It is this role which is of interest to the neuropsychiatrist. GABA is synthesized from Glutamate as shown below. The marker enzyme is Glutamic acid decarboxylase GAD. GAD is a pyridoxal cofactor dependent enzyme. A congential form of B-6 vitamin deficiency is known to predispose to seizures which are B-6 responsive.
Glutamate is a pivotal amino acid in the brain. It is dervied from alpha keto glutarate which is one of the intermediates in the Krebs cycle by way of the addition of an amine group.
Glutamate also undergoes transamination to form glutamine by addition of another amine group. Glutamine then proceeds to the liver where it is deaminated to regenerated glutamate which then returns to the brain. This is brain's nitorgen cycle. In situations where the liver is unable to deaminate the glutamine the brain must obtain glutamate by draining the Kreb's cycle intermediates.
This in turn begins to impair cerebral energy metabolism. Following release GABA can be taken back up by the neurons or by astrocytes. It appears that the release of GABA is also under autoreceptor control.
Succinic acid semialdehyde is metabolized further to form succinic acid which is also a Kreb's cycle intermediate. GABA-T is inhibited by valproic acid. This is the basis for the belief that valproic acid is GABAergic. There are other alternative pathways for GABA metabolism.
GABA-a is the most prevalent in the mammalian brain. The GABA-a receptor is similar to acetylcholine receptor in that it is related to an ion channel. In the case of GABA-a it is the chloride ionophore. Binding of GABA to this receptor increases the permeability to chloride ion which causes a hyperpolarization of the neuron or inhibition. The GABA-a receptor has four basic subunits, 2-alpha and 2 beta peptides which surround a chloride channel.
There are three basic binding sites on this complex. The first is the GABA site. The second is a benzodiazepine site. The third is in the channel and is essentially a barbiturate site. Binding to the benzodiazepine site can have three effects, agonism, inverse agonism, or antagonism.
The typical anxiolytic and sedative hypnotic agents such as diazepam and lorazepam act as agonist at these receptors. This results in an increase in Cl- influx. Inverse agonism occurs with the beta carbolines. These agents act in the opposite direction as the agonist.
Binding of these agents reduces the influx of Cl- below the baseline state. Clinically this is accompanied by anxiety. The antagonist such as flumazenil act to displace the agonist and inverse agonist without a direct effect on the chloride channel it's self. There is much speculation and a little evidence for an endogenous benzodiazepine ligand. It has been found to be increased in some metabolic conditions such as hepatic encephalopathy.
In fact there are case reports of the use of benzodiazepine antagonist in the treatment of hepatic encephalopathy. Some patients have been noted to become less somnolent and more oriented. It remains to be seen whether flumazenil will have any use beyond reversing benzodiazepine overdoses. Clinically agents which are GABA-A agonist are generally anticonvulsant in activity as well as muscle relaxants.
The highest concentrations of GABA-b receptors is in the interpeduncular nuclie and cerebellum. This would result in a hyperpolarization. Pharmacologically baclofen is considered a GABA-b agonist. The principle effect of GABA-b agonism is muscle relaxation. A significant relationship of dopamine and GABA exists. In general GABA acts to reduce the firing of the dopaminergic neurons in the tegmentum and substantia nigra. It forms the basis for the use of benzodiazepines as augmentation strategies in the treatment of psychosis.
In addition benzodiazepines may be helpful in cases where there is an over activity of dopamine in the motor striatum such as Huntington's Chorea or Tardive Dyskinesia. It is believed that they act by increasing the feedback inhibition. The feedback inhibition from the GABA neurons of the globus pallidus and putamen to the dopaminergic neurons of the substantia nigra is an important modulating force on the activity of the dopamine neurons.
Excitatory amino acids Glutamate is considered the principle excitatory amino acid in the CNS. Its role in cellular metabolism is well known. Glutamate is distributed widely throughout the neuroaxis. Regions in which it seem particularly important include the granular cells of the cerebellum, the pyramidal cells of the hippocampus, the Betz cells of the motor strip, and the projections of the frontal lobe to the basal ganglia.
One of the major difficulties in recognizing the role of glutamate as a neurotransmitter was the fact that there is only a small percentage of the glutamate present in synaptic vesicles. The vast majority of glutamate is present as part of intermediary metabolism. The ability to define the role of glutamte came as a result of finding receptors for glutamte and labeling them with various analogs.
There are four glutamate receptor subtypes of importance. More will undoubtably be found and the nomenclature may change in the next few years.
The four receptor subtypes include the NMDA receptor, the quisqualte receptor also called the AMPA receptor , the kainate receptor, and the metabotropic receptor. A common feature of these receptors is depolarization of the membrane potential. In addition there are some special characteristic which make this system interesting.
