Kindling (substance withdrawal)
Encyclopedia
Kindling due to substance withdrawal, refers to the neurological condition which results from repeated withdrawal episodes from sedative
-hypnotic drugs such as alcohol
or benzodiazepine
s. Each withdrawal leads to more severe withdrawal symptoms than the first withdrawal syndrome. Individuals who have had more withdrawal episodes are at an increased risk of very severe withdrawal symptoms, up to and including seizures. Withdrawal from GABA
ergic acting sedative-hypnotic drugs causes acute GABA-under-activity as well as glutamate over-activity which can lead to sensitization
and hyper-excitability of the central nervous system
, excito-neurotoxicity
and increasingly profound neuroadaptions.
(alcohol), has a very similar mechanism of tolerance and withdrawal as benzodiazepines, involving the GABAA receptors, NMDA receptor
s and AMPA receptor
s; these receptors are involved in kindling. The research into kindling, a phenomenon which results in increased sensitivity of the nervous system due to multiple acute withdrawals with for example increased seizures, has primarily focused on alcohol.
explains long-term potentiation as well as neuro kindling phenomena. Tolerance is defined as a loss of pharmacological effects after a repeated or regular use of a drug. Use of a short-acting benzodiazepine at night as a sleeping pill causes repeated acute dependence followed by acute withdrawal. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor down-regulation (decrease in number), however, there is very limited evidence to support this and comes from animal studies using very high doses. Instead other mechanisms are believed to play a more important role in the development of benzodiazepine dependence, such as receptor uncoupling which may lead to prolonged comformational changes in the receptors or altered subunit composition of the receptors.
.
is also thought to cause impulsivity due to altered functioning of prefrontal–subcortical and orbitofrontal circuits. Binge drinking and alcoholics who have undergone multiple detoxifications is associated with an inability to interpret facial expressions properly; this is believed to be due to kindling
of the amygdala with resultant distortion of neurotransmission. Adolescents, females and young adults are most sensitive to the neuropsychological effects of binge drinking. Adolescence, particularly early adolescence, is a developmental stage which is particularly vulnerable to the neurotoxic and neurocognitive adverse effects of binge drinking due to it being a time of significant brain development.
Repeated acute intoxication followed by acute withdrawal is associated with profound behavioural changes and neurobiological alterations in several brain regions. Much of the documented evidence of kindling due to multiple detoxifications regards increased seizure frequency. Increased fear and anxiety and cognitive impairments are also associated with alcohol withdrawal kindling due to binge drinking or alcoholics with multiple alcohol withdrawal experiences. Impairments induced by binge drinking or multiple detoxifications of alcoholic individuals cause a loss of behavioural inhibition of the prefrontal cortex; the prefrontal cortex
is mediated by subcortical systems such as the amygdala. This loss of behavioral control due to brain impairment predisposes an individual to alcoholism
and increases the risk of an abstaining alcoholic relapsing and additionally this impairment may result in long-term adverse effects on emotional behavior. Impaired associative learning may make behavioural therapies involving conditioning approaches for alcoholics less effective.
Binge drinkers and alcoholics with multiple detoxifications have impairments in executive control tasks sensitive to dysfunction of prefrontal cortex. Animal studies show that repeated withdrawals are associated with an inability to learn new information. The mechanims of neurotoxicity and kindling of neurotransmission systems is due to alcohol's acute effects on GABAergic enhancement and NMDA suppression, leading to CNS depression leading to a partial acute tolerance to these effects, followed by a rebound effect
, during acute withdrawal due to the partial tolerance that developed. The acute withdrawal/rebound causes the neurotransmission systems to go into a hyper-excitability state; if this hyper-excitability state occurs multiple times, kindling and possible neurotoxicity can occur. There is some evidence that excitotoxicity may also result as a result of repeated withdrawals. Similar to people who have been detoxified multiple times from alcohol, binge drinkers show a higher rate of emotional disturbance.
Binge drinking regimes are associated with causing an imbalance between inhibitory and excitatory amino acids and changes in monoamines release in the central nervous system, which increases neurotoxicity and may result in cogitive impairments, psychological problems and in long-term heavy binge drinkers may cause irreversible brain damage in both adolescents and adults.
