Chloride channel
Tolerance (larger doses of BDZs are needed to exert similar response)
Withdrawal symptoms (If BDZs are withdrawn, then the downregulated GABAA receptors will not be able to normalize Cl
ion influx – causing a net excitatory effect)
Cl ions GABAA GABA Cell nucleus Decreased intracellular chloride concentration BDZs BDZ receptor
(during chronic abuse of BDZs)
Abnormal transcription factor (?) Abnormal mRNA for the a1 subunit (relatively closed due to diminished GABAA stimulation) Convulsant receptor a1 subunit Stimulates Induces Downregulated receptor
Intracellular events following chronic stimulation of the BDZ receptor
BDZ Benzodiazepine GABA c-Aminobutyric acid
Notes about the scheme
Benzodiazepines exert their therapeutic effects
by increasing the affinity of c-aminobutyric acid (GABA) to the GABAAreceptor and thus
increasing chloride influx into the intracellular space. The increased influx hyperpolarizes the neuron and further enhances the inhibitory effects of the GABAergic neuron. Therefore,
benzodiazepines act as neuromodulators that
enhance the inhibitory effects of GABA.
Benzodiazepine abuse is different from
other substance abuse disorders (opiates,
amphetamines, and nicotine) because benzodiazepines cause much less euphoria
and do not activate the ‘classic’ reward systems that are activated with other substances (mainly the mesolimbic and mesocortical dopaminergic projections). In fact, most people do not find the subjective effects of benzodiazepines pleasant beyond their therapeutic anxiolytic or sleep-inducing effects. Therefore, abuse of
benzodiazepines is usually secondary to
other substance-abuse disorders, with the
benzodiazepine being taken for relief from
symptoms induced by the use of another drug. As potential drugs of abuse, short-acting
benzodiazepines seem to be preferred among
addicts because of the rapidity of their onset of action (alprazolam, flunitrazepam, and
lorazepam).
Benzodiazepines enhance the activities of
GABA at its receptor site, and at the same time, and when they are chronically abused, they suppress the expression of the specific
messenger ribonucleic acid (mRNA) coding for the production of the a1subunit of the GABAA
receptor. This subunit is one of the major components responsible for the effective coupling between the GABAAreceptor and the
adjacent chloride channel. Thus, chronic
benzodiazepine abuse impairs the
effectiveness of the GABAAreceptors, leading
eventually to their downregulation and to a decrease in chloride influx. Because of the decreased chloride influx into the intracellular GABAergic nerves that follows chronic
benzodiazepine abuse, larger doses of
benzodiazepines are needed to exert the same
clinical effects. This is the physiological basis for the development of tolerance. When
benzodiazepines are withdrawn, the GABAA
receptors are still downregulated and their activities are relatively suppressed compared with their baseline status. Since GABAergic nerves exert inhibitory effects on major brain regions, when they are suppressed, the affected brain regions are in a relatively hyperexcitable state. This excitability causes increased noradrenergic neurotransmission and it might play a major role in the induction of
characteristic withdrawal symptoms (agitation, insomnia, anxiety, and tremor).
Several treatment options are relevant in the case of benzodiazepine abuse. Gradual
tapering of benzodiazepines is probably the hallmark and the most effective approach. The tapering schedule should include a reduction of about 20–25% of the consumed dosage per week. Detoxification can be accomplished within 7–21 days. For short-acting benzodiazepines (e.g. alprazolam), a more conservative detoxification plan should be taken (e.g.
