4.0 mg/kg body weight on the common frog wakefulness-sleep cycle (WSC). Usually the frog WSC is represented by wakefulness and three types of passive-protective behavior: the immobility states of the type of catalepsy, catatonia, and cataplexy that are characterized by high thresholds of arousal and by different (corresponding to the name) skeletal muscle tones. These immobility forms are considered as homologues of mammalian stressreaction, hibernation, and sleep. Low apomorphine doses produced in WSC a marked decrease of portion of wakefulness and an increase of the immobility state of the catalepsy type; high doses, on the contrary, initially promoted in CNS an increase of wakefulness and the state of catalepsy by demonstrating thereby its stressogenic action; after this, in WSC there increased the portion of the sleep-like immobility state of the catalepsy type that is considered a functional homologue of sleep of homoiothermal animals. In spectra of electrograms of the frog telencephalon the representation of waves of the delta diapason rose. Taking into account that the states of catalepsy and cataplexy in frogs are under control of anterior hypothalamus, it can be suggested that manifestations of cataplexy (sleep) in frog are due to the low level of dopaminergic activity, whereas manifestations of catalepsy (the homologue of stress reaction) are due to the high dopamine content in the anterior hypothalamic structures. Comparative analysis of changes in WSC of amphibians and mammals in response to administration of dopamine and its agonists allows thinking that the role of the dopaminergic neurotransmitter system in regulation of the vertebrate WSC certainly consists in that the low level of activity of this system facilitates development of sleep (catalepsy), whereas the high level provides reaction of arousal and is actively included in the system providing stress-reaction.     

Haloperidol impairs auditory filial imprinting and modulates monoaminergic neurotransmission in an imprinting-relevant forebrain area of the domestic chick

In vivo microdialysis and behavioural studies in the domestic chick have shown that glutamatergic as well as monoaminergic neurotransmission in the medio-rostral neostriatum/hyperstriatum ventrale (MNH) is altered after auditory filial imprinting. In the present study, using pharmaco-behavioural and in vivo microdialysis approaches, the role of dopaminergic neurotransmission in this juvenile learning event was further evaluated. The results revealed that: (i) the systemic application of the potent dopamine receptor antagonist haloperidol (7.5 mg/kg) strongly impairs auditory filial imprinting; (ii) systemic haloperidol induces a tetrodotoxin-sensitive increase of extracellular levels of the dopamine metabolite, homovanillic acid, in the MNH, whereas the levels of glutamate, taurine and the serotonin metabolite, 5-hydroxyindole-3-acetic acid, remain unchanged; (iii) haloperidol (0.01, 0.1, 1 mm) infused locally into the MNH increases glutamate, taurine and 5- hydroxyindole-3-acetic acid levels in a dose-dependent manner, whereas homovanillic acid levels remain unchanged; (iv) systemic haloperidol infusion reinforces the N-methyl-d-aspartate receptor-mediated inhibitory modulation of the dopaminergic neurotransmission within the MNH. These results indicate that the modulation of dopaminergic function and its interaction with other neurotransmitter systems in a higher associative forebrain region of the juvenile avian brain displays similar neurochemical characteristics as the adult mammalian prefrontal cortex. Furthermore, we were able to show that the pharmacological manipulation of monoaminergic regulatory mechanisms interferes with learning and memory formation, events which in a similar fashion might occur in young or adult mammals.     

Amino Acid Levels and γ-Aminobutyric AcidA Receptors in Rat Neostriatum, Cortex, and Thalamus After Neonatal 6-Hydroxydopamine Lesion

