Kindling (sedative-hypnotic withdrawal)

Kindling due to substance withdrawal, refers to the neurological condition which results from repeated withdrawal episodes from sedative-hypnotic drugs such as alcohol or benzodiazepines. Each withdrawal leads to more severe withdrawal symptoms than the previous 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 GABAergic 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.

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. Ethanol (alcohol), has a very similar mechanism of tolerance and withdrawal to benzodiazepines, involving the GABAA receptors, NMDA receptors and AMPA receptors; 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. An intensification of anxiety and other psychological symptoms of alcohol withdrawal also occurs.

Symptoms
Binge drinking is believed to increase 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.

Approximately 3 percent of people who are alcohol dependent experience psychosis during acute intoxication or withdrawal. Alcohol related psychosis may manifest itself through a kindling mechanism. The mechanism of alcohol-related psychosis is due to distortions to neuronal membranes, gene expression, as well as thiamin deficiency. It is possible in some cases that alcohol abuse via a kindling mechanism can cause the development of a chronic substance induced psychotic disorder, i.e. schizophrenia. The effects of an alcohol-related psychosis include an increase risk of depression and suicide as well as psychosocial impairments.

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.

Causes
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. Similar to binge drinkers individuals suffering from alcohol dependence develop changes to neurotransmitter systems occur as a result of kindling and sensitisation during withdrawal which progressively lowers the threshold needed to cause alcohol-related brain damage, cognitive impairments leading to altered neuro-behaviour. The changes in activity of excitatory and inhibitory neurotransmitter systems is similar to that which occurs in individuals suffering from limbic or temporal lobe epilepsy.

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 dependence 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 syndrome.

Alcohol
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 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.

Treatment
Failure to manage the alcohol withdrawal syndrome appropriately can lead to permanent brain damage or death.

Acamprosate, 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.