ABSTRACT | PDF
Seminar II
Biogenic Amines in Psychiatry
Subhashish Nath
Postgraduate Trainee of Psychiatry
Silchar Medical College and Hospital
Introduction An amine is any of a class of organic chemical compounds in which one or more of the hydrogen atoms of ammonia have been replaced by other groups of atoms. A biogenic amine is a biogenic substance with an amine group. It can be defined as any of a group of naturally occurring, biologically active amines that act primarily as neurotransmitters and are capable of affecting mental functioning and regulating body temperature, blood pressure and other bodily processes. Each biogenic amine neurotransmitter system modulates many different neural pathways which themselves subserve multiple behavioural and physiological processes. The important biogenic amines in our body are: (1) Dopamine; (2) Adrenaline and noradrenaline (NA); (3) Serotonin; (4) Histamine.
Dopamine (DA), structurally 3, 4 dihydroxyphenylethylamine, is a cathecholamine. It was discovered as a neurotransmitter in the brain during the late 1950s (Carlsson 1959).
Nuclei and pathways In 1964, Dahlstrom and Fuxe located and numbered nuclei in the hindbrain (pons and medulla) in which either DA (A8-A12) or NA (1-7) was concentrated. DA neurons are more widely distributed, residing in the midbrain, substantia niagra and ventral tegmental area (VTA) and in the periaqueductal gray, hypothalamus, olfactory bulb and retina. Most of the DA cell bodies (about 400,000) are found in the A9 nucleus which forms the zona compacta (dorsal part) of the substantia niagra although a few cell bodies are found in the more ventral zona reticulata and in the zona lateralis as well.
Three DA systems are highly relevant to psychiatry – nigrostriatal, mesocorticolimbic and tuberohypophyseal system.
Axons from A9 form the major contribution, together with some from A8, to the principal DA nigrostriatal pathway running to the striatum (caudate nucleus and putamen) and amygdala. This pathway modulates motor control and degeneration of this pathway causes Parkinson’s disease as well as the extrapyramidal syndrome (EPS) of antipshychotic drugs are thought to result from the blockade of these striatal DA receptors. This pathway is lateral to, but runs with, a more medial DA pathway, predominantly from A10, which innervates the nucleus accumbens and olfactory tubercle (mesolimbic pathway) as well as parts of the cortex (mesocortical) such as prefrontal and perirhinal cortex.
The mesoaccumbens pathway is a central element of the neural representation of reward. The mesolimbic pathway is believed to be a major target for the antipsychotic properties of many drugs in controlling the positive symptoms of schizophrenia. The mesocortical pathway is responsible for modulating working memory and attention.
A further totally separate DA pathway arises from A12 in the hypothalamic arcuate and paraventricular nuclei (PVN) and forms the tuberoinfundibular tract in the median eminence to the pituitary gland and thereby inhibits prolactin release.
Additional dopaminergic pathways are thalamic dopamine system involved in arousal and sleep as well as incertohypothalamic pathway involved in sexual behaviour.
Neurochemistry Synthesis and metabolism: Phenylalanine is converted to tyrosine in liver by phenylalanine hydroxylase and then tyrosine is transported to brain where it acts as the starting point for synthesis of DA and NA. DA is stored in vesicles and physiologically released by a Ca++ dependent process initiated by a nerve impulse activity. Released DA is approximately 80% effectively and rapidly transported back into the nerve terminal by a DA specific transporter. Extravesicular DA is intracellularly metabolised by monoamine oxidase (MAO) to 3, 4-dihydroxyphenylacetic acid (DOPAC) and then to homovanillic acid (HVA) by catechol-O-methyl transferase (COMT). Released extracellular DA is sequentially degraded by COMT and MAO to 3-methoxytyramine and HVA.
Storage: Most DA (up to 75%) is stored in vesicles like NA.
Release and turnover: Upon neuronal stimulation, vesicles within nerve terminal fuse with presynaptic terminal and release neurotransmitter in the synaptic cleft. Once released, DA interacts with postsynaptic receptors to alter the function of postsynaptic cells and they may also interact with presynaptic autoreceptors on the nerve terminal to suppress further release. In addition, released amines can also be taken back up from synaptic cleft into the nerve terminal by plasma membrane transporter protein, a process called reuptake.
Dopamine receptors In 1979, it was clearly recognised that actions of DA are mediated by more than one receptor subtype. There are currently five known DA receptor subtypes categorised according to structural, functional and pharmacological characteristics and divided into two main families (D1-like and D2-like) based upon their sequence homology. The D1-like receptors (D1/D1A and D5/D1B) activate adenylyl cyclase, whereas D2-like receptors (D2/D2A, D3/D2B and D4/D2C) inhibit adenylyl cyclase. This nomenclature was suggested by Sibley and Mosma (1992).
