Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

Everitt, Barry J.; Belin, David; Economidou, Daina; Pelloux, Yann; Dalley, Jeffrey W.; Robbins, Trevor W.

doi:10.1098/rstb.2008.0089

Cited by 882 publications

(709 citation statements)

References 93 publications

(146 reference statements)

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“…Our results, obtained after 13 weeks of nicotine administration, are consistent with previous reports of elevated Met-enkephalin in the striatum following nicotine treatment for periods of 2 weeks, which was measured using immunoassay (15). These results parallel the persistent activation of the DS during long term nicotine exposure or the preoccupation/craving stage of drug dependence (5,45), and the results further support a close functional link between dopamine and enkephalin systems, which are both under the regulation of nicotine (46). Enhancements of the remaining three PENK peptides have not been previously reported and suggest a broader involvement of the PENK pathway than has not been previously uncovered using immunoassay.…”

Section: Table I Changed Prohormone-derived Peptides and Unchanged Knsupporting

confidence: 91%

Chronic Nicotine Treatment Impacts the Regulation of Opioid and Non-opioid Peptides in the Rat Dorsal Striatum

Petruzziello

Falasca

Andrén

et al. 2013

Molecular & Cellular Proteomics

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The chronic use of nicotine, the main psychoactive ingredient of tobacco smoking, alters diverse physiological processes and consequently generates physical dependence. To understand the impact of chronic nicotine on neuropeptides, which are potential molecules associated with dependence, we conducted qualitative and quantitative neuropeptidomics on the rat dorsal striatum, an important brain region implicated in the preoccupation/ craving phase of drug dependence. We used extensive LC-FT-MS/MS analyses for neuropeptide identification and LC-FT-MS in conjunction with stable isotope addition for relative quantification. The treatment with chronic nicotine for 3 months led to moderate changes in the levels of endogenous dorsal striatum peptides. Five enkephalin opioid peptides were up-regulated, although no change was observed for dynorphin peptides. Specially, nicotine altered levels of nine non-opioid peptides derived from precursors, including somatostatin and cerebellin, which potentially modulate neurotransmitter release and energy metabolism. This broad but selective impact on the multiple peptidergic systems suggests that apart from the opioid peptides, several other peptidergic systems are involved in the preoccupation/craving phase of drug dependence. Our finding permits future evaluation of the neurochemical circuits modulated by chronic nicotine exposure and provides a number of novel molecules that could serve as potential therapeutic targets for treating drug dependence. Molecular & Cellular

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Section: Table I Changed Prohormone-derived Peptides and Unchanged Knsupporting

confidence: 91%

Chronic Nicotine Treatment Impacts the Regulation of Opioid and Non-opioid Peptides in the Rat Dorsal Striatum

Petruzziello

Falasca

Andrén

et al. 2013

Molecular & Cellular Proteomics

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“…Although we have demonstrated that phasic dopamine release does indeed develop at a later stage of drug use in the DLS than in the VMS, the training regimen used typically is not sufficient to produce compulsive responding or the significant escalation of drug intake that emerges following extended or long-access training in drug self-administration (31,32). Thus, our data demonstrate that the engagement of DLS dopamine, which is thought to be linked closely to stimulus-response processing (13), is not sufficient to account for the loss of control over drug intake characteristic of addiction, underlining the important dissociation between the habitual and compulsive stages of drug taking and their neural substrates (33). In fact, the behavioral measure that most closely correlated with the emergence of phasic dopamine release in the DLS was the efficiency of response, that is, the number of active nose-poke responses as a proportion of the total number of responses (including time-out responses and responses in the inactive port).…”

Section: Dopamine Signaling In the Sensorimotor Striatum Emerges Beforementioning

confidence: 75%

“…Together with our study, these findings underline the functional significance of the network interaction between the VMS and the DLS in drugrelated behavior. Specifically, they indicate that this circuit is used for multiple, related processes in the procurement of drugs, both in prioritization of drug-taking behavior and the exploitation of a drug environment in animals with a moderate drug history (present study) and in energizing and driving drug-seeking behavior in an environment where the drug is not readily available in animals with an extended drug-taking history (33). Therefore, the hierarchical recruitment of striatal subregions for dopaminemediated control of behavior may signify an overarching organizing principle throughout the stages of drug use to enable representation of drug cues in DLS.…”

