The advances outlined above point the way to future directions for research in the neurocircuitry of addiction in the same conceptual framework of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. The rich resources of modern neurosciences applied to the neurobiology of addiction offer an opportunity to not only understand the neurocircuitry of the addiction process but also to provide the keys to understanding vulnerability and providing treatment for this devastating disease.
In the binge/intoxication stage of the addiction cycle, how neuroplasticity that begins with a change in firing in mesolimbic dopamine neurons during initial drug exposure is translated to engagement of the dorsal striatum, disruption of frontal system function, and recruitment of brain stress systems and results in a residual powerful drive for drug-seeking behavior even months after withdrawal remains to be determined. For example, what is the relationship between vulnerability to impulsivity and subsequent compulsivity in the neuroplasticity of the circuits described above? Such future studies may involve molecular genetic approaches that range from selective breeding to upregulation or knockdown of molecular mechanisms within specific brain circuits using short-hairpin RNA technology.
In the withdrawal/negative affect stage, engagement of the brain stress systems, such as CRF, in animal models needs to be extended to other interactive brain stress systems and explored in human studies. Numerous other neurotransmitter systems that interact with the brain stress system are only now being explored, such as dynorphin, NPY, substance P, nociceptin, and orexin. Virtually unexplored at this stage are human imaging studies of this component of the addiction cycle and human imaging of brain neurotransmitter systems implicated in motivational aspects of drug withdrawal. The development of novel radioactive ligands for human imaging studies that bind to the receptors of the above neurotransmitter systems would be a great boost to the field.
In the preoccupation/anticipation stage, human neuroimaging studies show that the prefrontal cortex (orbitofrontal, medial prefrontal, prelimbic/cingulate) and the basolateral amygdala are critical in drug- and cue-induced craving. Whether such associations reflect a disruption of frontal brain regions secondary to changes in striatal dopamine activity, or alternatively reflect a primary disruption of frontal regions that regulate dopamine cell activity, remains to be determined. New approaches to the study of memory reconsolidation may help elucidate the strong associations between context and drug. The importance in addiction of the interoceptive circuit involving the insula and other regions that most likely interface with the extended amygdala and ventral striatum remains to be determined. The reactivity of these brain circuits may serve as a biomarker to help predict relapse and help predict treatment efficacy. Human post-mortem studies, human laboratory studies, and neurocircuitry studies in parallel animal models will likely yield promising results in this domain.
Finally, molecular and genetic changes that convey the changes in activity of the neurocircuits in all three stages of the addiction cycle described above are only now being elucidated. Changes in transmitter regulatory systems, transcription factors, and even gene regulation at the epigenetic level may explain how circuits are dysregulated, stay dysregulated, and provide vulnerability to dysregulation initially or long into abstinence. Ultimately, neurobiological targets elucidated through the framework of the neurocircuitry of addiction will provide targets for identifying genetic vulnerability in the human population, and genetic vulnerability in the human studies may identify novel targets to be explored at the mechanistic level in animal studies.
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Acknowledgments
This is publication number 20084 from The Scripps Research Institute. Preparation of this work was supported by the Pearson Center for Alcoholism and Addiction Research and National Institutes of Health grants AA12602, AA08459, and AA06420 from the National Institute on Alcohol Abuse and Alcoholism; DA04043, DA04398, and DA10072 from the National Institute on Drug Abuse; DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases; and 17RT-0095 from the Tobacco-Related Disease Research Program from the State of California. We thank Michael Arends and Ruben Baler for their assistance with paper preparation.
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Footnotes
DISCLOSURE
The authors declare no conflicts of interest.