Distribution of receptors
D1 receptor family: D1 – Highest expression in striatum, nucleus accumbens and olfactory tubercle but also some in cortex and hypothalamus.
D5 – Highest expression in hypothalamus and hippocampus but much lower expression overall.
D2 receptor family: D2 – Mostly in striatum, nucleus acumbens and olfactory tubercle but also on neuron cell bodies in substantia niagra and VTA where they are autoreceptors for locally released DA. The affinity for DA is slightly higher for D2 than for D1 receptors.
D3 – Much less abundant than D2. Mainly in the limbic regions (nucleus accumbens and olfactory tubercle) but also in hypothalamus. Some in caudate and cortex and also on DA neurons in substantia niagra, presumably as autoreceptors.
D4 – Located in frontal cortex, midbrain and amygdala. High affinity for DA.
Functions of individual DA receptors D1 receptor: (1) Prominent motor effects. Modulate motor control along with D2 in the striatum. (2) Central nervous system (CNS) effects of cocaine. (3) Cognitive functions of DA such as control of working memory and attention.
D2 receptor: (1) Modulate motor control in the striatum along with D1. (2) Rewarding effects of drugs of abuse. (3) Positive symptoms of schizophrenia in the mesolimbic pathway. (4) Dopaminergic inhibition of prolactin in the anterior pituitary and alpha melanocytic hormone release.
Noradrenaline (NA) is structurally 3, 4-dihydroxyphenylethanolamine. It was originally called as ‘sympathin’ (Canon and Uridil 1921) and was subsequently identified as NA by Von Euler in 1946. Holtz in 1950 identified NA in brain and Vogt in 1954 proposed that NA is in fact a neurotransmitter in the CNS.
Neuronal pathways The cell bodies of central NA neurons are all clustered within two bilateral groups of nuclei (numbered A1 to A7) in the brainstem. These comprise the locus coeruleus (LC) complex and the lateral tegmental (LT) nuclei. The LC accounts for approximately 45% of all the NA neurons in the brain.
The activity of NA neurons within the LC is governed by gamma-aminobutyric acid (GABA)-ergic (inhibitory) input from the nucleus prepositus hyperglossi and an excitatory glutamatergic projection from the nucleus paragigantocellularis (Aston – Jones 1991). The LC is found in the dorsal portion of the caudal pons. The LT nuclei are loosely scattered throughout the ventral pons and medulla.
Projection areas: Areas innervated entirely by LC neurons are frontal cortex, hippocampus and olfactory bulb. Areas innervated entirely by LT neurons consist of most hypothalamic nuclei except PVN. Areas innervated by neurons from both systems are spinal cord, cerebellum, thalamus, hypothalamus (PVN), amygdala and septum.
Adrenaline or epinephrine neurons are relatively scarce and are located in the caudal pons and medulla intermingled with NA neurons. Projections from the groups ascend to innervate the hypothalamus, LC and visceral efferent and afferent nuclei of the midbrain.
Neurochemistry Synthesis: The pathway for the synthesis of catecholamines was first proposed by Herman Blaschko in 1939 but was not confirmed until 30 years later.
Storage: NA is concentrated and stored in synaptic vesicles by vesicular transporter. Two vesicular monoamine transporter (VMAT) have been identified which is same for dopaminergic, noradrenergic as well as serotonergic neurons. Both the transporters – VMAT1 and VMAT2 – have 12 transmembrane spanning domains.
Release: In similarity to other neurotransmitter synaptically released by depolarisation of the nerve terminals by a process called ‘vesicular exocytosis’. Release of NA is regulated by presynaptic alpha2 autoreceptors mostly of the alpha2a subtype. Release can also be modulated by somatodendritic alpha2 autoreceptors found in the LC neurons. Most of the NA released in the CNS is secondary to neuronal activation of LC.
Reuptake: After being released into the synaptic cleft NA is either metabolised or transported back into the neurons by a high affinity transporter. The transporter is a presynaptically located glycoprotein and this intraneuronal high affinity uptake is called uptake1. NA can also be taken up extraneuronally by a different mechanism which has lower affinity for and is less selective for NA called uptake2. Both these uptakes require a source of energy which is provided by transmembrane Na+ electrochemical gradient achieved by Na+ K+ ATPase.
Metabolism: After reuptake into the cytosol, some NA may be taken up to into the storage vesicles by vesicular transporter and stored in the vesicles for subsequent release. However majority is broken down in the cytosol of nerve terminal by MAO. MAO-A preferentially metabolises NA. In humans predominate metabolite of NA is 3-methoxy 4-hydroxyphenylethyleneglycol.
