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In the central nervous system (CNS), excitatory neurons fire regularly, and inhibitory neurons inhibit the transmission of these impulses. Whenever action is required, the inhibitory tone diminishes, permitting the excitatory nerve impulses to travel to their end organs. Thus, all action in human neurophysiology can be considered to result from disinhibition.56,104,108


Tonic neurological activity of a xenobiotic produces an adaptive change in affected neurons. For example, tonic stimulation of inhibitory neurons reduces their activity so that the baseline level of function is regained. A withdrawal syndrome occurs when the constant presence of this xenobiotic is removed or reduced and the adaptive changes persist. In this example withdrawal produces a dysfunctional condition in which inhibitory neurotransmission is significantly reduced, essentially producing excitation (Fig. 14–1). Every withdrawal syndrome has two characteristics: (1) a pre-existing physiologic adaptation to a xenobiotic, the continuous presence of which prevents withdrawal, and (2) decreasing concentrations of that xenobiotic. In contrast, simple tolerance to a xenobiotic is characterized as a physiologic adaptation that shifts the dose–response curve to the right; that is, greater amounts of a xenobiotic are required to achieve a given effect. Patients with withdrawal syndromes have often developed tolerance, but tolerance does not require the continued presence of the xenobiotic to prevent withdrawal.41,93

Figure 14–1.
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Alcohol intoxication, tolerance, and withdrawal. Alcohol consumption in alcohol-naive persons produces intoxication and sedation by simultaneous agonism at the γ-aminobutyric acid (GABA) receptor–chloride channel complex and antagonism at the N-methyl-D-aspartate (NMDA)-glutamate receptor. Continuous alcohol consumption leads to the development of tolerance through changes in both the GABA receptor–chloride channel complex (a subunit shift from α1 to α4 results in reduced sensitivity to the sedating effects of alcohol) and the NMDA subtype of glutamate receptor (upregulation in number, resulting in enhanced wakefulness). There is conceptually a concentration at which the tolerant patient may appear clinically normal despite having an elevated blood alcohol concentration. Tolerant patients who are abstinent lose the tonic effects of alcohol on these receptors, resulting in withdrawal.


The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) provides a helpful and descriptive set of criteria that mesh with our understanding of the pathophysiology of withdrawal syndromes.32 According to DSM-IV, withdrawal is manifested by either of the following: (1) a characteristic withdrawal syndrome for the substance or (2) the same (or a closely related) substance is taken to relieve withdrawal symptoms. Note that either criterion fulfills this definition. Logically, all syndromes have the first criterion, so it is the presence of the second criterion that is critical to understanding physiology and therapy.


For the purposes of defining a unifying pathophysiologic pattern of withdrawal syndromes, this chapter considers syndromes in which both features are present. An analysis from this perspective distinguishes xenobiotics that affect the inhibitory neuronal pathways from those ...

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