Trends in Neurosciences
ReviewNeurobiology of the incubation of drug craving
Introduction
Relapse to drug use in humans can occur after prolonged abstinence [1] and is often precipitated by exposure to drug-associated cues that provoke drug craving [2] (see Glossary). In an attempt to account for this persistent relapse, it was hypothesized that cue-induced cocaine craving progressively increases over the first weeks of abstinence and remains high over extended periods [3]. An analogous incubation phenomenon, termed ‘incubation of drug craving’ [4], was subsequently identified in rats, based on observations that time-dependent increases in cue-induced cocaine or heroin seeking occurred after withdrawal from the drug 4, 5, 6.
Incubation of craving has also been observed in rats with a history of methamphetamine [7], alcohol [8], nicotine [9] or oral sucrose self-administration 10, 11 (Figure 1; see [12] for an early demonstration of ‘incubation of food craving’). Such a phenomenon has been demonstrated using several established procedures to assess the motivational impact of reward cues and cue-induced relapse to drug seeking 13, 14, 15, including extinction 16, 17, 18, 19, cue-induced reinstatement 4, 8, 9, 20, 21 and acquisition of a new response [22].
In humans, drug craving is induced not only by drug cues, but also by re-exposure to the drug itself or exposure to stress 23, 24. These stimuli are known to cause reinstatement of drug seeking in non-human laboratory animals 25, 26, 27, 28, 29; however, unlike drug cues, evidence for ‘incubation’ of the response of the rat to drug re-exposure (often termed ‘drug priming’) is mixed, with reports of time-dependent increases [30], decreases [31] or no change 18, 32 in cocaine priming-induced reinstatement of drug seeking. However, there is evidence for time-dependent changes in intermittent footshock stress-induced reinstatement after withdrawal from heroin or cocaine 6, 17. This ‘stress incubation’ effect, however, was not observed in reinstatement of methamphetamine seeking by the pharmacological stressor yohimbine [7].
Several factors influence the magnitude of incubation of cocaine craving in rodents, including age, housing conditions, exercise and sex hormones. Incubation of craving was observed to be weaker in adolescent rats than in adult rats [33]. Housing in an enriched environment during abstinence was found to decrease the magnitude of incubation of craving for cocaine in rats 34, 35 (see also [36] for similar results observed for the reinstatement of sucrose seeking). Exercise during abstinence decreased extinction responding and cue-induced reinstatement of cocaine seeking in rats [37] under self-administration training conditions that led to incubation of cocaine craving [38]. Finally, incubation of cocaine craving was more pronounced in female rats during estrus than in non-estrus females or in males [39].
In this review, we discuss recent studies that have investigated neurobiological mechanisms underlying the incubation of drug craving. Earlier studies on the incubation of cocaine craving have been covered in previous reviews [40]. Because of space limitations, we do not review correlational studies in which changes in gene expression and proteins were assessed in the absence of experimental manipulations to assess a causal role of the molecular changes in incubation of craving for cocaine 41, 42, 43, 44, 45 or other drugs 9, 46, 47, 48, 49.
Section snippets
Brain regions and molecular mechanisms involved in the incubation of drug craving
Many studies using animal models indicate that the mesocorticolimbic dopamine system and the nigrostriatal dopamine system both contribute to cue-induced cocaine seeking 14, 50, 51 and other behavioral effects of cocaine, including cocaine reward 52, 53. The mesocorticolimbic dopamine system is comprised of cell bodies in the ventral tegmental area (VTA) that project to many forebrain areas, including the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and amygdala, whereas the
Concluding remarks
In this review, we have discussed recent findings that have advanced understanding of neural mechanisms underlying the incubation of drug craving. These studies indicate that signaling pathways in the VTA that are downstream of the neurotrophins BDNF and GDNF play an important role in the incubation of cocaine craving. There is also evidence that neuronal activation of the ventral mPFC and ERK activation in the CeA mediate this incubation. Finally, results from several recent studies indicate
Acknowledgments
The writing of this review was supported (in part) by the Intramural Research Program of the NIH, NIDA. We thank Marina Wolf and Kuei Tseng for helpful comments, and Aldo Badiani for providing the template for Figure 2.
Glossary
- Acquisition of a new response
- a procedure in which an animal learns to make a new operant response (e.g. a lever press) reinforced solely by a cue previously paired with a reward (e.g. drug) earned by performing a different operant response (e.g. a nose poke).
- Conditioned place preference (CPP)
- a classical (Pavlovian) conditioning procedure in which one distinct context is paired with drug injections, while another context is paired with vehicle injections. During a subsequent drug-free test, the
References (118)
The anxiogenic drug yohimbine reinstates methamphetamine seeking in a rat model of drug relapse
Biol. Psychiatry
(2004)Time-dependent changes in alcohol-seeking behaviour during abstinence
Eur. Neuropsychopharmacol.
