Anatomical distribution of the central cholinergic system
The cholinergic pathways in the mammalian brain are extremely diffuse and arise from cell bodies located in the hindbrain and the midbrain. Of these areas, there has been considerable interest of late in the nucleus basalis magnocellularis of Meynert because this region appears to be particularly affected in some patients with familial Alzheimer’s disease. As the projections from this area innervate the cortex, it has been speculatedthat a disruption of the cortical cholinergic system may be responsible for many of the clinical features of the illness. Much attention has been paid to the catecholamines noradrenaline and dopamine following the discovery that their depletion in the brain leads to profound mood changes and locomotor deficits. Thus noradrenaline has been implicated in the mood changes associated with mania and depression, while an excess of dopamine has been implicated in schizophrenia and a deficit in Parkinson’s disease. Noradrenaline is the main catecholamine in postganglionic sympathetic nerves and in the central nervous system; it is also released from the adrenal gland together with adrenaline. Recently adrenaline has also been shown to be a transmitter in the hypothalamic region of the mammalian brain so, while the terms ‘‘noradrenergic’’ and ‘‘adrenergic’’ are presently used interchangeably, it is anticipated that they will be used with much more precision once the unique functions of adrenaline in the brain have been established. The catecholamines are formed from the dietary amino acid precursors phenylalanine and tyrosine.The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. Drugs have been developed which specifically inhibit the L-aromatic amino acid decarboxylase step in catecholamine synthesis and thereby lead to a reduction in catecholamine concentration. Carbidopa and benserazide are examples of decarboxylase inhibitors which are used clinically toprevent the peripheral catabolism of L-dopa (levodopa) in patients being treated for parkinsonism. As these drugs do not penetrate the blood–brain barrier they will prevent the peripheral decarboxylation of dopa so that it can enter the brain and be converted to dopamine by dopamine betaoxidase (also called dopamine beta-hydroxylase). Dopamine beta-oxidase inhibitors are only of limited clinical use at the present time, probably due to their relative lack of specificity. Diethyldithiocarbamate and disulfiram are examples of drugs that inhibit dopamine betaoxidase by acting as copper-chelating agents and thereby reducing the availability of the cofactor for this enzyme. Whether their clinical use in the
treatment of alcoholism is in any way related to the reduction in brain catecholamine concentrations is uncertain. The main action of these drugs is to inhibit liver aldehyde dehydrogenase activity, thereby leading to an accumulation of acetaldehyde, and the onset of nausea and vomiting, should the patient drink alcohol. Two enzymes are concerned in the metabolism of catecholamines, namely monoamine oxidase, which occurs mainly intraneuronally, and catechol-O-methyltransferase, which is restricted to the synaptic cleft. The importance of the two major forms of monoamine oxidase, A and B, will be considered elsewhere. The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. Anatomical distribution
One of the first demonstrations of the central monoamine pathways in the mammalian brain was by a fluorescence technique in which thin sections of the animal brain were exposed to formaldehyde vapour which converted the amines to their corresponding fluorescent isoquinolines. The distribution of these compounds could then be visualized under the fluorescent microscope. Using this technique it has been possible to map the distribution of the noradrenergic, dopaminergic and serotonergic pathways in the animal and human brain.The central noradrenergic system. This is not so diffusely distributed as the cholinergic system. In the lower brainstem, the neurons innervate the medulla oblongata and the dorsal vagal nucleus, which are thought to be important in the central control of blood pressure. Other projections arising from cell bodies in the medulla descend to the spinal cord where they are believed to be involved in the control of flexor muscles. However, the most important noradrenergic projections with regard to psychological functions arise from a dense collection of cells in the locus coeruleus and ascend from the brainstem to innervate the thalamus, dorsal hypothalamus, hippocampus and cortex. The ventral noradrenergic bundle occurs caudally and ventrally to the locus coeruleus and terminates in the hypothalamus and the subcortical limbic regions. The dorsal bundle arises from the locus coeruleus and innervates the cortex. Both the dorsal and ventral noradrenergic systems appear to be involved psychologically in drive and motivation, in mechanisms of reward and in rapid eye movement (REM) sleep. As such processes are severely deranged in the major affective disorders it is not unreasonable to speculate that the central noradrenergic system is defective in such disorder
