Приклади розладів, пов’язаних із дефектами нейротрансмісії

Disorder	Pathophysiology	Treatment
Neurotransmitter imbalance
Alzheimer disease	Extracellular beta-amyloid deposits, intracellular neurofibrillary tangles, and senile plaques, particularly in the limbic system (eg, hippocampus), in the association area of the cortex, and in neurons that synthesize and use acetylcholine (eg, in the basal nucleus of Meynert and its wide projections to the cortex)	Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) delay synaptic degradation of acetylcholine and thus modestly improve cognitive function and memory. Memantine, an NMDA-receptor antagonist, may slow progression of the disease and increase autonomy. Future treatments may involve drugs that increase H2S levels in the brain and thus improve short-term memory or affect NO levels in the brain and thus improve long-term memory.
Anxiety	May reflect reduced activity of GABA, perhaps due to imbalance of endogenous inhibitors, stimulators of the GABA receptor, or both May also involve imbalances in norepinephrine and 5-HT responses	Benzodiazepines increase the probability of opening chloride channels modulated by GABA through GABA-A receptor activation. SSRIs are the drugs of choice for long-term treatment because tolerance to benzodiazepines can develop.
Autism spectrum disorders	Possible hyperserotonemia, which occurs in 30–50% of autistic people, with no evidence of central 5-HT abnormalities	SSRIs and risperidone may be helpful.
Brain injury	Injury (eg, trauma, hypoxia, prolonged seizures) stimulating excessive release of excitatory neurotransmitters (eg, glutamate) and accumulation of intracellular calcium, which contribute to neuronal death	In experimental models of ischemia and injury, calcium channel blockers, glycine, and older NMDA-receptor antagonists (eg, dextromethorphan, ketamine) may reduce the extent of neuronal loss, but these drugs are not effective in people.
Depression	Complex abnormalities in cholinergic, catecholaminergic (noradrenergic, dopaminergic) and serotonergic (5-HT) transmission Possible involvement of other hormones and neuropeptides (eg, substance P, dopamine, acetylcholine, GABA)	Antidepressants downregulate receptors indirectly or directly by inhibiting reuptake of 5-HT (as with SSRIs) and norepinephrine or dopamine or by blocking MAO. Blockade of 5-HT2A/2C (a type of 5-HT receptor abundant in the prefrontal area) may increase the efficacy of SSRIs (eg, trazodone).
Seizure disorders	Seizures consisting of sudden synchronous high-frequency firing by localized groups of neurons in certain brain areas, perhaps caused by increased activity of glutamate or reduced activity of GABA	Phenytoin, lamotrigine, carbamazepine, valproate, topiramate, and some other antiseizure drugs (eg, zonisamide, oxcarbazepine) stabilize voltage-dependent sodium channels. Ethosuximide and gabapentin decrease certain calcium currents. Phenytoin also reduces excessive neurotransmitter release. Lamotrigine may decrease levels of glutamate and aspartate. Phenobarbital and benzodiazepines enhance GABA activation by affecting the GABA-A receptor–chloride channel complex. Tiagabine blocks GABA glial uptake. Valproate increases levels of GABA. Topiramate increases GABA activity.
Huntington disease (chorea)	Major neuronal damage in the cortex and striatum due to polyglutamine expansion (encoded by CAG repeat), produced by an abnormal gene on chromosome 4 (the abnormal gene overproduces the protein huntingtin, which may combine with molecules that induce excessive stimulation of cells by excitatory amino acid neurotransmitters such as glutamate)	No specific treatment exists, but drugs that block NMDA receptors may block the toxic effects of excess glutamate. GABA-mimetic drugs are ineffective.
Mania	Increased norepinephrine and dopamine activity, reduced 5-HT levels, and abnormal glutamate neurotransmission	Lithium is the traditional first choice. It reduces norepinephrine release and increases 5-HT synthesis. Valproate and lamotrigine are beneficial, possibly by normalizing glutamate transmission. Topiramate blocks voltage-dependent sodium channels, augments GABA activity at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. Gabapentin is thought to bind to the alpha-2/delta subunit (1 and 2) of the voltage-dependent calcium channel in the CNS. Carbamazepine and oxcarbazepine stabilize voltage dependent sodium channels.
