Neural Sensitization

Presumably the reason that so many different behaviors and psychological functions can be sensitized by repeated exposure to drugs is that drugs change many different neural systems, neural systems that mediate the behaviors and psychological functions that sensitize (Thomas et al. 2008). Many studies of neural sensitization have focused on ► mesotelencephalic dopamine systems, and a number of sensitization-related changes in dopamine systems have been described, including an increase in stimulated dopa-mine release and striatal D2 receptors (Robinson and Becker 1986; Robinson and Berridge 2008). However, sensitization-related changes have been described in nearly every neurotransmitter system within the relevant mes-encephalic-striatal-amygdala-cortical circuitry, including glutamate, GABA, serotonin, acetylcholine, norepineph-rine, etc. systems, and in a host of intracellular ► signaling cascades. Indeed, sensitization has been associated with changes in patterns of synaptic connectivity in these circuits, suggesting a level of reorganization that may fundamentally and persistently change their operation. Despite considerable research on neural sensitization, cause-effect relations are not well understood. What changes in what neural systems are causally-related to what changes in behavior and psychological function remains a topic of active investigation.

The Induction Versus the Expression of Sensitization

Most major drugs of abuse are capable of inducing sensitization, including psychostimulants (amphetamine, cocaine,

► MDMA, cathinone, fencamfamine, ► methylpheni-date, phenylethylamine, etc.), opiates, ► phencyclidine,

► alcohol, and ► nicotine. Direct agonists that act on the D2 receptor also produce robust psychomotor sensi-tization, although it is not clear the mechanism is the same as with ► drugs of abuse, which influence dopami-nergic activity indirectly. In addition, repeated intermittent exposure to stress can produce cross-sensitization to drugs, and vice versa (Kalivas and Barnes 1988; Stewart and Badiani 1993).

For some drugs it is thought that an action at the level of dopamine cell bodies in the midbrain is necessary to induce sensitization. However, once induced, sensitiza-tion may be expressed by drug actions in structures that receive dopaminergic inputs (Vezina and Leyton 2009). Whatever the case, one remarkable feature of sensitization is that, once induced, it can persist for very long periods of time in the absence of any further exposure to the drug - for weeks, months, or years. The persistence of sensitization depends on many factors, including the drug, the dose, the number of exposures, and the pattern of exposure. Furthermore, sensitization can be induced when a drug is administered by an experimenter, or when it is self-administered, including when it is self-administered under conditions that promote the development of symptoms of addiction (i.e., under extended access conditions).

Modulation of Induction and Expression

Although the repeated, intermittent administration of a number of drugs of abuse may produce sensitization, it is important to emphasize that there are a host of factors that modulate both the induction and expression of sen-sitization. Whether a given dose of a drug induces sensiti-zation, or how robust the effect, is dependent on many factors beside dose and the treatment regimen, including, the strain of the animal, its sex (females generally sensitize more), hormonal status, past experience with ► stress, age, the rate of drug delivery (faster rates produce greater sensitization), and the context in which the drug is administered, amongst others (Badiani and Robinson 2009; Kalivas and Barnes 1988). Indeed, there are large individual differences in susceptibility to sensitization. After neural sensitization is induced there are also a number of factors that determine if it is expressed in behavior at any particular place or time. For example, when an animal that has developed psychomotor sensitization is re-exposed to drug in a context where it has never before experienced drug, sensitization may not be expressed in behavior (this is so-called context-specific sensitization; Fig. 3). Exactly, how contextual factors modulate the expression of sensitization is not well understood. The available data suggest that contexts not associated with drugs may act to actively inhibit expression, perhaps through a kind of inhibitory ► occasion-setting type mechanism. This is because specific ► extinction procedures and ECS can "release" this inhibition so that sensitization is now expressed in a nondrug context (Stewart and Badiani 1993; Vezina and Leyton 2009; Fig. 3). Of course, drug-associated contexts can also elicit drug-like conditioned responses that may add to sensitization effects, but this kind of conditioned response appears to be a different process than contextual modulation of sensitization. Indeed, it may be misleading to speak of "context-specific sensitization'' versus "context-independent sensitization'' as if they represent two different forms of sensitization. It appears there is one form of sensitiza-tion, a nonassociative increase in responsiveness to various stimuli because of changes in the relevant neural systems. However, the expression of sensitization can be powerfully modulated by associative learning, and if it is,

Sensitization to Drugs. Fig. 3. Context-specificity of sensitization (adapted from Vezina and Leyton 2009). Paired rats received amphetamine in the test environment on one day and saline in the home cage (or somewhere else) the following day. Unpaired animals were subjected to the opposite configuration while Control animals received saline in both environments. After repeated treatments, all animals were then administered a challenge injection of the drug in the test environment to assess the expression of sensitization. The results on the left illustrate that sensitization was only expressed in Paired animals. Rats that received the same number of drug injections but explicitly Unpaired with the test environment showed levels of responding similar to animals receiving the drug for the first time (controls). Evidence that this is due to Conditioned Inhibition of the expression of sensitization in Unpaired rats comes from the finding that after these rats were subjected to a procedure known to extinguish Conditioned Inhibition (but spare conditioned excitation), they now expressed sensitization (right panel). This suggests that the failure of unpaired animals to express sensitization in the first test was due to some form of conditioned inhibition (see Vezina and Leyton 2009 for further discussion).

sensitization may be expressed only under specific conditions. How contextual factors (and other stimuli) modulate the expression of sensitization is an important (but little investigated) topic, because of the potential importance of such factors in relapse. Addicts are much more prone to ► relapse in contexts associated with drugs than in other contexts. This may be related not only to the ability of drug-associated contexts to evoke conditioned responses, which is well-documented, but also because context can gate the expression of sensitization. Thus, conditions that promote the expression of neural sensiti-zation in behavior may also promote relapse, whereas conditions that inhibit the expression of sensitization may inhibit the propensity to relapse. For this reason a better understanding of factors that modulate the induction and expression of sensitization (especially incentive sensitization) may prove useful in developing treatments for addiction (Robinson and Berridge 2008; Stewart and Badiani 1993; Vezina and Leyton 2009).

Sensitization in Humans

By necessity, most research on sensitization has involved preclinical studies in nonhuman animals. However, it is worth noting that similar effects have been described in humans (Leyton 2007). As mentioned above, it has long been recognized that the psychotomimetic effects of psychostimulant drugs sensitize, as does their ability to produce complex stereotyped behavioral patterns (in humans this is called "punding"). Indeed, sensitization of psy-chotomimetic effects has been interpreted as involving sensitization of incentive salience, whereby otherwise innocuous stimuli in the environment acquire pathological importance (Featherstone et al. 2007). In addition, there are now a number of reports that repeated exposure to amphetamine induces both behavioral sensitization (e.g., increased eye-blink responses, vigor, and energy ratings), and neural sensitization (e.g., an increase in evoked dopamine "release" as indicated by raclopride displacement). Finally, as in nonhuman animals, the expression of

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