Abstract: The amino acid γ-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in brain, and GABAergic neurons have been proposed to play a major role in basal ganglia physiology. In the neostriatum (caudate putamen), medium-sized aspiny interneurons, as well as neostriatal output neurons that project to several brain regions, use GABA as their neurotransmitter. Dopamine fibers arising from the substantia nigra represent a major input to the neostriatum where, besides their classic neurotransmitter role, they are seemingly involved in the regulation of amino acid neurotransmitter release. To further characterize the nature of some of the amino acid/dopamine interactions, selective dopaminergic deafferentations were produced in neonatal rats (3 days postnatal) by intraventricular administration of the neurotoxin 6-hydroxydopamine (6-OHDA); the noradrenergic neurons were protected by prior administration of desmethylimipramine. After a 3-month survival, levels of catecholamines, indoleamines, and amino acids were determined in cingulate cortex, thalamus, and neostriatum. In addition, GABA_A receptors were measured in membrane preparations from these three regions, using the specific agonist [³H]muscimol. In the 6-hydroxydopamine-lesioned rats, levels of dopamine and its metabolites homovanillic acid, 3,4-dihydroxyphenylacetic acid, and 3-methoxytyramine were decreased, as expected, in cortex and neostriatum, but remained unmodified in thalamus. In all three regions, serotonin content was increased; its metabolite, 5-hydroxyindole-3-acetic acid, was also elevated, but only in cortex and neostriatum. The levels of GABA were increased in neostriatum and thalamus, but remained unmodified in cortex. Glycine was increased in all three regions examined. There were also increases of phosphatylethanolamine and serine in thalamus, and of aspartic acid and alanine in neostriatum. The density of GABA_A binding sites was increased in neostriatum, but remained unchanged in cortex and thalamus. The changes in amino acid levels and [³H]muscimol binding sites induced by a neonatal 6-hydroxydopamine treatment differ from those found after similar lesions in adult animals, possibly because of the plastic and synaptic rearrangements that can still occur during early postnatal development. The present results also demonstrate that adaptations occur in response to a dopaminergic deafferentation at an early age and that these exhibit a regional specificity.     

Effect of apomorphine on the wakefulness--sleep cycle of the common frog Rana temporaria

This work considers effects of introduction into spinal lymphatic sac of dopamine agonist--apomorphine-(APO) at doses of 0.1, 1.0, 2.0 and 4.0 mg/kg body weight on the common frog wakefulness-sleep cycle (WSC). Usually the frog WSC is represented by wakefulness and three types of passive-protective behavior: by immobility states of the type of catalepsy, catatonia, and cataplexy that are characterized by high thresholds of arousal and by different (corresponding to the name) skeletal musculature tones. These immoboloty forms are considered as homologues of mammalian stress-reaction, hibernation, and sleep. Low apomorphine doses produced in WSC a marked decrease of portion of wakefulness and an increase of the immoboloty state of the catalepsy; high doses, on the contrary, initially promoted in CNS an increase of wakefulness and the state of catalepsy by demonstrating thereby its stressogenic action; after this, in WSC these increased the portion of the sleep-like immobility state of the catalepsy type that is considered as a functional homologue of sleep of homoiotherms. In spectra of electrograms of the flog telencephalon the representation of waves of the delta diapason rose. Taking into account that the states of catalepsy and cataplexy in frogs are under control of the anterior hypothalamus, it can be suggested that manifestations of cataplexy (sleep) in frog are due to the low level of dopaminergic activity, whereas manifestations of catalepsy (the homologue of stress reaction) are due to the high dopamine content in the anterioi hypothalamic structures. Comparative analysis of changes in WSC of amphibians and mammals in response to administration of dopamine and its agonists allows thinking that the role of the dopaminergic neurotransmitter system in regulation of the vertebrate WSC is unanimous: the low level of activity of this system facilitates development of sleep (catalepsy), whereas the high level provides reaction of arousal and is actively included in the system providing stress-reaction.     

Reserpine-induced suppression of cortifugal influences on neostriatal neurons in cats and rats

In acute experiments on cats and rats, we demonstrated that the relative number of neostriatal neurons responding to stimulation of the motor cortex with latencies below 8.0 msec significantly decreased after functional destruction of the nigro-striatal dopaminergic system caused by injections of reserpine. Despite the fact that the level of dopamine (DA) in the neostriatum returned to the initial value 24 h after injection of the above neuroleptic, cortico-striatal impulsation recovered slowly, and the number of short-latency corticofugal reactions attained a near-control value only in one month. The data obtained confirm our earlier hypothesis on the toxic effect of excessive amounts of glutamate (which is observed under conditions of the DA deficiency) on receptors of this neurotransmitter. We conclude that, under normal conditions, DA exerts an inhibitory/protective effect on transmission of impulsation through direct cortico-striatal connections influencing D₂ receptors localized on cortico-striatal glutamatergic efferents. Neirofiziologiya/Neurophysiology, Vol. 39, No. 1, pp. 47–51, January–February, 2007.     