Neuroleptic malignant syndrome	Blockage of dopamine (D2) receptors by drugs (eg, antipsychotic drugs, methylphenidate) or abrupt withdrawal of a dopaminergic agonist, resulting in muscle rigidity, fever, change in mental status, and autonomic instability	Treatment with a D2 agonist (eg, bromocriptine) reverses the disordered neurotransmission. Other drugs are also used as needed (eg, dantrolene, a direct muscular blocker, is used to block the muscle spasms).
Pain	Tissue injury, which causes release of substance P and glutamate in the posterior horn of the spinal cord and release of other macromolecules that mediate pain signals, such as CGRP (which can dilate cranial blood vessels and lead to migraine pain) and neurokinin A and bradykinin (which are localized primarily in the lamina II and IV of the spinal cord) Further modulation of these signals by endorphins (in the spinal cord) and by 5-HT and norepinephrine (in the descending pathways that originate in the brain)	NSAIDs inhibit prostaglandin synthesis selectively (with COX-2 inhibitors—eg, celecoxib, parecoxib) or nonselectively (with COX-1 and -2 inhibitors—eg, ibuprofen, naproxen) and reduce pain impulse formation. Opioid analgesics (eg, morphine) activate endorphin-enkephalin (mu, delta, and kappa) receptors, reducing pain impulse transmission. New treatments that can block CGRP receptors can treat pain in the nervous system. These treatments alter CGRP signaling and thus alleviate pain during migraines; they may be considered for treatment of facial pain, diabetic neuropathies, and pain after cancer treatments.
Parkinsonism	Inhibition of the dopaminergic system due to blockage of dopaminergic receptors by antipsychotic drugs	Anticholinergic drugs reduce cholinergic activity and restore balance between cholinergic and dopaminergic systems.
Parkinson disease	Loss of dopaminergic neurons of the pars compacta in the substantia nigra and other areas, with reduced levels of dopamine and metenkephalin, altering the dopamine/acetylcholine balance and resulting in striatal acetylcholine overactivity	Levodopa reaches the synaptic cleft, is taken up by the axon through presynaptic nigral neurons, and is decarboxylated to dopamine, which is secreted into the cleft to activate dendritic dopamine receptors. Amantadine increases the presynaptic release of dopamine; dopamine agonists stimulate dopamine receptors, although bromocriptine, pramipexole, and ropinirole bind only to D2, D3, and D4 dopamine receptor subtypes. Anticholinergic drugs reduce activity of the cholinergic system, restoring the balance of dopamine and acetylcholine. MAO-B inhibitors prevent reuptake of dopamine, increasing its levels. Selegiline, an MAO-B inhibitor, blocks dopamine breakdown and thus prolongs the response to levodopa and allows the dosage of carbidopa/levodopa to be reduced. Catechol O-methyltransferase (COMT) inhibitors also inhibit dopamine breakdown.
Schizophrenia	Increased presynaptic release, synthesis of dopamine, sensitivity or density of postsynaptic dopamine receptors, or a combination	Antipsychotic drugs block dopamine receptors and reduce dopaminergic overactivity to normal. Haloperidol preferentially blocks D2 and D3 receptors (high affinity) and D4 receptors (low affinity) in mesocortical areas. Clozapine has a high affinity for binding D4 and 5-HT2 receptors, suggesting 5-HT system involvement in the pathogenesis of schizophrenia and its response to treatment. Clozapine has a significant risk of leukopenia. Olanzapine and risperidone, similar to haloperidol, also have high affinity for 5-HT2 and D2 receptors.
Tardive dyskinesia	Hypersensitive dopamine receptors due to chronic blockade by antipsychotic drugs	Reducing doses of antipsychotics may reduce hypersensitivity of dopamine receptors; however, in some cases, changes can be irreversible.