Binge drinking may induce brain damage due to the repeated cycle of acute intoxication followed by an acute abstinence withdrawal state. Based on animal studies, regular binge drinking in the long-term is thought to be more likely to result in brain damage than chronic (daily) alcoholism. The reason for this is due to the 4 to 5-fold increase in glutamate release which is released during the acute withdrawal state in between binges. In contrast during withdrawal from chronic alcoholism only a 2 to 3 fold increase in glutamate release occurs. The high levels of glutamate release causes a chain reaction in other neurotransmitter systems. The reason that chronic sustained alcoholism is thought by some researchers to be less brain damaging than binge drinking is because tolerance develops to the effects of alcohol and unlike binge drinking repeated periods of acute withdrawal does not occur, but there are also many alcoholics who typically drink in binges followed by periods of no drinking. Excessive glutamate release is a known major cause of neuronal cell death. Glutamate causes neurotoxicity due to excitotoxicity
and oxidative glutamate toxicity. Evidence from animal studies suggests that some people may be more genetically sensitive to the neurotoxic and brain damage associated with binge drinking regimes. Binge drinking activates microglial cells which leads to the release of inflammatory cytokines and mediators such as tumour necrosis factor, and nitric oxide
causing neuroinflamation leading to neuronal destruction.
The problems of alcoholism are well known, such as memory disorders, liver disease, high blood pressure, muscle weakness, heart problems, anaemia, low immune function, disorders of the digestive system and pancreatic problems as well as depression, unemployment and family problems including child abuse. Recently attention has been increasingly focused on binge drinking by adolescents and young adults due to neurochemical changes and brain damage which unlike with alcoholism can occur after a relatively short period of time; the damage is particularly evident in the corticolimbic region. This brain damage increases the risk of mood and cognitive abilities, increases the risk of dementia and additionally binge drinkers have an increased risk of developing chronic alcoholism.
Impairments in impulse control in binge drinkers, which is more prominent in female binge drinkers, is due to dysfunction of the frontal lobe
. The findings in humans have been largely concordant with animal studies. Such animal studies find that heavy and regular binge drinking causes neurodegeneration in corticolimbic brain regions areas which are involved in learning and spatial memory, such as the olfactory bulb
, piriform cortex
, perirhinal cortex
, entorhinal cortex
, and the hippocampal dentate gyrus
. A study in rats found that a heavy 2 day drinking binge caused extensive neurodegeneration in the entorhinal cortex
with resultant learning deficits. While brain damage from binge drinking is known to occur as a result of binge drinking patterns, it is unclear how long drinking sessions last and how regular binge drinking is done to cause brain damage in humans. One study found that humans who drank at least 100 drinks (male) or 80 drinks (female) per month (concentrated to 21 occasions or less per month) throughout a 3 year period had impaired decision making skills compared to non-binge drinkers. In the same study, an MRI brain scan found that levels of N-acetylaspartate (NAA) which is a metabolite biomarker for neural integrity was lower in binge drinkers and additionally found that brain metabolism was abnormal and found loss of white brain matter in the frontal lobe
and higher parietal gray matter NAA. There was a correlation between binge drinking and poor executive functioning and working memory; frontal NAA loss was associated with impaired executive functioning and processing speed in neuro-performance tests. Repeated acute withdrawal from alcohol which occurs in heavy binge drinkers has been shown in several studies to be associated with cognitive deficits as a result of neural kindling
; neural kindling due to repeated withdrawals is believed to be the mechanism of cognitive damage in both binge drinkers and alcoholics. Neural kindling may explain the advancing pathogenesis and progressively deteriorating course of alcoholism and explain continued alcohol abuse as due to avoidance of distressing acute withdrawal symptoms which get worse with each withdrawal. Multiple withdrawals from alcohol is associated with impaired long-term nonverbal memory impairment in adolescents and to poor memory in adult alcoholics. Adult alcoholics who experienced two or more withdrawals showed more frontal lobe impairments than alcoholics who had a history of one or no prior alcohol withdrawals. The findings of kindling in alcoholism is consistent with the mechanism of brain damage due to binge drinking and subsequent withdrawal.
, a drug used to promote abstinence from alcohol, an NMDA antagonist drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage.
Sedative
A sedative or tranquilizer is a substance that induces sedation by reducing irritability or excitement....