Receptors There are three main adrenergic receptor subfamilies – alpha1, alpha2 and beta. Each subfamily consists of 3 receptor subtypes – alpha1A, alpha1B, alpha1D, alpha2A, alpha2B, alpha2C and beta1, beta2 and beta3.
Alpha1 receptors are expressed in cerebral cortex, hippocampus, septum, amygdala and thalamus. Alpha2A and Alpha2C receptor densities are found in the LC, amygdala, hippocampus and all LC neurons contain Alpha2A receptor subtype. Alpha2B is located mostly in the thalamus. Beta1 predominates in the cerebral cortex, dentate gyrus and CA1 and medial dorsal hypothalamic nuclei. Beta2 is more abundant in the cerebellum and reticular, paraventricular and central thalamic nuclei. Beta3 receptors are found in the periphery.
Neurons in the LC are central to the NA release and actions in the CNS. They are responsible for vigilance, attention and behavioural responses to external stimuli. LC also responds to noxious stimuli and moreover monitors the internal autonomic and vegetative state. NA system regulates mood, arousal, cognition and many other functions.
Serotonin, an indolamine, was discovered by Brodie in 1900 as a serum vasoconstrictor and was isolated, characterised and named serotonin by Rapport and collaborators in 1948. In 1956, Bogdansky proposed serotonin to be a neurotransmitter in the CNS.
Nuclei and pathways Dahlstrom and Fuxe in 1964 mapped the serotonergic cell bodies and showed their extensive projections to all brain areas. The cell bodies of serotonergic neurons aggregate around the midline of the upper brainstem forming distinct clusters or nuclei called midline raphe nuclei. These nuclei are grouped into two major groups:
Superior – Includes dorsal raphe nucleus (DRN), median raphe nucleus (MRN), caudal linear nucleus and nucleus prosupralemniscus.
Inferior – Includes N.R.pallidus, N.R.obscurus, N.R.magnus, neurons of the lateral paragigantocellular nucleus and the intermediate reticular nuclei.
The inferior group projects mainly to brainstem nuclei, the head nuclei of some cranial nerves, spinal cord and cerebellum. The neurons in the superior group project mainly to the limbic and sensory areas of the forebrain.
Storage: Like other monoamines, serotonin is stored mainly in storage vesicles where ‘serotonin binding proteins’ have also been identified. Its uptake and storage into vesicles resemble that of NA in all respects.
Release: The main mechanism for release, “exocytosis”, is triggered by depolarisation and involves membrane proteins e. g. synapsin1. A second mechanism for release is carrier mediated for release of cytoplasmic pool of serotonin.
Regulation of release: Autoregulation by 5-HT1A autoreceptors on the cell bodies in the raphe nuclei and 5-HT1B/1D receptors on the nerve terminal. Heteroregulation by GABA and GABA agonists in DRN and MRN (inhibitory effects), and substance P and direct and indirect DA agonists (facilitatory effects). Alpha2 adrenoceptors are involved in heteroregulation in the terminal projection areas. Ach increases serotonin release in forebrain by nicotinic receptor activation while histamine inhibits it most likely via H3 heteroreceptor. The carrier mediated release is blocked by serotonin transporter (SERT) inhibitors.
Reuptake: Transported from the synaptic cleft into the neuron by a high affinity transporter, ‘SERT’ located presynaptically. Intracellular serotonin is subsequently carried by a vesicular transporter into secretory vesicles.
Metabolism: The major serotonin metabolic pathway is deamination by MAO, in particular MAO-A. 5-Hydroxyindoleacetic acid (5-HIAA) is the major metabolic product of serotonin and its measurement in human cerebrospinal fluid (CSF), brain tissue and in awake, freely moving animals in microdialysates from specific brain regions are standard tools for assessment of serotonin release and metabolism.
Receptors The pioneering work of Peroutka and Synder (1979) using labeled serotonin, lysergic acid diethylamide (LSD) and spiroperidol established the existence of multiple serotonin receptors. Currently there are 14 recognized receptors of serotonin grouped into 7 distinct families – 5HT1, 5HT2….5HT7. 5HT1 receptors are further divided into 5 subtypes – A, B, D, E and F. 5HT2 into A, B and C. 5HT5 into A and B. All of these except 5HT3 are G-protein coupled with 7 transmembrane spanning domains. 5HT3 receptor belongs to the ligand gated ion channel family. 5HT1A, 1B, 1D and 5HT3 are both pre and post synaptic. 5HT1E, 1F, 4, 5, 6 and 7 are postsynaptic. The 3 subtypes of 5HT2 are postsynaptic.