Normal neurotransmitters that are blocked or destroyed by the immune system
Myasthenia gravis	Reflects inactivation of acetylcholine receptors and postsynaptic histochemical changes at the neuromuscular junction due to autoimmune reactions	Anticholinesterase drugs inhibit acetylcholinesterase, increase acetylcholine levels at the junction, and stimulate remaining receptors, increasing muscle activity.
Decreased neuronal uptake of neurotransmitters
Amyotrophic lateral sclerosis	Destruction of upper and lower motor neurons, possibly caused in part by glutamate neurotoxicity	Riluzole, which inhibits glutamate transmission, modestly extends survival.
Normal neurotransmitters but ion channel defects
Episodic ataxias	Defective voltage-gated potassium channels, causing distal rippling and incoordination (myokymia)	Treatment with acetazolamide is effective in some types of episodic ataxia.
Hyperkalemic periodic paralysis	Decreased sodium channel inactivation	Severe attacks may be terminated by calcium gluconate, glucose, and insulin.
Hypokalemic periodic paralysis	Defective voltage-gated calcium channels	Acute attacks can be terminated by potassium salts. Acetazolamide is effective for prevention.
Lambert-Eaton syndrome*	Antibodies that decrease presynaptic release of acetylcholine	Corticosteroids, 3,4-diaminopyridine (DAP), guanidine, IVIG, and plasmapheresis can be helpful.
Paramyotonia congenita	Defective voltage-gated sodium channels, causing cold-induced myotonia and episodic weakness	Mexiletine (a sodium channel blocker) and acetazolamide (a carbonic anhydrase inhibitor) may be helpful.
Rasmussen encephalitis	Postviral production of antibodies to glutamate receptors, affecting glutamate-gated channels Most distinctive form of epilepsia partialis continua	Corticosteroids and antiviral drugs are usually ineffective. Functional hemispherectomy (eg, cutting the corpus callosum) can control seizures if spontaneous remission does not occur.
Startle disease (hyperekplexia, stiff baby syndrome)	Mutation in the gene for the alpha-1 subunit of the glycine-gated channel Characterized by stiffness, nocturnal myoclonus, and an exaggerated startle reflex, with hyperreflexia and falling	Clonazepam or certain other antiseizure drugs (eg, phenytoin, phenobarbital, diazepam, valproate) may result in improvement.
Poisoning
Botulism	Inhibition of acetylcholine release from motor neurons by toxin from Clostridium botulinum	No specific drug therapy exists. Tiny amounts of the toxin are used to treat certain dystonias, spasticity, neuropathic pain, and migraines or cosmetically to reduce skin wrinkles.
Mushroom poisoning	Amanita muscaria: Contains ibotenic acid (which has effects similar to those of glutamate) and a metabolite similar to muscimol (which has effects similar to those of GABA) Inocybe and Clitocybe spp: Stimulation of muscarinic receptors by muscarine and related compounds	Treatment is supportive because no drugs reverse the effects on neurotransmission. Atropine helps reverse muscarinic manifestations.
Organophosphates	Irreversible inhibition of acetylcholinesterase and marked increase in acetylcholine levels in synaptic cleft	Pralidoxime removes toxin from acetylcholinesterase and helps reverse nicotinic as well as muscarinic manifestations. Atropine helps rapidly reverse muscarinic effects.
Snake venom from Bungarus multicinctus (Taiwanese banded krait)	Blocks acetylcholine receptors at neuromuscular junction by alpha-Bungarus toxin	Antivenom appears to be effective and is available.
* Eaton-Lambert syndrome is an antibody-mediated paraneoplastic syndrome that typically occurs in small cell lung cancer. It can be present before the tumor manifests.
CGRP = calcitonin gene-related peptide; CRF = corticotropin (ACTH)-releasing factor; GABA = gamma-aminobutyric acid; H2S = hydrogen sulfide; 5-HT = serotonin; IVIG = IV immune globulin; MAO = monoamine oxidase; MAO-B = MAO type B; NMDA = N-methyl-d-aspartate; NO = nitric oxide; NSAID = nonsteroidal anti-inflammatory drug; PIP2 = phosphatidylinositol 4,5-bisphosphate; SSRI = selective serotonin reuptake inhibitor.