Modulation of Ionotropic Glutamate Receptor Channels

Glutamate is the major excitatory neurotransmitter in the brain. It acts at ligand-gated cationic channels (NMDA, AMPA and kainate receptors) and at G protein-coupled metabotropic glutamate receptors as well. The glutamatergic transmission is suggested to be involved in development, learning and memory. Its dysfunction can be detected in epilepsy, stroke, neurodegenerative disorders and drug abuse. This paper summarizes the present knowledge on the modulation of glutamate-gated ion channels in the central nervous system by phosphorylation. An inhibitory interaction between adenosine A_2A receptors and NMDA receptors in the neostriatum is described as an example, mediated by the phospholipase C/inositol trisphosphate/calmodulin and calmodulin kinase II pathway.     

Stereospecific binding of a new benzazepine, [3H]SCH23390, in cortex and neostriatum

The binding of the D1 antagonist SCH23390 to membrane preparations from rat cerebral cortex was examined using enantiomers of dopamine agonists and antagonists to compete with the bound [3H]SCH23390 at its Kd value. The competition curves were compared with those obtained with preparations from the neostriatum. The results demonstrate that specific [3H]SCH23390 binding in the cerebral cortex has the same pharmacological profile as in the neostriatum, so that this radioligand can be used to label dopamine D1 receptors in brain regions with a sparse dopaminergic innervation.     

Huntington’s Disease and Group I Metabotropic Glutamate Receptors

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movement, cognitive impairment and psychiatric disturbance. A polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein is the genetic cause of HD. Htt protein interacts with a wide variety of proteins, and htt mutation causes cell signaling alterations in various neurotransmitter systems, including dopaminergic, glutamatergic, and cannabinoid systems, as well as trophic factor systems. This review will overview recent findings concerning htt-promoted alterations in cell signaling that involve different neurotransmitters and trophic factor systems, especially involving mGluR1/5, as glutamate plays a crucial role in neuronal cell death. The neuronal cell death that takes place in the striatum and cortex of HD patients is the most important factor underlying HD progression. Metabotropic glutamate receptors (mGluR1 and mGluR5) have a very controversial role in neuronal cell death and it is not clear whether mGluR1/5 activation either protects or exacerbates neuronal death. Thus, understanding how mutant htt protein affects glutamatergic receptor signaling will be essential to further establish a role for glutamate receptors in HD and develop therapeutic strategies to treat HD.     

Intrinsic period and light intensity determine the phase relationship between melatonin and sleep in humans

The internal circadian clock and sleep-wake homeostasis regulate the timing of human brain function, physiology, and behavior so that wakefulness and its associated functions are optimal during the solar day and that sleep and its related functions are optimal at night. The maintenance of a normal phase relationship between the internal circadian clock, sleep-wake homeostasis, and the light-dark cycle is crucial for optimal neurobehavioral and physiological function. Here, the authors show that the phase relationship between these factors-the phase angle of entrainment (psi)-is strongly determined by the intrinsic period (tau) of the master circadian clock and the strength of the circadian synchronizer. Melatonin was used as a marker of internal biological time, and circadian period was estimated during a forced desynchrony protocol. The authors observed relationships between the phase angle of entrainment and intrinsic period after exposure to scheduled habitual wakefulness-sleep light-dark cycle conditions inside and outside of the laboratory. Individuals with shorter circadian periods initiated sleep and awakened at a later biological time than did individuals with longer circadian periods. The authors also observed that light exposure history influenced the phase angle of entrainment such that phase angle was shorter following exposure to a moderate bright light (approximately 450 lux)-dark/wakefulness-sleep schedule for 5 days than exposure to the equivalent of an indoor daytime light (approximately 150 lux)-dark/wakefulness-sleep schedule for 2 days. These findings demonstrate that neurobiological and environmental factors interact to regulate the phase angle of entrainment in humans. This finding has important implications for understanding physiological organization by the brain's master circadian clock and may have implications for understanding mechanisms underlying circadian sleep disorders.     

Serotonin and molecular neuroimaging in humans using PET

The serotonergic system is one of the most important modulatory neurotransmitter systems in the human brain. It plays a central role in major physiological processes and is implicated in a number of psychiatric disorders. Along with the dopaminergic system, it is also one of the phylogenetically oldest human neurotransmitter systems and one of the most diverse, with 14 different receptors identified up to this day, many of whose function remains to be understood. The system's functioning is even more diverse than the number of its receptors, since each is implicated in a number of different processes. This review aims at illustrating the distribution and summarizing the main functions of the serotonin (5-hydroxytryptamin, 5-HT) receptors as well as the serotonin transporter (SERT, 5-HTT), the vesicular monoamine transporter 2, monoamine oxidase type A and 5-HT synthesis in the human brain. Recent advances in in vivo quantification of these different receptors and enzymes that are part of the serotonergic system using positron emission tomography are described.     