alprazolam should be tapered at a maximum
rate of 0.5 mg every 3 days). Alternatively, a short-acting benzodiazepine can be replaced by a longer-acting one, with tapering-off starting only afterwards. The gradual tapering enables the downregulated GABAAreceptors to recover
in parallel with the decrease in benzodiazepine dose.51–53Buspirone (a 5-HT
1Apartial agonist)
or ‘antidepressants’ (especially selective
serotonin reuptake inhibitors (SSRIs))
should be considered if tapering is not fully successful and there is still a need for an anxiolytic agent. Both are used primarily as anxiolytic agents, and their main advantages are diminished abuse potential, the absence of withdrawal syndromes during acute abstinence, non-impaired psychomotor performance, and no anterograde amnesia. Buspirone has been found to be beneficial in reducing the craving for benzodiazepines, probably due to its anxiolytic effects. The main drawback in using
buspirone or SSRIs is the relatively long time
needed before the anxiolytic effects are achieved (at least 1–2 weeks). Another drawback is related to accumulating data suggesting that
buspirone is not as effective in
ongoing/formerly benzodiazepine-treated patients as in benzodiazepine-naive/free patients.51–53
6.10 Abused substances – nicotine
Supposed mechanism of dependence, withdrawal symptoms, and treatment options
Na Na Na Acetylcholine Dopamine Nicotine Na
Neuronal mechanism of 'reward' Neuronal mechanism leading to withdrawal symptoms Downregulated (?) opioid receptors (following enhanced secretion of endorphins/enkephalins) Postsynaptic noradrenergic neurons originating
from the locus ceruleus
Net effect during withdrawal from nicotine
Decreased inhibition of the postsynaptic neurons (due to the downregulated opioid receptors),
leading to excessive stimulation of noradrenergic neurotransmission
Net effect during acute intoxication
Increased secretion of dopamine in the mesolimbic pathway (the 'reward' pathway)
Enhanced secretion of endorphins/enkephalins Opioid receptors AChN AChN Increased action potential frequency Increased concentration Stimulates Inhibits Downregulated receptor
AChN Acetylcholine nicotinic receptor
In developed countries, smoking is presently estimated to cause 20% of all deaths, making it the largest single cause of preventable death.
Nicotine is the primary psychoactive component
of tobacco. It motivates smoking by about 1.1 billion people all over the world, representing approximately one-third of the global population aged 15 and over. The addictive power of tobacco is exemplified by the difficulty in quitting. Most attempts to quit smoking fail, and success is achieved only after repeated attempts in the minority of smokers.54
Notes about the scheme
For nicotine and other psychostimulant drugs of abuse, the accumulation of evidence
supports the hypothesis that mesocorticolimbic dopaminergic systems mediate the
reinforcement for continued drug use despite the harmful consequences. The
mesocorticolimbic pathway originates in the ventral tegmental area, innervating the striatum, the amygdala, and the prefrontal cortex. An oversimplification of the standard hypothesis of addiction, and for nicotine in particular, may be summarized as follows:
nicotine elevates dopamine in the nucleus
accumbens, and that elevation reinforces tobacco use. Blocking dopamine release in the nucleus accumbens with antagonists or lesions attenuates the rewarding effects of nicotine, as indicated by reduced self-administration in animals.55 The strongest evidence for the
reinforcing influence of nicotine is that it supports self-administration, which is attenuated by preventing dopaminergic signaling in the nucleus accumbens. Cigarette smoke provides an ideal vehicle for the administration of
nicotine, since it delivers the drug directly to
the lungs, from which it reaches the brain very rapidly as series of boli each time the smoker takes a puff of cigarette smoke. This
administration route serves to maximize the addictive potential of nicotine because it provides a means of frequent and repetitive exposure to the drug in the context of cues that can rapidly develop conditioned or secondary reinforcing properties. Thus, dependence on cigarette smoke represents a particularly potent form of nicotine addiction, which perhaps explains the difficulty many smokers experience when they try to quit the habit.56
Treatment of tobacco dependence involves a combination of behavioral therapies and pharmacological treatment. Pharmacological treatments include nicotine-replacement therapy and non-nicotine medications,
including ‘antidepressants’. To date, the most efficacious ‘antidepressant’ for the treatment of tobacco dependence is bupropion, the efficacy of which is attributed to blockade of dopamine reuptake in the mesolimbic dopaminergic system. This area of the brain is believed to mediate reward for nicotine use and for other drugs of dependence. Nortriptyline, a
tricyclic antidepressant, is a non-selective
norepinephrine reuptake inhibitor. Some anecdotal data suggest that it may have similar beneficial effects as bupropion, at least in long-term abstinence outcomes. However, to date, only nicotine-replacement therapy and
bupropion are approved by the US FDA for the
treatment of tobacco dependence.57
Nortriptyline carries the risk of postural
hypotension, cardiac arrhythmia, and serious toxicity with overdose.58 Clonidine, a central
a2-agonist that enhances the inhibitory effects of
a2-adrenergic auto- and heteroreceptors (with
consequent decreased secretion of
norepinephrine and serotonin from presynaptic nerve terminals), may also be effective in prevention of smoking relapse. However, data concerning its efficacy are limited and not well-established.59
6.11 Abused substances – psilocybin
Supposed mechanism of dependence, withdrawal symptoms, and treatment options