Drug Tolerance Dependence And Withdrawal

From a clinical standpoint, withdrawal can be one of the most powerful factors driving dependence and addictive behaviors. This seems particularly true for opioids, alcohol, benzodiazepines, nicotine, and to a lesser extent stimulants such as cocaine. For hallucinogens, cannabinoids, or inhalants, withdrawal symptoms seem of more limited importance. Treatment of the patient's withdrawal symptoms is based on understanding how withdrawal is related to the brain's adjustment to these drugs after chronic repeated high doses.

Repeated exposure to escalating dosages of most drugs alters the brain, so that it functions more or less normally when the drugs are present and abnormally when they are not. Two clinically important results of this alteration are drug tolerance (the need to take higher and higher dosages of drugs to achieve the same effect) and drug dependence (susceptibility to withdrawal symptoms). Withdrawal symptoms occur only in patients who have developed tolerance.

Tolerance occurs because the brain cells that have receptors or transporters on them gradually become less responsive to the stimulation by the exogenous substances. For example, more opioid is needed to inhibit the cyclic AMP system in the N-Ac neurons, as well as to stimulate the VTA brain cells of the mesolimbic reward system to release the same amount of DA in the N-Ac. Therefore, more opioid is needed to produce pleasure comparable to that provided in previous drug-taking episodes. The mechanism for this reduction in response is related to the cyclic AMP coupling for opioids, but direct reductions in the number of receptors or increases in the number of transporters can occur. For example, it appears that after chronic cocaine inhibition of the DA transporter, the number of DA receptors decreases, while the number of transporters may increase to compensate for this chronic overstimulation of the N-Ac DA receptors and chronic inhibition of the transporter (Kosten, 2002). These changes associated with tolerance might be considered an attempt by the brain to attain relative homeostasis in the face of the disruption induced by these abused drugs. Tolerance to alcohol may be due to a more complex series of neu-robiological changes at the neuronal and molecular levels, and involve GABA, opioid, DA, and other neurochemical systems, including the excitatory amino acid neurotransmitters such as glutamate and its multiplicity of receptor subtypes (Fadda & Rossetti, 1998). Tolerance to cannabinoids probably has a similar mechanism to opioids, since the cannabinoid CBt receptor is also a G-protein-coupled, cyclic AMP type receptor (Kosten, 2000; Stahl, 1998). Tolerance to hallucinogens such as lysergic acid (LSD) probably involves changes in the serotonergic 5HT2 receptors, which involve the phosphoinositol phosphate (PIP) second messenger system, but this system's relationship to chronic LSD use has not been as extensively studied as the cyclic AMP system for the opioids and cannabinoids (Kosten, 2000).

Opioids provide an outstanding example to illustrate how the neurobiolo-gical changes associated with tolerance are related to dependence and withdrawal symptoms. Opioid dependence and some of the most distressing opioid withdrawal symptoms stem from changes in the locus coeruleus (LC), another important brain system at the base of the brain (Figure 1.2). Neurons in the LC produce noradrenaline (NA) and widely distribute it to other parts of the brain including the cerebral cortex, brainstem, and various subcortical regions, where

A. Baseline

B. Acute opioid inhibition of converting enzyme

0. Discontinuing opioid leads to increased cyclic AMP due to loss of inhibition by opioid

C. Chronic opioid leads to increased converting enzyme activity

FIGURE 1.2. Neuronal coupling of receptor to G protein and adenyl cyclase (converting enzyme) at baseline (Panel A), changes during acute opiate effects (Panel B), changes after chronic opiate use (Panel C), and changes during acute opiate withdrawal (Panel D). After "resetting" of opiate receptors with naltrexone, the number of receptors appears to increase to match the increased converting enzyme activity (see text).

A. Baseline

Outside Neuron

Neuron cell wall opiate receptor Converting enzyme

Inside Neuron

0. Discontinuing opioid leads to increased cyclic AMP due to loss of inhibition by opioid

Inside Neuron

C. Chronic opioid leads to increased converting enzyme activity

Outside Neuron

Neuron cell wall opiate receptor Converting enzyme

B. Acute opioid inhibition of converting enzyme

Morphine

Morphine

FIGURE 1.2. Neuronal coupling of receptor to G protein and adenyl cyclase (converting enzyme) at baseline (Panel A), changes during acute opiate effects (Panel B), changes after chronic opiate use (Panel C), and changes during acute opiate withdrawal (Panel D). After "resetting" of opiate receptors with naltrexone, the number of receptors appears to increase to match the increased converting enzyme activity (see text).

it stimulates wakefulness, breathing, blood pressure, and general alertness, among other functions. When opioid molecules link to mu receptors on brain cells in the LC, they suppress the neurons' release of NA, resulting in drowsiness, slowed respiration, and low blood pressure—familiar effects of opioid intoxication. With repeated exposure to opioids, however, LC neurons adjust by increasing their level of activity. Now, when opioids are present, their sup-pressive impact is offset by this heightened activity, with the result that roughly normal amounts of NA are released and the patient feels more or less normal. When opioids are not present to suppress the LC brain cells' enhanced activity, however, the neurons release excessive amounts of NA, triggering jitters, anxiety, muscle cramps, and diarrhea. Figure 1.2 illustrates this development of opiate tolerance and withdrawal.

Other brain areas in addition to the LC also contribute to the production of opiate withdrawal symptoms, including the mesolimbic reward system. For example, opioid tolerance that reduces the VTA's release of DA into the N-Ac may prevent the patient from obtaining pleasure from normally rewarding activities such as eating. These changes in the VTA and the DA reward systems, though not fully understood, form an important brain system underlying craving and compulsive drug use.

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