Disorder

Pathophysiology

Treatment

Neurotransmitter imbalance

Extracellular beta-amyloid deposits, intracellular neurofibrillary tangles, and senile plaques, particularly in the limbic system (eg, hippocampus), in the association area of the cortex, and in neurons that synthesize and use acetylcholine (eg, in the basal nucleus of Meynert and its wide projections to the cortex)

Cholinesterase inhibitors (donepezil, rivastigmine, galantamine) delay synaptic degradation of acetylcholine and thus modestly improve cognitive function and memory.

Memantine, an NMDA-receptor antagonist, may slow progression of the disease and increase autonomy.

Future treatments may involve drugs that increase H2S levels in the brain and thus improve short-term memory or affect NO levels in the brain and thus improve long-term memory.

Anxiety

May reflect reduced activity of GABA, perhaps due to imbalance of endogenous inhibitors, stimulators of the GABA receptor, or both

May also involve imbalances in norepinephrine and 5-HT responses

Benzodiazepines increase the probability of opening chloride channels modulated by GABA through GABA-A receptor activation.

SSRIs are the drugs of choice for long-term treatment because tolerance to benzodiazepines can develop.

Autism spectrum disorders

Possible hyperserotonemia, which occurs in 30–50% of autistic people, with no evidence of central 5-HT abnormalities

SSRIs and risperidone may be helpful.

Brain injury

Injury (eg, trauma, hypoxia, prolonged seizures) stimulating excessive release of excitatory neurotransmitters (eg, glutamate) and accumulation of intracellular calcium, which contribute to neuronal death

In experimental models of ischemia and injury, calcium channel blockers, glycine, and older NMDA-receptor antagonists (eg, dextromethorphan, ketamine) may reduce the extent of neuronal loss, but these drugs are not effective in people.

Depression

Complex abnormalities in cholinergic, catecholaminergic (noradrenergic, dopaminergic) and serotonergic (5-HT) transmission

Possible involvement of other hormones and neuropeptides (eg, substance P, dopamine, acetylcholine, GABA)

Antidepressants downregulate receptors indirectly or directly by inhibiting reuptake of 5-HT (as with SSRIs) and norepinephrine or dopamine or by blocking MAO.

Blockade of 5-HT2A/2C (a type of 5-HT receptor abundant in the prefrontal area) may increase the efficacy of SSRIs (eg, trazodone).

Seizure disorders

Seizures consisting of sudden synchronous high-frequency firing by localized groups of neurons in certain brain areas, perhaps caused by increased activity of glutamate or reduced activity of GABA

Phenytoin, lamotrigine, carbamazepine, valproate, topiramate, and some other antiseizure drugs (eg, zonisamide, oxcarbazepine) stabilize voltage-dependent sodium channels.

Ethosuximide and gabapentin decrease certain calcium currents.

Phenytoin also reduces excessive neurotransmitter release.

Lamotrigine may decrease levels of glutamate and aspartate.

Phenobarbital and benzodiazepines enhance GABA activation by affecting the GABA-A receptor–chloride channel complex.

Tiagabine blocks GABA glial uptake.

Valproate increases levels of GABA.

Topiramate increases GABA activity.

Huntington disease (chorea)

Major neuronal damage in the cortex and striatum due to polyglutamine expansion (encoded by CAG repeat), produced by an abnormal gene on chromosome 4 (the abnormal gene overproduces the protein huntingtin, which may combine with molecules that induce excessive stimulation of cells by excitatory amino acid neurotransmitters such as glutamate)

No specific treatment exists, but drugs that block NMDA receptors may block the toxic effects of excess glutamate.

GABA-mimetic drugs are ineffective.

Mania

Increased norepinephrine and dopamine activity, reduced 5-HT levels, and abnormal glutamate neurotransmission

Lithium is the traditional first choice. It reduces norepinephrine release and increases 5-HT synthesis.

Valproate and lamotrigine are beneficial, possibly by normalizing glutamate transmission.

Topiramate blocks voltage-dependent sodium channels, augments GABA activity at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV.

Gabapentin is thought to bind to the alpha-2/delta subunit (1 and 2) of the voltage-dependent calcium channel in the CNS.