-hypnotic drugs such as alcohol
Alcohol
In chemistry, an alcohol is an organic compound in which the hydroxy functional group is bound to a carbon atom. In particular, this carbon center should be saturated, having single bonds to three other atoms....
or benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s. Each withdrawal leads to more severe withdrawal symptoms than the first withdrawal syndrome. Individuals who have had more withdrawal episodes are at an increased risk of very severe withdrawal symptoms, up to and including seizures. Withdrawal from GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
ergic acting sedative-hypnotic drugs causes acute GABA-under-activity as well as glutamate over-activity which can lead to sensitization
Sensitization
Sensitization is an example of non-associative learning in which the progressive amplification of a response follows repeated administrations of a stimulus. An everyday example of this mechanism is the repeated tonic stimulation of peripheral nerves that will occur if a person rubs his arm...
and hyper-excitability of the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, excito-neurotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
and increasingly profound neuroadaptions.
Definition
Kindling is the phenomenon which occurs as a result of repeated withdrawal from benzodiazepines or alcohol that leads to increasingly severe withdrawal symptoms, including an increased risk of seizures. EthanolEthanol
Ethanol, also called ethyl alcohol, pure alcohol, grain alcohol, or drinking alcohol, is a volatile, flammable, colorless liquid. It is a psychoactive drug and one of the oldest recreational drugs. Best known as the type of alcohol found in alcoholic beverages, it is also used in thermometers, as a...
(alcohol), has a very similar mechanism of tolerance and withdrawal as benzodiazepines, involving the GABAA receptors, NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s and AMPA receptor
AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system . Its name is derived from its ability to be activated by the artificial glutamate analog AMPA...
s; these receptors are involved in kindling. The research into kindling, a phenomenon which results in increased sensitivity of the nervous system due to multiple acute withdrawals with for example increased seizures, has primarily focused on alcohol.
Causes
Adaptational changes at the GABAA benzodiazepine receptor complex do not fully explain tolerance, dependence and withdrawal from benzodiazepines. Other receptor complexes are believed to be involved, in particular the excitatory glutamate system. The involvement of glutamate in benzodiazepine dependenceBenzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
explains long-term potentiation as well as neuro kindling phenomena. Tolerance is defined as a loss of pharmacological effects after a repeated or regular use of a drug. Use of a short-acting benzodiazepine at night as a sleeping pill causes repeated acute dependence followed by acute withdrawal. There is some evidence that a prior history of CNS depressant dependence (e.g. alcohol) increases the risk of dependence on benzodiazepines. Tolerance to drugs is commonly believed to be due to receptor down-regulation (decrease in number), however, there is very limited evidence to support this and comes from animal studies using very high doses. Instead other mechanisms are believed to play a more important role in the development of benzodiazepine dependence, such as receptor uncoupling which may lead to prolonged comformational changes in the receptors or altered subunit composition of the receptors.
Benzodiazepines
Repeated benzodiazepine withdrawal episodes may result in similar neuronal kindling as that seen after repeated withdrawal episodes from alcohol, with resultant increased neuro-excitability. The glutamate system is believed to play an important role in this kindling phenomenon with AMPA receptors which are a subtype of glutamate receptors being altered by repeated withdrawals from benzodiazepines. The changes which occur after withdrawal in AMPA receptors in animals have been found in regions of the brain which govern anxiety and seizure threshold; thus kindling may result in increased severity of anxiety and a lowered seizure threshold during repeated withdrawal. Changes in the glutamate system and GABA system may play an important role at different time points during benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
.
Alcohol
Binge drinkingBinge drinking
Binge drinking or heavy episodic drinking is the modern epithet for drinking alcoholic beverages with the primary intention of becoming intoxicated by heavy consumption of alcohol over a short period of time. It is a kind of purposeful drinking style that is popular in several countries worldwide,...
is also thought to cause impulsivity due to altered functioning of prefrontal–subcortical and orbitofrontal circuits. Binge drinking and alcoholics who have undergone multiple detoxifications is associated with an inability to interpret facial expressions properly; this is believed to be due to kindling
Kindling
Kindling is a term to describe small pieces of wood and twigs used to start a fire.Kindling may also refer to:* Kindling, a 1915 film directed by Cecil B...
of the amygdala with resultant distortion of neurotransmission. Adolescents, females and young adults are most sensitive to the neuropsychological effects of binge drinking. Adolescence, particularly early adolescence, is a developmental stage which is particularly vulnerable to the neurotoxic and neurocognitive adverse effects of binge drinking due to it being a time of significant brain development.