The cholinergic pathways in the mammalian brain are extremely diffuse and arise from cell bodies located in the hindbrain and the midbrain. Of these areas, there has been considerable interest of late in the nucleus basalis magnocellularis of Meynert because this region appears to be particularly affected in some patients with familial Alzheimer’s disease. As the projections from this area innervate the cortex, it has been speculatedthat a disruption of the cortical cholinergic system may be responsible for many of the clinical features of the illness. Much attention has been paid to the catecholamines noradrenaline and dopamine following the discovery that their depletion in the brain leads to profound mood changes and locomotor deficits. Thus noradrenaline has been implicated in the mood changes associated with mania and depression, while an excess of dopamine has been implicated in schizophrenia and a deficit in Parkinson’s disease. Noradrenaline is the main catecholamine in postganglionic sympathetic nerves and in the central nervous system; it is also released from the adrenal gland together with adrenaline. Recently adrenaline has also been shown to be a transmitter in the hypothalamic region of the mammalian brain so, while the terms ‘‘noradrenergic’’ and ‘‘adrenergic’’ are presently used interchangeably, it is anticipated that they will be used with much more precision once the unique functions of adrenaline in the brain have been established. The catecholamines are formed from the dietary amino acid precursors phenylalanine and tyrosine.The rate-limiting step in the synthesis of the catecholamines from tyrosine is tyrosine hydroxylase, so that any drug or substance which can reduce the activity of this enzyme, for example by reducing the concentration of the tetrahydropteridine cofactor, will reduce the rate of synthesis of the catecholamines. Under normal conditions tyrosine hydroxylase is maximally active, which implies that the rate of synthesis of the catecholamines is not in any way dependent on the dietary precursor tyrosine. Catecholamine synthesis may be reduced by end product inhibition. This is a process whereby catecholamine present in the synaptic cleft, for example as a result of excessive nerve stimulation, will reduce the affinity of the pteridine cofactor for tyrosine hydroxylase and thereby reduce synthesis of the transmitter. The experimental drug alpha-methyl-para-tyrosine inhibits the rate-limiting step by acting as a false substrate for the enzyme, the net result being a reduction in the catecholamine concentrations in both the central and peripheral nervous systems. Drugs have been developed which specifically inhibit the L-aromatic amino acid decarboxylase step in catecholamine synthesis and thereby lead to a reduction in catecholamine concentration. Carbidopa and benserazide are examples of decarboxylase inhibitors which are used clinically toprevent the peripheral catabolism of L-dopa (levodopa) in patients being treated for parkinsonism. As these drugs do not penetrate the blood–brain barrier they will prevent the peripheral decarboxylation of dopa so that it can enter the brain and be converted to dopamine by dopamine betaoxidase (also called dopamine beta-hydroxylase). Dopamine beta-oxidase inhibitors are only of limited clinical use at the present time, probably due to their relative lack of specificity. Diethyldithiocarbamate and disulfiram are examples of drugs that inhibit dopamine betaoxidase by acting as copper-chelating agents and thereby reducing the availability of the cofactor for this enzyme. Whether their clinical use in the
treatment of alcoholism is in any way related to the reduction in brain catecholamine concentrations is uncertain. The main action of these drugs is to inhibit liver aldehyde dehydrogenase activity, thereby leading to an accumulation of acetaldehyde, and the onset of nausea and vomiting, should the patient drink alcohol. Two enzymes are concerned in the metabolism of catecholamines, namely monoamine oxidase, which occurs mainly intraneuronally, and catechol-O-methyltransferase, which is restricted to the synaptic cleft. The importance of the two major forms of monoamine oxidase, A and B, will be considered elsewhere. The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. Anatomical distribution
One of the first demonstrations of the central monoamine pathways in the mammalian brain was by a fluorescence technique in which thin sections of the animal brain were exposed to formaldehyde vapour which converted the amines to their corresponding fluorescent isoquinolines. The distribution of these compounds could then be visualized under the fluorescent microscope. Using this technique it has been possible to map the distribution of the noradrenergic, dopaminergic and serotonergic pathways in the animal and human brain.The central noradrenergic system. This is not so diffusely distributed as the cholinergic system. In the lower brainstem, the neurons innervate the medulla oblongata and the dorsal vagal nucleus, which are thought to be important in the central control of blood pressure. Other projections arising from cell bodies in the medulla descend to the spinal cord where they are believed to be involved in the control of flexor muscles. However, the most important noradrenergic projections with regard to psychological functions arise from a dense collection of cells in the locus coeruleus and ascend from the brainstem to innervate the thalamus, dorsal hypothalamus, hippocampus and cortex. The ventral noradrenergic bundle occurs caudally and ventrally to the locus coeruleus and terminates in the hypothalamus and the subcortical limbic regions. The dorsal bundle arises from the locus coeruleus and innervates the cortex. Both the dorsal and ventral noradrenergic systems appear to be involved psychologically in drive and motivation, in mechanisms of reward and in rapid eye movement (REM) sleep. As such processes are severely deranged in the major affective disorders it is not unreasonable to speculate that the central noradrenergic system is defective in such disorder
No comments:
Post a Comment