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Withdrawal Syndromes. Fig. 1. Global behavioral analysis of naloxone-precipitated opiate withdrawal. The upper panel (curves) shows the expression of two groups of somatic signs of withdrawal (means ± SEM) in response to naloxone injections at the following doses: 0, 10, 15, 50, 100 and 1,000mg/kg. The first group is represented by the blue curve that fits the means of the signs showing an ED50 below 20mg/kg (body shake, mastication, writhing, and vocalization). The second group is represented by the red curve that fits the means of the signs showing an ED50 above 20mg/kg (weight loss, jumping, diarrhea, and salivation). The global ED50 values corresponding to the first and the second group of somatic signs were respectively 10.2 and 36.7mg/kg. The lower panel (histogram) shows the expression of naloxone-induced conditioned place aversion using the following doses of naloxone during the conditioning phase: 0, 1.8, 3.75, 7.5, 15, 30 and 120mg/kg. Each bar represents the aversion score (means ± SEM) for one arm of an unbiased Y-maze, which had been previously paired with a naloxone injection during the conditioning phase (brown histograms illustrate significant aversions). Adapted from Frenois et al. (2005).

according to a scale designed by Malin et al. (1992). No scale exists for psychostimulants, as somatic symptoms from psychostimulants have not yet been reported.

Neural Circuits and Neurotransmitters Involved

The expression ofawithdrawal syndrome is the consequence of neuroadaptations, which have been engendered by continuous/repeated drug exposure. These neuroadaptations can take place within the brain system on which the drug is acting directly (within system adaptations) and lead, for instance, to decreased or increased sensitivity and/or number of receptors, and increased or decreased release of the neurotransmitter, which activates these receptors endog-enously. These neuroadaptations can also take place in systems different from the one on which the drug is acting directly (between system adaptations), which are often counteracting the drug effects. These within- and between-system adaptations might develop with very different kinetics and may follow one after the other. Some of them are directly responsible for the onset of the behavioral manifestations of withdrawal but others can be very long lasting and persist long after the drug is cleared and the overt signs of withdrawal have disappeared (Koob et al. 1989).

Using the different behavioral paradigms mentioned above, the neural substrates of withdrawal syndromes have been studied using different approaches such as brain site-specific injections of drug antagonist, c-fos imaging, and knockout mice (KO) for specific receptors. A brief synthesis of the findings related to the neurobiological substrates of the withdrawal syndrome is given below.

Brain structures involved: One of the major findings related to drug withdrawal is the dissociation between the neural systems involved in the motivational and somatic components of withdrawal. In terms of brain structures, it has been shown that limbic structures encompassing the nucleus accumbens, amygdala, BNST and prefrontal cortex are involved in the negative affective part of withdrawal from drugs like opiates, cocaine, alcohol, and nicotine, whereas other structures such as the locus coeruleus and the periacqueductal grey (PAG) are involved in the somatic aspect of withdrawal. Using intracerebral injections of either ► opiate receptor antagonists (naloxone or methynaloxonium), ► nicotinic receptor antagonists (mecamylamine, and dihydro-beta-erythroidine), or

► cannabinoid receptor antagonists (SR141716A or AM251), negative affective states are produced and expressed, either by conditioned place aversion, increased anxiety, and increased threshold for ICSS (reviews, Koob et al. 1992 for opiates; Kenny and Markou 2001 for nicotine; Tanda and Goldberg 2003 for cannabinoids). However when the antagonists were injected in other structures such as the locus coeruleus (for opiates), somatic signs emerged even with low doses (Koob et al. 1992). These data were corroborated by c-fos imaging data showing that with low doses of antagonists, limbic structures were activated (among them the central nucleus of the amygdala has been shown to be activated with all drug withdrawal), whereas with higher doses leading to the expression of somatic signs, structures such as the locus coeruleus or PAG are activated (for example, see Frenois et al. 2005 for opiate withdrawal.).

Neurotransmitters and receptors involved: KO mice have been used for different types of receptors, showing that opiate mu-receptor KO mice do not show opiate withdrawal and cannabinoid CB1 receptor KO mice do not show THC withdrawal. Regarding nicotinic receptor KO mice, there is some evidence that some receptor subtypes are involved in the motivational component (a4b2) while others are involved in the physical component (a5b4) of withdrawal. However, available data are conflicting and there is at present no consensus over the role of receptor subtypes in nicotine withdrawal. Among neurotransmitters,

► corticotropin-releasing factors (► CRF) and ► dopa-mine have been repeatedly involved in the negative affective state associated with withdrawal. Peripheral administration of a CRF antagonist blocks the conditioned place aversion produced by either opiate withdrawal, nicotine withdrawal, or alcohol withdrawal. This effect takes place principally at the level of the central nucleus of the amygdale (CEA) where local CRF receptor antagonist administration (principally CRF1 receptor) diminishes the negative affective state of opiate- nicotine- and alcohol-withdrawal, using CPA, ICSS or anxiety measures (Koob 2008). Thus, intra-amygdala injection of CRF precipitates a negative affective state in opiate-, nicotine-, and alcohol-dependent rats. In rodents, during nicotine-, alcohol-, opiate- and cannabinoid-withdrawal, CRF neurotransmission is increased (review Koob 2008). This CRF neurotransmission involvement which has for long been related to the stress system and the stress response may participate in the anxiogenic aspect of withdrawal.

Dopamine release is decreased in the nucleus accumbens during withdrawal from cocaine, opiate, nicotine, alcohol, and cannabinoid. This reduced release of dopamine may explain the decreased sensitivityto rewards, as demonstrated using ICSS or sweet solution consumption. However, this might be over-simple as, for example, a lesion of dopamine neurons does not modify the affective and somatic aspects of withdrawal (Caille et al. 2003).

Besides dopamine, other monoamines have also been involved. It has been suggested that noradrenergic functional antagonists can block some aspects of ethanol or nicotine withdrawal (Koob 2008 for alcohol). However, a noradrenergic lesion did not block opiate withdrawal, whereas clonidine (alpha2 agonist) abolished the negative affective state of opiate withdrawal and some (but not all) aspects of somatic withdrawal.

Other neurotransmitters have also been involved, though data are still incomplete. For instance, an increase in glutamatergic neurotransmission has been associated with opiate withdrawal and dynorphin neurotransmission has also been proposed to mediate the negative state of drug withdrawal (Koob 2008).

It is clear that our understanding of the behavioral and neurobiological effects of drug withdrawal is far from complete, though it is progressing rapidly. Using behavioral and neurobiological screening, systematic comparisons among withdrawal from different drugs should bring important information about potential therapeutic targets that can ameliorate withdrawal states and maintain abstinence.

Cross-References

► Addictive Disorder: Animal Models

► Cannabinoids

► Classical Conditioning

► Conditioned Place Preference and Aversion

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