Drug Wanting: Behavioral Sensitization and Relapse to Drug-Seeking Behavior

Steketee, Jeffery D.; Kalivas, Peter W.

doi:10.1124/pr.109.001933

Cited by 600 publications

(487 citation statements)

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“…Previous reports have shown that VTA dopamine neurons excitability is enhanced by a history of repeated exposure to amphetamine, cocaine or ethanol; and this augmented dopamine signaling is associated with behavioral sensitization to these stimuli (Steketee and Kalivas, 2011). Current data show that daily and time-limited HFD consumption is associated not only to an intake escalation over successive exposures but also to an enhanced activation of specific VTA dopamine neurons sub-populations.…”

Section: Discussionmentioning

confidence: 57%

“…Still, the study of rodent models in a short term fashion can be useful to get insights into some of the neuronal circuits recruited under particular conditions, as it has been previously done in the drugs of abuse research field (Goeders et al, 2009;Steketee and Kalivas, 2011). Some of the proposed mechanisms mediating intake escalation during the successive exposures to drugs of abuse include tolerance, behavioral sensitization or habit formation, and the mesolimbic dopamine pathway have been suggested as a potential target underlying these behavioral changes (Berridge, 2007;Steketee and Kalivas, 2011). Importantly, the current study was performed using satiated mice that were exposed to HFD at a time of the day when spontaneous food intake is minimal and while they remained with free access to RC.…”

Section: Discussionmentioning

confidence: 99%

“…Sensitization is a form of neuronal plasticity in which repeated exposure to a stimulus leads to an enhanced response to that stimulus together with a long-lasting increase in behavioral activation and Acb dopamine release (Steketee and Kalivas, 2011). Previous reports have shown that VTA dopamine neurons excitability is enhanced by a history of repeated exposure to amphetamine, cocaine or ethanol; and this augmented dopamine signaling is associated with behavioral sensitization to these stimuli (Steketee and Kalivas, 2011).…”

Section: Discussionmentioning

confidence: 99%

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Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

Valdivia¹,

Cornejo²,

Reynaldo³

et al. 2015

Psychoneuroendocrinology

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Please cite this article in press as: Valdivia, S., et al., Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling. Psychoneuroendocrinology (2015) and time-limited exposed to a high-fat diet (HFD) display robust binge eating events that gradually escalate over the initial accesses. Intake escalation is proposed to be part of the transition from a controlled to a compulsive or loss of control behavior. Here, we used a combination of behavioral and neuroanatomical studies in mice daily and time-limited exposed to HFD to determine the neuronal brain targets that are activated -as indicated by the marker of cellular activation c-Fos -under these circumstances. Also, we used pharmacologically or genetically manipulated mice to study the role of orexin or ghrelin signaling, respectively, in the modulation of this behavior. We found that four daily and time-limited accesses to HFD induce: (i) a robust hyperphagia with an escalating profile, (ii) an activation of different sub-populations of the ventral tegmental area dopamine neurons and accumbens neurons that is, in general, more pronounced than the activation observed after a single HFD consumption event, and (iii) an activation of the hypothalamic orexin neurons, although orexin signaling blockage fails to affect escalation of HFD intake. In addition, we found that ghrelin receptor-deficient mice fail to both escalate the HFD consumption over the successive days of exposure and fully induce activation of the mesolimbic pathway in response to HFD consumption. Current data suggest that the escalation in high fat intake during repeated accesses differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Escalation in high fat intake in a binge eating model differentially engages dopamine neurons of the ventral tegmental area and requires ghrelin signaling

Valdivia¹,

Cornejo²,

Reynaldo³

et al. 2015

Psychoneuroendocrinology

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“…Perhaps the most common qualm is skepticism about whether the neural underpinnings of sensitization parallel those that occur in addiction, however, a recent review suggests substantial overlap between the two models (Steketee and Kalivas, 2011). Nonetheless, given the controversy, we decided to conduct a similar investigation of the role mPFC mGluR5 in drug-seeking using the self-administration paradigm to further corroborate both the role of mPFC mGluR5 in addiction as well as the relevance of sensitization as a model of addiction.…”

Section: Animal Models Of Addictionmentioning

confidence: 99%

“…Sensitization also occurs in response to other drugs of abuse, such as amphetamine, nicotine, alcohol, and morphine (Robinson and Becker, 1986;Steketee and Kalivas, 2011). The role of sensitization in addiction is presently controversial, however, a good deal of evidence suggests common mechanisms mediate both processes (Robinson and Berridge, 1993).…”

Section: Sensitization and Addictionmentioning

confidence: 99%

Metabotropic Glutamate Receptor 5 in the Medial Prefrontal Cortex: Role in Cocaine Sensitization and Addiction

Timmer¹

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AcknowledgementsI would like to thank my advisor, Dr. Jeff Steketee, for his guidance and support throughout this process, as well as my outstanding committee, Drs. Matthew Ennis, Kristin Hamre, Rennolds Ostrom, and Wen Lin Sun for their input, suggestions, and evaluation. I am thankful for my lab buddy, Kyle Summers, for his exceptional conversation and collaboration on the self-administration project, and former post-doc Kun "Luke" Liu for teaching me microdialysis. I would like to thank my husband, Steve, for existing, as I could not have been this happy spending my life with anyone else. Last but absolutely not least, I would like to thank my children, Jack and Cassidy, for motivating me to complete this work.iv AbstractCocaine sensitization is associated with cocaine-induced hyperexcitability of pyramidal projection neurons within the medial prefrontal cortex (mPFC). Such hyperexcitability presumably results in increased glutamatergic input to reward-affiliated brain regions such as the ventral tegemental area (VTA) and nucleus accumbens (NAc), consequently facilitating drug-seeking behavior. Metabotropic glutamate receptor 5 (mGluR5) has been implicated in cocaine addiction and demonstrated to increase neuronal excitability, therefore, the aim of the present study was to investigate the effect of intra-mPFC mGluR5 manipulation on behavioral and neurochemical sensitization and drug-seeking. Bilateral cannulae were implanted into the mPFC of male Sprague-Dawley rats and mGluR5 antagonist MTEP (15 nmol/side) or saline was microinjected into the region five minutes prior to a challenge cocaine injection. Our data showed that intramPFC mGluR5 blockade via MTEP prevented late, but not early, behavioral sensitization. Further, intra-mPFC mGluR5 activation via DHPG (30 uM) increased mPFC and NAc glutamate levels in sensitized animals during early and late withdrawal, respectively. Finally, we observed a nonsignificant trend toward an MTEP-induced reduction in drug-seeking following the presentation of a cocaine-associated cue in animals that had been trained to self-administer cocaine. Taken together, our data suggest mPFC mGluR5 plays a role in cocaine addiction, possibly through the modulation of mPFC pyramidal neuronal excitability.

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