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Figure 15.1. Summary of mode of action of alcohol on amino acid, opioid and dopamine dependent neurotransmission in the brain.
neurotoxins to lesion the noradrenergic and serotonergic systems. Thus lesions of the central noradrenergic system block the development of both environmentally dependent and independent tolerance. (Environmentally dependent tolerance is the situation in which tolerance to alcohol develops more rapidly when the drug is consumed or administered in the same environment.) Lesions of the serotonergic system are associated only with a block of the environmentally linked tolerance. The results of such studies suggest that tolerance is a phenomenon which can be separated from the development of physical dependence, and may not therefore be a part of a unitary mechanism for all drugs of abuse.
With regard to the neurotransmitter correlates of alcohol withdrawal and dependence, there is evidence of decreased GABA-benzodiazepine receptor function following chronic alcohol administration, which may be causally related to dependence. Changes in the number of cholinergic muscarinic receptors in the cortex and hippocampus have been reported to occur in alcohol-dependent animals, which return to control levels following withdrawal, but the precise significance of this is unknown.
Experimental studies have also suggested that alcohol may reduce N-methyl-D-aspartate (NMDA) receptor function following acute administration, and following withdrawal of alcohol the functioning of these receptors is enhanced.
Disulfiram (Antabuse) and calcium carbide are sometimes used to assist the detoxified alcoholic to remain abstinent. The rationale behind the use of disulfiram is that it inhibits liver aldehyde dehydrogenase. Any alcohol consumed will lead to an elevation in blood acetaldehyde levels and the aversive toxic effects of acetaldehyde will become apparent. These include facial flushing, nausea, vomiting, gastrointestinal distress and potentially hazardous hypotension and tachycardia. It should be noted that other drugs which may be given for other medical conditions can also inhibit liver aldehyde dehydrogenase and can cause the disulfiram reaction. These include the sulphonylurea antihyperglycaemics, metronidazole and fur-azolidone (both antimicrobial agents). It must also be emphasized that alcohol will potentiate the action of any drug that has a sedative effect.
Activating drugs and the treatment of alcohol dependence
The aversive effects of alcohol withdrawal are associated with decreased mesolimbic dopaminergic activity and increased extracellular glutamate in the nucleus accumbens. The recently introduced anti-craving drug acamprosate has been shown to reduce the enhanced glutamate release that occurs following abrupt alcohol withdrawal. In addition, the neuronal hyperexcitability which occurs during alcohol withdrawal is accompanied by an increased expression of the immediate-early gene c-fos in several regions of the rat brain; acamprosate has been shown to suppress the elevated c-fos expression in these structures. Unlike the sedative drugs, such as the benzodiazepines, which by enhancing GABAergic function are cross-tolerant with alcohol, acamprosate has no effect on the GABAergic system but acts primarily by modulating the activity of the glutamatergic system. In neocortical neurons for example, it has been shown that acamprosate reduces the activation of excitatory glutamatergic synapses and the depolarizing responses evoked by the iontophoretic application of glutamate and NMDA without changing the membrane potential or the input resistance of the cells. In the hippocampus, the NMDA-initiated changes following the block of transmission have been shown to be enhanced by acamprosate. These effects suggest that acamprosate may act postsynaptically to modulate excitatory transmission in both the neocortex and hippocampus. In addition to the specific changes in the glutamatergic-NMDA system, acamprosate interacts with voltage-gated calcium channels and inhibits the up-regulation of calcium channels in alcohol withdrawn rats.
Clinically it has been shown that acamprosate can prevent relapse in alcoholics. In a large double-blind, placebo-controlled European study, acamprosate was shown to be effective in the treatment of alcoholism. Thus at the end of a 1-year period of treatment followed by a 1-year period without medication, 39% of the patients were still abstinent compared with 17% of the placebo-treated patients. Its main clinical effect would appear to be due to its anti-craving properties as it does not interfere with the pharmacokinetics or pharmacodynamics of alcohol. Furthermore, it does not have any reinforcing effects or discriminative stimulus properties of its own. Acamprosate has now been registered for the treatment of alcoholism in most European countries.
Numerous pharmacological and behavioural studies suggest that alcohol interacts with endogenous opioids. Earlier studies had suggested that condensation products of alcohol-derived acetaldehyde and dopamine, tetrahydroisoquinoline, may stimulate opioid receptors but in vivo evidence is lacking. However, experimental studies have shown that transgenic mice lacking beta-endorphin showed a reduction in voluntary consumption when compared to their wild-type, suggesting that a high alcohol intake is associated with an enhancement of endogenous opioid activity. These findings support the hypothesis that drugs blocking the opioid receptors will decrease alcohol intake. Numerous experimental and clinical studies have now indicated that the opiate antagonist naltrexone reduces alcohol intake and the drug has been registered in many countries as an adjunct for the treatment of alcoholism. However, there is evidence that its ability to facilitate abstinence when compared to placebo diminishes over time.