Carbamazepine and oxcarbazepine stabilize voltage dependent sodium channels.

Neuroleptic malignant syndrome

Blockage of dopamine (D2) receptors by drugs (eg, antipsychotic drugs, methylphenidate) or abrupt withdrawal of a dopaminergic agonist, resulting in muscle rigidity, fever, change in mental status, and autonomic instability

Treatment with a D2 agonist (eg, bromocriptine) reverses the disordered neurotransmission.

Other drugs are also used as needed (eg, dantrolene, a direct muscular blocker, is used to block the muscle spasms).

Pain

Tissue injury, which causes release of substance P and glutamate in the posterior horn of the spinal cord and release of other macromolecules that mediate pain signals, such as CGRP (which can dilate cranial blood vessels and lead to migraine pain) and neurokinin A and bradykinin (which are localized primarily in the lamina II and IV of the spinal cord)

Further modulation of these signals by endorphins (in the spinal cord) and by 5-HT and norepinephrine (in the descending pathways that originate in the brain)

NSAIDs inhibit prostaglandin synthesis selectively (with COX-2 inhibitors—eg, celecoxib, parecoxib) or nonselectively (with COX-1 and -2 inhibitors—eg, ibuprofen, naproxen) and reduce pain impulse formation.

Opioid analgesics (eg, morphine) activate endorphin-enkephalin (mu, delta, and kappa) receptors, reducing pain impulse transmission.

New treatments that can block CGRP receptors can treat pain in the nervous system. These treatments alter CGRP signaling and thus alleviate pain during migraines; they may be considered for treatment of facial pain, diabetic neuropathies, and pain after cancer treatments.

Parkinsonism

Inhibition of the dopaminergic system due to blockage of dopaminergic receptors by antipsychotic drugs

Anticholinergic drugs reduce cholinergic activity and restore balance between cholinergic and dopaminergic systems.

Parkinson disease

Loss of dopaminergic neurons of the pars compacta in the substantia nigra and other areas, with reduced levels of dopamine and metenkephalin, altering the dopamine/acetylcholine balance and resulting in striatal acetylcholine overactivity

Levodopa reaches the synaptic cleft, is taken up by the axon through presynaptic nigral neurons, and is decarboxylated to dopamine, which is secreted into the cleft to activate dendritic dopamine receptors. Amantadine increases the presynaptic release of dopamine; dopamine agonists stimulate dopamine receptors, although bromocriptine, pramipexole, and ropinirole bind only to D2, D3, and D4 dopamine receptor subtypes.

Anticholinergic drugs reduce activity of the cholinergic system, restoring the balance of dopamine and acetylcholine.

MAO-B inhibitors prevent reuptake of dopamine, increasing its levels. Selegiline, an MAO-B inhibitor, blocks dopamine breakdown and thus prolongs the response to levodopa and allows the dosage of carbidopa/levodopa to be reduced.

Catechol O-methyltransferase (COMT) inhibitors also inhibit dopamine breakdown.

Schizophrenia

Increased presynaptic release, synthesis of dopamine, sensitivity or density of postsynaptic dopamine receptors, or a combination

Antipsychotic drugs block dopamine receptors and reduce dopaminergic overactivity to normal.

Haloperidol preferentially blocks D2 and D3 receptors (high affinity) and D4 receptors (low affinity) in mesocortical areas.

Clozapine has a high affinity for binding D4 and 5-HT2 receptors, suggesting 5-HT system involvement in the pathogenesis of schizophrenia and its response to treatment. Clozapine has a significant risk of leukopenia.

Olanzapine and risperidone, similar to haloperidol, also have high affinity for 5-HT2 and D2 receptors.

Tardive dyskinesia

Hypersensitive dopamine receptors due to chronic blockade by antipsychotic drugs

Reducing doses of antipsychotics may reduce hypersensitivity of dopamine receptors; however, in some cases, changes can be irreversible.