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Figure 1
Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of drugs of abuse. Cocaine and amphetamines activate the release of dopamine in the nucleus accumbens and amygdala through direct actions on dopamine terminals. Opioids activate opioid receptors in the VTA, nucleus accumbens, and amygdala through direct or indirect actions via interneurons. Opioids facilitate the release of dopamine in the nucleus accumbens by an action either in the VTA or the nucleus accumbens, but also are hypothesized to activate elements independent of the dopamine system. Alcohol activates γ-aminobutyric acid-A (GABAA) receptors or GABA release in the VTA, nucleus accumbens, and amygdala by either direct actions at the GABAA receptor or through indirect release of GABA. Alcohol is hypothesized to facilitate the release of opioid peptides in the VTA, nucleus accumbens, and central nucleus of the amygdala. Alcohol facilitates the release of dopamine in the nucleus accumbens through an action either in the VTA or the nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the VTA, nucleus accumbens, and amygdala, either directly or indirectly, through actions on interneurons. Cannabinoids activate cannabinoid CB1 receptors in the VTA, nucleus accumbens, and amygdala. Cannabinoids facilitate the release of dopamine in the nucleus accumbens through an unknown mechanism either in the VTA or the nucleus accumbens. The blue arrows represent the interactions within the extended amygdala system hypothesized to have a key function in drug reinforcement. The medial forebrain bundle represents ascending and descending projections between the ventral forebrain (nucleus accumbens, olfactory tubercle, septal area) and the ventral midbrain (VTA) (not shown in figure for clarity). AC, anterior commissure; AMG, amygdala; ARC, arcuate nucleus; BNST, bed nucleus of the stria terminalis; Cer, cerebellum; C-P, caudate-putamen; DMT, dorsomedial thalamus; FC, frontal cortex; Hippo, hippocampus; IF, inferior colliculus; LC, locus coeruleus; LH, lateral hypothalamus; N Acc., nucleus accumbens; OT, olfactory tract; PAG, periaqueductal gray; RPn, reticular pontine nucleus; SC, superior colliculus; SNr, substantia nigra pars reticulata; VP, ventral pallidum; VTA, ventral tegmental area (taken with permission f
Figure 2
Neural circuitry associated with the three stages of the addiction cycle. (a) Binge/intoxication stage. Reinforcing effects of drugs may engage reward neurotransmitters and associative mechanisms in the nucleus accumbens shell and core and then engage stimulus?response habits that depend on the dorsal striatum. Two major neurotransmitters mediating the rewarding effects of drugs of abuse are dopamine and opioid peptides. (b) Withdrawal/negative affect stage. The negative emotional state of withdrawal may engage the activation of the extended amygdala. The extended amygdala is composed of several basal forebrain structures, including the bed nucleus of the stria terminalis, central nucleus of the amygdala, and possibly a transition zone in the medial portion (or shell) of the nucleus accumbens. Major neurotransmitters in the extended amygdala hypothesized to have a function in negative reinforcement are corticotropin-releasing factor, norepinephrine, and dynorphin. Major projections of the extended amygdala are to the hypothalamus and brainstem. (c) Preoccupation/anticipation (craving) stage. This stage involves the processing of conditioned reinforcement in the BLA and the processing of contextual information by the hippocampus. Executive control depends on the prefrontal cortex and includes representation of contingencies, representation of outcomes, and their value and subjective states (ie, craving and, presumably, feelings) associated with drugs. The subjective effects termed drug craving in humans involve activation in functional imaging studies of the orbital and anterior cingulate cortices and temporal lobe, including the amygdala. A major neurotransmitter involved in the craving stage is glutamate localized in pathways from frontal regions and the BLA that project to the ventral striatum. Green/blue arrows, glutamatergic projections; orange arrows, dopaminergic projections; pink arrows, GABAergic projections; Acb, nucleus accumbens; BLA, basolateral amygdala; VTA, ventral tegmental area; SNc, substantia nigra pars compacta; VGP, ventral globus pallidus; DGP, dorsal globus pallidus; BNST, bed nucleus of the stria terminalis; CeA, central nucleus of the amygdala; NE, norepinephrine; CRF, corticotropin-releasing factor; PIT, Pavlovian instrumental transfer (modified with permission from Koob et al, 2008a).
Figure 3
Brain images obtained at different times after administration for [11C]-methamphetamine and for [11C]cocaine (n=19 for each drug) showing axial planes at a level that transects the basal ganglia. Note the fast uptake of both drugs in the brain and the much slower clearance for [11C]-methamphetamine than for [11C]cocaine (taken with permission from Fowler et al, 2008).
Figure 5
Neurocircuitry schematic illustrating the combination of neuroadaptations in the brain circuitry for the three stages of the addiction cycle that promote drug-seeking behavior in the addicted state. Note the activation of the ventral striatum/dorsal striatum/extended amygdala driven by cues through the hippocampus and basolateral amygdala and stress through the insula. The frontal cortex system is compromised, producing deficits in executive function and contributing to the incentive salience of drugs compared to natural reinforcers. Dopamine systems are compromised, and brain stress systems such as CRF are activated to reset further the salience of drugs and drug-related stimuli in the context of an aversive dysphoric state (modified with permission from Koob et al, 2008a).
Neuron. Author manuscript; available in PMC 2009 September 22.