Behavioural and physiological responses affected by serotonin receptors
5HT1A: Modulator of anxiety and depression. 5HT1A agonists increase concentration of extracellular DA in the frontal cortex. Agonists increase food intake. Thermoregulation, agonists induce hypothermia.
5HT1B: Modulation of locomotor activity level consistent with its high level of expression in basal ganglia. Activation increases locomotor activity. Circadian rhythm regulation by blunting serotonin release in the suprachiasmatic nucleus. Activation mediates vasoconstriction in the cerebral vasculature (antimigraine effects of sumatriptan). Food intake. Thermoregulation. Sexual function.
5HT1D: Located in trigeminal ganglion and inhibit nociceptive transmission.
5HT1F: Similar to 5HT1D.
5HT2A: Excite cortical pyramidal neurons, enhance glutamate release and inhibit DA release and play a role in sleep and hallucination. Temperature regulation, activation causes hyperthermia.
5HT2C: Regulate both DA and NA release and may play a role in obesity, mood and cognition. In choroid plexus, regulate CSF formation. Activation causes reduced locomotor activity and hyperthermia. Agonists appear to be anxiogenic and reduce food intake.
5HT3: Stimulate DA release. Also influence releases of other neurotransmitters – GABA, acetylcholine (Ach) and NA.
5HT4: Agonists at this receptor are being explored as possible cognitive enhancers.
5HT6: Antagonists increase seizure threshold and could turn out to be beneficial in the treatment of epilepsy.
5HT7: In the suprachiasmatic nucleus of the hypothalamus, they are thought to synchronise circadian rhythms with the light cycle and linked to sleep and mood.
Histamine
Neurons and pathways Histaminergic neurons are located within a region of the hypothalamus termed the tuberomammilary nucleus. The activity of the tuberomammilary neurons is characterised by firing that varies across the sleep-wake cycle with the highest activity during the waking state, slowed firing during slow-wave sleep and absence of firing during REM sleep.
Ventral ascending projections course through the medial forebrain bundle and then innervate the hypothalamus, septum and olfactory bulb. Dorsal ascending projections innervate the thalamus, hippocampus, amygdala and rostral forebrain. Descending projections travel through the midbrain central gray to the dorsal hindbrain and spinal cord. The hypothalamus receives the densest histaminergic innervations consistent with a role in the regulation of autonomic and neuroendocrine processes. Additionally strong histaminergic innervation is seen on monoaminergic and cholinergic nuclei.
H3 receptor antagonists have been proposed to have appetite suppressant, arousal and cognitive enhancing properties.
Psychiatric correlation of biogenic amines
Schizophrenia Mesolimbic DA pathway: Hyperactivity of and increased DA release in this pathway correlates with positive symptoms. Hyperactivity of this pathway may also be related to aggressive and hostile symptoms in schizophrenia and related illness, especially if serotonergic control of DA is aberrant in patients who lack impulse control.
Mesocortical DA pathway: Cognitive and negative symptoms of schizophrenia are due to deficit of DA activity in mesocortical projections to dorsolateral prefrontal cortex (DLPFC). Affective and other negative symptoms of schizophrenia are due to deficit of DA activity in mesocortical projections to ventromedial prefrontal cortex (VMPFC).
Nigrostriatal DA pathway: In schizophrenia this pathway is preserved. Hyperactivity of DA in this pathway causes chorea, dyskinesias and tics. Hypoactivity causes rigidity, bradykinesia and akinesia. Chronic blockade of D2 receptors in this pathway may result in a hyperkinetic movement disorder – neuroleptic induced tardive dyskinesia.
Tuberoinfundibular pathway: This pathway is normal in schizophrenia. Blockade of D2 receptors in this pathway by many antipsychotics may cause hyperprolactinaemia.
Antipsychotic agents Typical antipsychotics: The primary pharmacological property of typical antipsychotics is D2 antagonism. D2 blockade in mesolimbic pathway relieves positive symptoms of schizophrenia and other psychosis as well as blocks reward and reinforcement mechanisms leaving patients apathetic, anhedonic and lacking motivation. D2 blockade in mesocortical pathway – Mesocortical projection to DLPFC worsens negative symptoms and cognitive symptoms. Mesocortical projection to VMPFC worsens negative and affective symptoms. D2 blockade in nigrostriatal pathway causes EPS. Chronic blockade causes tardive dyskinesia. D2 blockade in tuberoinfundibular pathway leads to hyperprolactinaemia. Reciprocal relation of DA and Ach in nigrostriatal pathway and D2 blockade by antipsychotics - D2 receptor blockade on the cholinergic dendrite causes enhanced release of Ach from cholinergic axons resulting in EPS. H1 receptor antagonism results in weight gain and drowsiness. Alpha1 receptor antagonism causes dizziness, drowsiness and low blood pressure.
