Conditioned cues and the expression of stimulant sensitization in animals and humans

Abstract

Repeated intermittent exposure to psychostimulants can lead to long-lasting sensitization of the drugs' behavioral and biochemical effects. Such findings have figured importantly in recent theories of drug addiction proposing that sensitized nucleus accumbens (NAcc) dopamine (DA) overflow in particular acts in concert with other alterations in the neurochemistry of this nucleus to promote drug seeking and self-administration. Yet, experiments in rodents, nonhuman primates and humans have not always detected behavioral or biochemical sensitization following drug exposure, bringing into doubt the utility of this model. In an effort to reconcile apparent discrepancies in the literature, this review assesses conditions that might affect the expression of sensitization during testing. Specifically, the role played by conditioned cues is reviewed. A number of reports strongly support a potent and critical role for conditioned stimuli in the expression of sensitization. Findings suggest that stimuli associated either with the presence or absence of drug can respectively facilitate or inhibit sensitized responding. It is concluded that the presence or absence of such stimuli during testing for sensitization in animal and human studies could significantly affect the results obtained. It is necessary to consider this possibility especially when interpreting the results of studies that fail to observe sensitized responding.Keywords conditioned inhibition; conditioning; dopamine; drug addiction; drug self-administration; excitatory Pavlovian conditioning; facilitation; occasion setters; sensitization Sensitization in animals and humansThere is general agreement that rats repeatedly exposed to psychostimulants like amphetamine will exhibit enhanced -sensitized -locomotor responding when subsequently challenged with the drug some time later. In these animals, the reactivity of mesoaccumbens dopamine (DA) neurons to the drug challenge is also enhanced (for critical reviews of the preclinical literature, see Kalivas and Stewart, 1991;Vanderschuren and Kalivas, 2000;Vezina, 2004). These are long-lasting effects in the rat. Sensitized locomotor responding has been reported up to one year (Paulson et al., 1991) and enhanced nucleus accumbens (NAcc) DA overflow up to three *Correspondence: Department of Psychiatry The University Of Chicago 5841 S. Maryland Avenue, MC3077 Chicago, IL 60637 TEL: 773/702-2890 FAX: 773/702-0857 E-MAIL: pvezina@yoda.bsd.uchicago.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptNeuropharmacology. Author manuscript; av...

Altered Acquisition and Extinction of Amphetamine-Paired Context Conditioning in Genetic Mouse Models of Altered NMDA Receptor Function

“…(Stewart and Vezina, 1991;Anagnostaras and Robinson, 1996;Mattson et al, 2008). The ability of that conditioned stimulus (drug-paired context) to produce a conditioned response (hyperactivity) on its own and still control the response to the unconditioned stimulus (drug exposure) after extinction of the conditioned response is consistent with theories that environment can serve as both an excitatory conditioned stimulus and an occasion setter (Vezina and Leyton, 2009). The degree to which these actions are separable and are regulated by independent neurocircuitry is open to speculation, but the demonstration that the spine density increases in the NAc are reversed by extinction suggests that this site may selectively regulate the excitatory conditioned stimulus properties.…”

“…Repeated intermittent psychostimulant exposure results in behavioral sensitization, often measured as an increased efficacy of that drug to stimulate locomotor activity (Vezina and Leyton, 2009). The acquisition of sensitization is facilitated by associative learning that links a specific context to drug exposure (Badiani et al, 1995).…”

Drug-Paired Contextual Stimuli Increase Dendritic Spine Dynamics in Select Nucleus Accumbens Neurons

“…Intermittent exposure, especially to psychostimulants like amphetamine and cocaine, is known to produce sensitization (Vezina, 2004), but as drugs are typically administered in the presence of a vast number of disparate environmental stimuli, the formation of multiple conditioned drug-stimulus associations is also ensured (Vezina and Leyton, 2009). Therefore, a major challenge for characterizing the neuroadaptations underlying associative conditioning is to study this form of plasticity in isolation.…”

“…This leads to the development of conditioned drugseeking behavior in the presence of cues, thereby increasing chances of reinforcement. Interestingly, the development of associative conditioning parallels the formation of nonassociative sensitized behavioral and neurochemical responding to amphetamine (Singer et al, 2009(Singer et al, , 2014aVezina and Leyton, 2009) and both have been implicated in escalated drug use in humans and animal models Vezina, 2013, 2014).…”

Repeated administration of caffeine induces either sensitization or tolerance of locomotor stimulation depending on the environmental context

“…Sensitization to amphetamine or cocaine is easily observed when the drug is injected in an environmental context different from that of the home cage [4,38]. Moreover, the sensitization is more robust if the locomotor effects of these drugs are tested in the same context (paired environment) as in previous administrations [2,25,48].…”