The mechanism of action of naltrexone in reducing alcohol consumption is complex but experimental studies show that opiate antagonists have direct effects on alcohol-seeking behaviour. A possible site for this action could be the mesolimbic dopaminergic reward circuit in which opioid receptors are located. The activity of endogenous opioids in the ventral tegmental area, the site of origin of the A10 mesolimbic dopaminergic neurons, blocks the activity of the GABAergic interneurons that impinge on the A10 neurons which leads to disinhibition. Thus an increase in the endogenous opioid system induced by alcohol would indirectly enhance dopamine release in the mesolimbic system and thereby induce the reward-enhancing effects of the drug. Naltrexone and other antagonists have been shown to antagonize these effects. As naltrexone and other antagonists such as naloxone block the opiate receptors and have been shown in both experimental and clinical studies to suppress alcohol-induced reinforcement, it can be assumed that the activation of the endogenous opioid system is crucially involved in the mediation of alcohol reinforcement.
In summary, naltrexone and acamprosate act via different mechanisms. Naltrexone interferes with the positive reinforcement effects of alcohol and attenuates the effects of conditioned stimuli that had been previously paired with the positive reinforcing effects of alcohol. Acamprosate appears to act by reducing neuronal hyperexcitability and probably inhibits reactivity induced by stimuli that are paired with alcohol withdrawal, an action which may explain the anti-craving action of the drug. While both drugs have been shown to prevent relapse after long abstinence periods, there is no evidence that these drugs also reverse the lasting changes in sensitivity to alcohol that is induced by their long-term use. Other compounds that act on NMDA receptors, such as the non-competitive antagonist memantine, appear to hold promise for the treatment of alcoholism in the future.
The pharmacological properties of these drugs are dealt with in Chapter 5, and therefore only their propensity to cause physical and psychological dependence is considered here. Because of their lack of efficacy, and particularly because of their toxicity, barbiturates should never be used now as anxiolytic or sedative drugs. For this reason, emphasis is placed here on the benzodiazepines, which are not only effective but also relatively safe. Nevertheless, problems have arisen regarding their ability to cause dependence, and so this aspect of their pharmacology must be considered.
Considering their widespread use, intentional abuse of prescribed benzodiazepines is relatively rare. Normally, following the administration of a benzodiazepine for several weeks, there is little tolerance or difficulty in stopping the drug when the condition no longer warrants its use. Following prolonged treatment however (several months for example) tolerance often develops and the abrupt cessation of treatment results in withdrawal symptoms. These consist of: anxiety; agitation; increased sensitivity to light and sound; paraesthesiae; muscle cramps, myoclonic jerks; sleep disturbance and dizziness. These effects are usually short lived and their onset following withdrawal of the benzodiazepine depends on the half-life of the drug. Following the administration of a high dose of a benzodiazepine however, seizures and delirium can also occur.
It is often difficult to distinguish withdrawal symptoms from the reappearance of the underlying anxiety state for which the benzodiazepine was originally prescribed. Furthermore, some patients may increase the dose of the drug over time, particularly if they are taking the drugs for the treatment of insomnia as tolerance often develops to their sedative effects. However, there is little evidence to suggest that tolerance develops as quickly to the anxiolytic effects of the benzodiazepines and most patients continue to take their medication for years without increasing the dose. The American Psychiatric Association (1990) formed a task force that reviewed these issues and published guidelines for the correct medical use of the benzodiazepines. They recommend intermittent use of these drugs when possible to reduce the occurrence of tolerance and dependence. Patients with a history of alcohol or drug abuse have an increased risk to develop benzodiazepine abuse and therefore their use in such patients should be avoided.
The benzodiazepines are the most widely used drugs for the management of insomnia, anxiety, muscle spasticity and seizures. About 12% of the adult population in the US have used such drugs on more than one occasion during the past year for the treatment of insomnia, while approximately 2.4% of adults have taken such drugs continuously for 4 months or longer. Figures from European countries vary, some being higher and some lower than those reported in the US, but in all cases detailed studies of the prescribing of benzodiazepines show that they are being used appropriately both in the US and in most European countries. Nevertheless, despite this there has been concern over the dependence potential of these drugs following their therapeutic use, and this has led to restrictions on their prescribing and the recognition of the need to limit administration to less than 6 weeks in most cases.
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