Section: Dopamine Signaling In the Sensorimotor Striatum Emerges Beforementioning

confidence: 84%

Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

Willuhn

Burgeno

Everitt

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

233

210

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Drug addiction is a neuropsychiatric disorder that marks the end stage of a progression beginning with recreational drug taking but culminating in habitual and compulsive drug use. This progression is considered to reflect transitions among multiple neural loci. Dopamine neurotransmission in the ventromedial striatum (VMS) is pivotal in the control of initial drug use, but emerging evidence indicates that once drug use is well established, its control is dominated by the dorsolateral striatum (DLS). In the current work, we conducted longitudinal neurochemical recordings to ascertain the spatiotemporal profile of striatal dopamine release and to investigate how it changes during the period from initial to established drug use. Dopamine release was detected using fast-scan cyclic voltammetry simultaneously in the VMS and DLS of rats bearing indwelling i.v. catheters over the course of 3 wk of cocaine self-administration. We found that phasic dopamine release in DLS emerged progressively during drug taking over the course of weeks, a period during which VMS dopamine signaling declined. This emergent dopamine signaling in the DLS mediated discriminated behavior to obtain drug but did not promote escalated or compulsive drug use. We also demonstrate that this recruitment of dopamine signaling in the DLS is dependent on antecedent activity in VMS circuitry. Thus, the current findings identify a striatal hierarchy that is instantiated during the expression of established responses to obtain cocaine. D rug use often begins as a recreational behavior driven by the rewarding properties of the abused drug. However, addiction is characterized by habitual and compulsive drug use in which other factors, such as withdrawal symptoms, stress, and drug-associated conditioned stimuli (CS), also contribute to the motivation to consume drugs, and drug taking becomes increasingly prioritized over other behaviors (1). A wealth of evidence shows that the mesolimbic dopamine projection from the ventral tegmental area to the ventromedial striatum (VMS) is central to drug reinforcement (2). The ambient concentration of dopamine in the VMS is increased when animals self-administer drugs of abuse, including cocaine (3), and animals maintain this elevated dopamine level by regulating their rate of responding for drug (4). In addition, with repeated pairing of environmental stimuli with the drug, these CS also gain the propensity to elicit changes in dopamine concentration in the VMS (5-8); and even though these phasic neurochemical responses last only a few seconds, they are capable of controlling drug-seeking and -taking behavior (5). Together, these results implicate dopamine release in the VMS as a critical substrate in the control of drug use (2, 3, 9).However, the progression of drug taking beyond recreational use is thought to reflect the engagement of different psychological processes mediated within several neural loci (10, 11), with a particular emphasis on the incorporation of the sensorimotor (dorsolateral) striatum (DLS) in the c...

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“…Only a proportion of individuals develop drug addiction after using drugs repeatedly (Everitt et al, 2008). Ample evidence from clinical studies show that stress during the perinatal period (prenatal and early postnatal) in the form of mental or physical stress could lead to increased addiction risk during adulthood (Charmandari et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

Hausknecht

Haj‐Dahmane

Shen

2012

Neuropsychopharmacol

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Prenatal stress exposure (PSE) is known to increase addiction risk. Dopamine (DA) neurons in the ventral tegmental area (VTA) play an important role in addiction. In order to understand the cellular mechanisms underlying PSE-induced increase in addiction risk, we examined the effects of PSE on the electrical impulse activity of VTA DA neurons using the in vivo extracellular single-unit recording technique. Amphetamine self-administration was also conducted to confirm increased addiction risk after PSE. The PSE was carried out by restraining pregnant dams from GD 11 to 20. Adult male offspring (3-6 months old) were used in the experiments. Animals with PSE showed enhanced amphetamine self-administration compared with controls when amphetamine dose was reduced after acquisition. The number of spontaneously active VTA DA neurons was also reduced in PSE rats. The reduction was reversed by acute apomorphine that normally inhibits the impulse activity of DA neurons. The reversal effect suggests that PSE-induced reduction in the number of spontaneously active VTA DA neurons is caused by overexcitation to the extent of depolarization block. Furthermore, the reduced number of spontaneously active VTA DA neurons was also reversed by acute psychostimulants (eg, amphetamine; cocaine), which in control rats inhibited the activity of VTA DA neurons. The reversal effect on VTA DA neuron in PSE animals represents an actual increase in the impulse activity. This effect might contribute to increased responding to psychostimulants and mediate increased addiction risk after PSE.

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Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

Cited by 882 publications

References 93 publications

Chronic Nicotine Treatment Impacts the Regulation of Opioid and Non-opioid Peptides in the Rat Dorsal Striatum

Chronic Nicotine Treatment Impacts the Regulation of Opioid and Non-opioid Peptides in the Rat Dorsal Striatum

Hierarchical recruitment of phasic dopamine signaling in the striatum during the progression of cocaine use

Prenatal Stress Exposure Increases the Excitation of Dopamine Neurons in the Ventral Tegmental Area and Alters Their Reponses to Psychostimulants

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