Repeated acute intoxication followed by acute withdrawal is associated with profound behavioural changes and neurobiological alterations in several brain regions. Much of the documented evidence of kindling due to multiple detoxifications regards increased seizure frequency. Increased fear and anxiety and cognitive impairments are also associated with alcohol withdrawal kindling due to binge drinking or alcoholics with multiple alcohol withdrawal experiences. Impairments induced by binge drinking or multiple detoxifications of alcoholic individuals cause a loss of behavioural inhibition of the prefrontal cortex; the prefrontal cortex
Prefrontal cortex
The prefrontal cortex is the anterior part of the frontal lobes of the brain, lying in front of the motor and premotor areas.This brain region has been implicated in planning complex cognitive behaviors, personality expression, decision making and moderating correct social behavior...
is mediated by subcortical systems such as the amygdala. This loss of behavioral control due to brain impairment predisposes an individual to alcoholism
Alcoholism
Alcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
and increases the risk of an abstaining alcoholic relapsing and additionally this impairment may result in long-term adverse effects on emotional behavior. Impaired associative learning may make behavioural therapies involving conditioning approaches for alcoholics less effective.
Binge drinkers and alcoholics with multiple detoxifications have impairments in executive control tasks sensitive to dysfunction of prefrontal cortex. Animal studies show that repeated withdrawals are associated with an inability to learn new information. The mechanims of neurotoxicity and kindling of neurotransmission systems is due to alcohol's acute effects on GABAergic enhancement and NMDA suppression, leading to CNS depression leading to a partial acute tolerance to these effects, followed by a rebound effect
Rebound effect
The rebound effect, or rebound phenomenon, is the tendency of some medications, when discontinued suddenly, to cause a return of the symptoms it relieved, and that, to a degree stronger than they were before treatment first began...
, during acute withdrawal due to the partial tolerance that developed. The acute withdrawal/rebound causes the neurotransmission systems to go into a hyper-excitability state; if this hyper-excitability state occurs multiple times, kindling and possible neurotoxicity can occur. There is some evidence that excitotoxicity may also result as a result of repeated withdrawals. Similar to people who have been detoxified multiple times from alcohol, binge drinkers show a higher rate of emotional disturbance.
Binge drinking regimes are associated with causing an imbalance between inhibitory and excitatory amino acids and changes in monoamines release in the central nervous system, which increases neurotoxicity and may result in cogitive impairments, psychological problems and in long-term heavy binge drinkers may cause irreversible brain damage in both adolescents and adults.
Binge drinking may induce brain damage due to the repeated cycle of acute intoxication followed by an acute abstinence withdrawal state. Based on animal studies, regular binge drinking in the long-term is thought to be more likely to result in brain damage than chronic (daily) alcoholism. The reason for this is due to the 4 to 5-fold increase in glutamate release which is released during the acute withdrawal state in between binges. In contrast during withdrawal from chronic alcoholism only a 2 to 3 fold increase in glutamate release occurs. The high levels of glutamate release causes a chain reaction in other neurotransmitter systems. The reason that chronic sustained alcoholism is thought by some researchers to be less brain damaging than binge drinking is because tolerance develops to the effects of alcohol and unlike binge drinking repeated periods of acute withdrawal does not occur, but there are also many alcoholics who typically drink in binges followed by periods of no drinking. Excessive glutamate release is a known major cause of neuronal cell death. Glutamate causes neurotoxicity due to excitotoxicity
Excitotoxicity
Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
and oxidative glutamate toxicity. Evidence from animal studies suggests that some people may be more genetically sensitive to the neurotoxic and brain damage associated with binge drinking regimes. Binge drinking activates microglial cells which leads to the release of inflammatory cytokines and mediators such as tumour necrosis factor, and nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
causing neuroinflamation leading to neuronal destruction.