多巴胺能神经系统对睡眠-觉醒和认知的调控作用

人的精神活动高级而又复杂,至今仍是未解之谜。目前研究认为多巴胺作为脑内重要神经递质,参与调节人的精神活动和运动功能,尤其在睡眠的主动性神经调节过程,以及学习记忆等认知功能的神经环路中,多巴胺都发挥着不可替代的作用。本文将通过对多巴胺神经系统,睡眠,认知功能的概述,以及通过对多巴胺神经系统与睡眠-觉醒系统和认知功能的解剖学联系的简述,结合多巴胺神经元、多巴胺受体及多巴胺转运体等不同角度分别阐述其对睡眠-觉醒和认知功能的调控作用,以期揭开人类精神活动的产生机制的一层面纱,以及对多巴胺药物对神经退行性变疾病的治疗靶点提供一定的理论支持。     

The effect of dopaminergic nigrostriatal system on sleep deprivation in rats

The analysis of the electrophysiological features of sleep-wakefulness cycle in Wistar rats for 9h after a 6h sleep deprivation was carried out. The delay of sleep rebound (since 2.5-3 h after deprivation) was found in the form of moderate increasing of slow-wave sleep and fast-wave sleep phases. According to these sleep-wakefulness cycle changes, a quantitative immunohistochemical study of tyrosine hydroxylase: a key enzyme of dopamine synthesis--and D1 and D2 receptors in nigro-striatal projections has been performed. After sleep, an elevation of D1 receptors immunoreactivity in caudate nucleus and reduction of tyrosine hydroxylase immunoreactivity in compact part of substancia nigra was found. After postdeprivation sleep, a decrease of D1 receptors immunoreactivity and increase of D2 receptors immunoreactivity in caudate nucleus together some increase of tyrosine hydroxilase immunoreactivity in substancia nigra compacta has been observed. These data can testify about active role of dopaminergic nigrostriatal system which provide at the same time with another neurotransmitters of the central nervous system the telencephalo-diencephalic interaction in sleep-wakefulness-sleep cycle.     

Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking

Alcoholism is a heritable disease that afflicts about 8% of the adult population. Its development and symptoms, such as craving, loss of control, physical dependence, and tolerance, have been linked to changes in mesolimbic, mesocortical neurotransmitter systems utilizing biogenic amines, GABA, and glutamate. Identification of genes predisposing to alcoholism, or to alcohol-related behaviors in animal models, has been elusive because of variable interactions of multiple genes with relatively small individual effect size and sensitivity of the predisposing genotype to lifestyle and environmental factors. Here, using near-isogenic advanced animal models with reduced genetic background interactions, we integrate gene mapping and gene mRNA expression data in segregating and congenic mice and identify glutamate receptor metabotropic 7 (Grm7) as a cis-regulated gene for alcohol consumption. Traditionally, the mesoaccumbal dopamine reward hypothesis of addiction and the role of the ionotropic glutamate receptors have been emphasized. Our results lend support to an emerging direction of research on the role of metabotropic glutamate receptors in alcoholism and drug addiction. These data suggest for the first time that Grm7 is a risk factor for alcohol drinking and a new target in addiction therapy.     

Regional analysis of neostriatal cholinergic and dopaminergic receptor binding and tyrosine hydroxylase activity as a function of aging

Tryosine hydroxylase (TH) activity, as well as dopaminergic and cholinergic muscarinic receptor binding were measured in discrete regions of the neostriatum of rats 7, 17, and 27 months old. Activity of TH was highest in the rostral neostriatum as compared to the caudal region. Age-related differences in TH were detected in only one region. The density of dopamine receptors was also highest in the rostral neostriatum of all age groups, but there were no significant age-related differences. The distribution of cholinergic muscarinic receptor binding was similar to that of TH and dopaminergic receptors, and showed age-related changes in discrete regions. These results, when considered with previous data, suggest that in selected striatal regions in the Sprague Dawley rat the cholinergic system is more vulnerable than the dopaminergic system to aging effects.