Normal neurotransmitters that are blocked or destroyed by the immune system

Myasthenia gravis

Reflects inactivation of acetylcholine receptors and postsynaptic histochemical changes at the neuromuscular junction due to autoimmune reactions

Anticholinesterase drugs inhibit acetylcholinesterase, increase acetylcholine levels at the junction, and stimulate remaining receptors, increasing muscle activity.

Decreased neuronal uptake of neurotransmitters

Amyotrophic lateral sclerosis

Destruction of upper and lower motor neurons, possibly caused in part by glutamate neurotoxicity

Riluzole, which inhibits glutamate transmission, modestly extends survival.

Normal neurotransmitters but ion channel defects

Episodic ataxias

Defective voltage-gated potassium channels, causing distal rippling and incoordination (myokymia)

Treatment with acetazolamide is effective in some types of episodic ataxia.

Hyperkalemic periodic paralysis

Decreased sodium channel inactivation

Severe attacks may be terminated by calcium gluconate, glucose, and insulin.

Hypokalemic periodic paralysis

Defective voltage-gated calcium channels

Acute attacks can be terminated by potassium salts.

Acetazolamide is effective for prevention.

Lambert-Eaton syndrome*

Antibodies that decrease presynaptic release of acetylcholine

Corticosteroids, 3,4-diaminopyridine (DAP), guanidine, IVIG, and plasmapheresis can be helpful.

Paramyotonia congenita

Defective voltage-gated sodium channels, causing cold-induced myotonia and episodic weakness

Mexiletine (a sodium channel blocker) and acetazolamide (a carbonic anhydrase inhibitor) may be helpful.

Rasmussen encephalitis

Postviral production of antibodies to glutamate receptors, affecting glutamate-gated channels

Most distinctive form of epilepsia partialis continua

Corticosteroids and antiviral drugs are usually ineffective.

Functional hemispherectomy (eg, cutting the corpus callosum) can control seizures if spontaneous remission does not occur.

Startle disease (hyperekplexia, stiff baby syndrome)

Mutation in the gene for the alpha-1 subunit of the glycine-gated channel

Characterized by stiffness, nocturnal myoclonus, and an exaggerated startle reflex, with hyperreflexia and falling

Clonazepam or certain other antiseizure drugs (eg, phenytoin, phenobarbital, diazepam, valproate) may result in improvement.

Poisoning

Botulism

Inhibition of acetylcholine release from motor neurons by toxin from Clostridium botulinum

No specific drug therapy exists.

Tiny amounts of the toxin are used to treat certain dystonias, spasticity, neuropathic pain, and migraines or cosmetically to reduce skin wrinkles.

Mushroom poisoning

Amanita muscaria: Contains ibotenic acid (which has effects similar to those of glutamate) and a metabolite similar to muscimol (which has effects similar to those of GABA)

Inocybe and Clitocybe spp: Stimulation of muscarinic receptors by muscarine and related compounds

Treatment is supportive because no drugs reverse the effects on neurotransmission.

Atropine helps reverse muscarinic manifestations.

Organophosphates

Irreversible inhibition of acetylcholinesterase and marked increase in acetylcholine levels in synaptic cleft

Pralidoxime removes toxin from acetylcholinesterase and helps reverse nicotinic as well as muscarinic manifestations.

Atropine helps rapidly reverse muscarinic effects.

Snake venom from Bungarus multicinctus (Taiwanese banded krait)

Blocks acetylcholine receptors at neuromuscular junction by alpha-Bungarus toxin

Antivenom appears to be effective and is available.

* Eaton-Lambert syndrome is an antibody-mediated paraneoplastic syndrome that typically occurs in small cell lung cancer. It can be present before the tumor manifests.

CGRP = calcitonin gene-related peptide; CRF = corticotropin (ACTH)-releasing factor; GABA = gamma-aminobutyric acid; H2S = hydrogen sulfide; 5-HT = serotonin; IVIG = IV immune globulin; MAO = monoamine oxidase; MAO-B = MAO type B; NMDA = N-methyl-d-aspartate; NO = nitric oxide; NSAID = nonsteroidal anti-inflammatory drug; PIP2 = phosphatidylinositol 4,5-bisphosphate; SSRI = selective serotonin reuptake inhibitor.

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