The problems of alcoholism are well known, such as memory disorders, liver disease, high blood pressure, muscle weakness, heart problems, anaemia, low immune function, disorders of the digestive system and pancreatic problems as well as depression, unemployment and family problems including child abuse. Recently attention has been increasingly focused on binge drinking by adolescents and young adults due to neurochemical changes and brain damage which unlike with alcoholism can occur after a relatively short period of time; the damage is particularly evident in the corticolimbic region. This brain damage increases the risk of mood and cognitive abilities, increases the risk of dementia and additionally binge drinkers have an increased risk of developing chronic alcoholism.
Impairments in impulse control in binge drinkers, which is more prominent in female binge drinkers, is due to dysfunction of the frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
. The findings in humans have been largely concordant with animal studies. Such animal studies find that heavy and regular binge drinking causes neurodegeneration in corticolimbic brain regions areas which are involved in learning and spatial memory, such as the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
, piriform cortex
Piriform cortex
In anatomy of animals, the piriform cortex, or pyriform cortex is a region in the brain.-Anatomy and function:The piriform cortex is part of the rhinencephalon situated in the telencephalon....
, perirhinal cortex
Perirhinal cortex
Perirhinal cortex is a cortical region in the medial temporal lobe that is made up of Brodmann areas 35 and 36. In rats, it is located along and dorsal to the rhinal sulcus. It receives highly-processed sensory information from all sensory regions, and is generally accepted to be an important...
, entorhinal cortex
Entorhinal cortex
The entorhinal cortex is located in the medial temporal lobe and functions as a hub in a widespread network for memory and navigation. The EC is the main interface between the hippocampus and neocortex...
, and the hippocampal dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
. A study in rats found that a heavy 2 day drinking binge caused extensive neurodegeneration in the entorhinal cortex
Entorhinal cortex
The entorhinal cortex is located in the medial temporal lobe and functions as a hub in a widespread network for memory and navigation. The EC is the main interface between the hippocampus and neocortex...
with resultant learning deficits. While brain damage from binge drinking is known to occur as a result of binge drinking patterns, it is unclear how long drinking sessions last and how regular binge drinking is done to cause brain damage in humans. One study found that humans who drank at least 100 drinks (male) or 80 drinks (female) per month (concentrated to 21 occasions or less per month) throughout a 3 year period had impaired decision making skills compared to non-binge drinkers. In the same study, an MRI brain scan found that levels of N-acetylaspartate (NAA) which is a metabolite biomarker for neural integrity was lower in binge drinkers and additionally found that brain metabolism was abnormal and found loss of white brain matter in the frontal lobe
Frontal lobe
The frontal lobe is an area in the brain of humans and other mammals, located at the front of each cerebral hemisphere and positioned anterior to the parietal lobe and superior and anterior to the temporal lobes...
and higher parietal gray matter NAA. There was a correlation between binge drinking and poor executive functioning and working memory; frontal NAA loss was associated with impaired executive functioning and processing speed in neuro-performance tests. Repeated acute withdrawal from alcohol which occurs in heavy binge drinkers has been shown in several studies to be associated with cognitive deficits as a result of neural kindling
Kindling
Kindling is a term to describe small pieces of wood and twigs used to start a fire.Kindling may also refer to:* Kindling, a 1915 film directed by Cecil B...
; neural kindling due to repeated withdrawals is believed to be the mechanism of cognitive damage in both binge drinkers and alcoholics. Neural kindling may explain the advancing pathogenesis and progressively deteriorating course of alcoholism and explain continued alcohol abuse as due to avoidance of distressing acute withdrawal symptoms which get worse with each withdrawal. Multiple withdrawals from alcohol is associated with impaired long-term nonverbal memory impairment in adolescents and to poor memory in adult alcoholics. Adult alcoholics who experienced two or more withdrawals showed more frontal lobe impairments than alcoholics who had a history of one or no prior alcohol withdrawals. The findings of kindling in alcoholism is consistent with the mechanism of brain damage due to binge drinking and subsequent withdrawal.
Treatment
AcamprosateAcamprosate
Acamprosate, also known as N-acetyl homotaurine and by the brand name Campral, is a drug used for treating alcohol dependence.Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutamatergic...
, a drug used to promote abstinence from alcohol, an NMDA antagonist drug, reduces excessive glutamate activity in the central nervous system and thereby may reduce excitotoxicity and withdrawal related brain damage.