(2004)Incubation of sucrose craving: effects of reduced training and sucrose pre-loading
Physiol. Behav.
(2005)Neural substrates of cocaine–cue associations that trigger relapse
Eur. J. Pharmacol.
(2005)- et al.
Conditioned reinforcing properties of stimuli paired with self-administered cocaine, heroin or sucrose: implications for the persistence of addictive behaviour
Neuropharmacology
(2004) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications
Eur. J. Pharmacol.
(2005)Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system
Neuropharmacology
(2004)- et al.
Time-dependent increases in cue-induced reinstatement of sucrose seeking after sucrose self-administration in adolescence
Behav. Brain Res.
(2010) The interactive effects of environmental enrichment and extinction interventions in attenuating cue-elicited cocaine-seeking behavior in rats
Pharmacol. Biochem. Behav.
(2011)Aerobic exercise attenuates reinstatement of cocaine-seeking behavior and associated neuroadaptations in the prefrontal cortex
Biol. Psychiatry
(2010)
Incubation of cocaine craving after withdrawal: a review of preclinical data
Neuropharmacology
Heroin self-administration: II. CNS gene expression following withdrawal and cue-induced drug-seeking behavior
Pharmacol. Biochem. Behav.
Parallel and interactive learning processes within the basal ganglia: relevance for the understanding of addiction
Behav. Brain Res.
The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?
Neurosci. Biobehav. Rev.
Roles for nigrostriatal-not just mesocorticolimbic-dopamine in reward and addiction
Trends Neurosci.
Role of ventral medial prefrontal cortex in incubation of cocaine craving
Neuropharmacology
Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior
Neuron
Dorsal striatum mediation of cocaine-seeking after withdrawal from short or long daily access cocaine self-administration in rats
Behav. Brain Res.
Mitogen-activated protein kinases in synaptic plasticity and memory
Curr. Opin. Neurobiol.
Role of ERK in cocaine addiction
Trends Neurosci.
ERK2: a logical AND gate critical for drug-induced plasticity?
Curr. Opin. Pharmacol.
Neurotrophic factors and structural plasticity in addiction
Neuropharmacology
Role of BDNF and GDNF in drug reward and relapse: a review
Neurosci. Biobehav. Rev.
Brain-derived neurotrophic factor and cocaine addiction
Brain Res.
Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving
Biol. Psychiatry
Neurotrophin trafficking by anterograde transport
Trends Neurosci.
Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving
Biol. Psychiatry
The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity
Neuron
Regulation of Ca21-permeable AMPA receptors: synaptic plasticity and beyond
Curr. Opin. Neurobiol.
AMPA receptor plasticity in the nucleus accumbens after repeated exposure to cocaine
Neurosci. Biobehav. Rev.
The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants
Prog. Neurobiol.
Glutamate receptors on dopamine neurons control the persistence of cocaine seeking
Neuron
Projections of the medial and lateral prefrontal cortices to the amygdala: a Phaseolus vulgaris leucoagglutinin study in the rat
Neuroscience
Relapse rates in addiciton programs
J. Clin. Psychol.
Classical conditioning in drug dependent humans
Ann. N. Y. Acad. Sci.
Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations
Arch. Gen. Psychiatry
Incubation of cocaine craving after withdrawal
Nature
Fos protein expression and cocaine-seeking behavior in rats after exposure to a cocaine self-administration environment
J. Neurosci.
Time-dependent changes in extinction behavior and stress-induced reinstatement of drug seeking following withdrawal from heroin in rats
Psychopharmacology
Incubation of nicotine seeking is associated with enhanced protein kinase A-regulated signaling of dopamine- and cAMP-regulated phosphoprotein of 32 kDa in the insular cortex
Eur. J. Neurosci.
Effect of cocaine and sucrose withdrawal period on extinction behavior, cue-induced reinstatement, and protein levels of the dopamine transporter and tyrosine hydroxylase in limbic and cortical areas in rats
Behav. Pharmacol.
The change with time of a Thorndikian response in the rat
J. Exp. Psychol.
Neural systems of reinforcement for drug addiction: from actions to habits to compulsion
Nat. Neurosci.
Neurobiology of relapse to heroin and cocaine seeking: a review
Pharmacol. Rev.
Cocaine-associated stimuli increase cocaine seeking and activate accumbens core neurons after abstinence
J. Neurosci.
Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement
Neuropsychopharmacology
Cocaine seeking over extended withdrawal periods in rats: different time courses of responding induced by cocaine cues versus cocaine priming over the first 6 months
Psychopharmacology
Cue-induced cocaine seeking and relapse are reduced by disruption of drug memory reconsolidation
J. Neurosci.
Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving
J. Neurosci.
AMPA-receptor GluR1 subunits are involved in the control over behavior by cocaine-paired cues
Neuropsychopharmacology
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These authors contributed equally to this review.