Atypical antipsychotics – Serotonergic antagonism: 5HT2A antagonism at the nigrostriatal DA pathway reduces chances of EPS by increasing DA release in the nigrostriatal pathway as a result of removal of the normal serotonergic inhibition of DA release. It also reduces negative, affective and cognitive symptoms by increasing DA release in the mesocortical pathway. It may improve positive symptoms by reducing glutamate release from descending glutamatergic cortical pyramidal neurons which in turn decrease mesolimbic DA release. It reduces hyperprolactinaemia. Normally serotonin increases prolactin release by binding to 5HT2A receptors in the pituitary lactotroph cells.
Rapid dissociation from D2 receptors.
Dopamine partial agonists.
5HT1A partial agonists increase DA release in the mesocortical, nigrostriatal and tuberoinfundibular pathway. They decrease glutamate release in the mesolimbic pathway.
Mood disorders – Depression All the symptoms of depression are related to defective monoaminergic system in specific brain areas.
1. Depressed mood: Dysfunction of serotonergic, dopaminergic and noradrenergic system in VMPFC and amygdala.
2. Apathy: Dysfunctional or hypoactive noradrenergic and dopaminergic system in prefrontal cortex (PFC) and hypothalamus.
3. Sleep disturbance: Defective noradrenergic, dopaminergic and serotonergic system in PFC, basal forebrain, hypothalamus and thalamus.
4. Fatigue: Mental fatigue is related to deficient noradrenergic and dopaminergic functioning in PFC. Physical fatigue is related to deficient noradrenergic functioning in descending spinal cord projections and deficient dopaminergic functioning in the striatum, nucleus accumbens, hypothalamus and spinal cord.
5. Executive dysfunction: Inefficient dopaminergic and noradrenergic system functioning in DLPFC.
6. Psychomotor agitation/retardation: Hypoactive serotonergic, noradrenergic and dopaminergic system in PFC, serotonergic and dopaminergic system in striatum and nucleus accumbens, serotonergic and noradrenegic system in the cerebellum.
7. Weight and appetite changes: Hypoactivity of the serotonergic control of the hypothalamus.
8. Suicidal ideation: Hypoactivity of the serotonergic control of the amygdala, VMPFC and orbitofrontal cortex (OFC).
9. Guilt/worthlesness: Dysfunction of serotonergic projections of amygdala and VMPFC.
Amines in mania 1. Irritable or expansive/elated mood: Serotonergic, noradrenergic and dopaminergic hyperactivity in VMPFC, OFC and amygdala.
2. Grandiosity, flight of ideas and racing thoughts: Serotonergic and dopaminergic hyperactivity in the nucleus accumbens.
3. Risk taking and pressure of speech: Serotonergic, dopaminergic and noradrenergic hyperactivity in the OFC, DLPFC and VMPFC.
4. Decreased need for sleep: Serotonergic, dopaminergic and noradrenergic hyperacivity in the thalamus, hypothalamus and basal forebrain.
5. Distractibility/poor concentration: Dopaminergic and noradrenergic hyperactivity in the DLPFC.
6. Increased goal directed activity/agitation: Serotonergic and dopaminergic hyperactivity in the striatum.
Anxiety disorders Serotonin and anxiety: Pathological anxiety/fear may be caused by overactivation of amygdala circuits. Amygdala receives serotonergic inhibitory inputs on some of its outputs and thus serotonergic agents can alleviate anxiety/fear.
Serotonin genetics and life stressors: The type of SERT with which we are born can affect the way we process fearful stimuli and perhaps also how we respond to stress. Individuals with ‘S’ variant of the gene for SERT appear to be more vulnerable to the effects of stress and anxiety than those with ‘I’ variant of the gene.
Noradrenaline and anxiety: There is hyperactivity of the NA projections to the amygdala. Alpha1 and beta1 adrenoceptors are specifically involved in the anxiety reactions.
Attention-deficit/hyperactivity disorder (ADHD) Due to inefficient information processing in the PFC resulting in defective arousal (deficient as well as excessive). This is due to low tonic firing of NA and DA (deficient arousal) and faster tonic firing of NA and DA (excessive arousal).
Substance abuse disorders The mesoaccumbens pathway is a central element in the neural representation of reward. All known drugs of abuse activate the mesoaccumbens DA pathway and plastic changes in this pathway are thought to underlie drug addiction.
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