First the receptor systems seem to have a degree of cooperativity. By this I mean that they function most completely as a group. The diagram below illustrates these resceptor systems. This is accomplished by membrane depolarization brought about by the other glutamate receptors.
Once this is done and the NMDA receptors are active a process known as excitotoxicity occurs. This may provide the basis for kindling and other longterm changes which result in neuronal specialization. Excitotoxicity is due to the opening of the calcium channels which results in an increase in free calcium. The degree of damage seems to be limited in most situations by an energy dependent mechanism of binding the calcium. Some of the junctional NE is metabolized within the extracellular space before reaching the capillaries.
The final product of these pathways is vanillylmandelic acid VMA. This final product, along with its precursors normetanephrine and metanephrine, is measured in urine and plasma in the diagnosis of pheochromocytoma , which can cause severe hypertension and cardiac arrhythmias. Acetylcholine Synthesis and Metabolism Acetyl-CoA is synthesized from pyruvate by mitochondria within cholinergic nerves.
This acetyl-CoA combines with choline that is transported into the nerve axon to form acetylcholine ACh. The enzyme responsible for this is choline acetyltransferase.
This is argued to provide direct support for the idea that genetic susceptibility to disease is not determined at birth, but varies with exposure to environmental influences. However, most individuals with conduct disorder or convictions did not have low activity of MAO-A; maltreatment was found to have caused stronger predisposition for antisocial behavior than differences in MAO-A activity.
The claim that an interaction between low MAO-A activity and maltreatment would cause anti-social behavior has been criticized since the predisposition towards anti-social behavior could equally well have been caused by other genes inherited from abusive parents. Prompt recognition and intervention are vital to treatment. Etiology There are three ways in which MAOI toxicity can occur: drug-food interaction, overdose, or drug-drug interactions. The most common MAOI toxicity involves the interaction with tyramine-containing foods.
When MAO found in the gut and liver is inhibited, dietary tyramine indirectly causes an amplification of adrenergic activity. MAOIs have a low therapeutic index. MAOI overdose may see a delay in symptoms of several hours or more.
Single exposures to MAOIs accounted for 90 of the cases. Adults accounted for 71 of these cases, and 28 cases were intentional ingestions. The decline in MAOI toxicity cases presumably reflects the preferential use of other classes of antidepressants. However, MAO has been found to play a central role in the pathogenesis of Alzheimer disease. MAOIs are currently being studied as potential neuroprotective agents . Pathophysiology The toxic effects of MAOIs are observed when their inhibitory effects on monoamine oxidase are compounded by drug-food interactions, overdose or drug-drug interactions.
Without MAO to break down epinephrine, norepinephrine, dopamine, serotonin, and tyramine, the storage, and release of these monoamines are increased. The time course can range from minutes for a drug-food interaction to several hours in a pure MAOI overdose.
They irreversibly bind monoamine oxidase except for moclobemide , removing the drug from circulation and making blood concentrations not indicative of effect. It takes two to three weeks to synthesize enough new monoamine oxidase, so clinical effects of MAOIs may last for that amount of time.The third is in the channel and is essentially a barbiturate site. Patients may present hypertensive, but treatment specifically for hypertension is usually not necessary. The time course can range from minutes for a drug-food interaction to several hours in a pure MAOI overdose. Some of the junctional NE is metabolized within the extracellular space before reaching the capillaries. Neuroscience has attempted to finding specific NMDA receptor blockers to protect against ischemic damage.
Acetylcholine is metabolized by cholinesterases. DNA cloning has identified five subtypes of muscarinic receptors.
Without MAO to break down epinephrine, norepinephrine, dopamine, serotonin, and tyramine, the storage, and release of these monoamines are increased. If needed, a short-acting agent such as nitroprusside or phentolamine is suggested as beta-blockers may result in unopposed alpha stimulation. This system is also a part of the sleep-wake system as we will discuss in a subsequent section. These agents act in the opposite direction as the agonist. The widespread network of these neurons includes innervation of specific hypothalamic and thalamic cell groups.
It is unclear if this is the site that Nitric oxide acts. The vast majority of glutamate is present as part of intermediary metabolism.
The chart below shows these pathways. Preganglionic fibers of the sympathetic nervous system synapse within the adrenals. In addition the 5HT-1a receptors are G-protein linked and have been implicated in thermoregulation, arteriolar vasomotor responses, hypotension, sexual behavior, and possibly sleep. It has been found to be increased in some metabolic conditions such as hepatic encephalopathy.
Etiology There are three ways in which MAOI toxicity can occur: drug-food interaction, overdose, or drug-drug interactions.