Elsevier

Drug and Alcohol Dependence

Volume 153, 1 August 2015, Pages 369-373
Drug and Alcohol Dependence

Short communication
Assessing contributions of nucleus accumbens shell subregions to reward-seeking behavior

https://doi.org/10.1016/j.drugalcdep.2015.05.001Get rights and content

Highlights

  • We explored functional heterogeneity across nucleus accumbens shell subregions.

  • Rats were trained to self-administer cocaine and subsequently extinguished.

  • Amphetamine microinfusions were targeted to subregions as reinstatement tests.

  • Targeting the dorsomedial shell led to significant reinstatement.

  • No significant reinstatement was observed when targeting the intermediate zone.

Abstract

Background

The nucleus accumbens (NAc) plays a key role in brain reward processes including drug seeking and reinstatement. Several anatomical, behavioral, and neurochemical studies discriminate between the limbic-associated shell and the motor-associated core regions. Less studied is the fact that the shell can be further subdivided into a dorsomedial shell (NAcDMS) and an intermediate zone (NAcINT) based on differential expression of transient c-Fos and long-acting immediate-early gene ΔFosB upon cocaine sensitization. These disparate expression patterns suggest that NAc shell subregions may play distinct roles in reward-seeking behavior. In this study, we examined potential differences in the contributions of the NAcDMS and the NAcINT to reinstatement of reward-seeking behavior after extinction.

Methods

Rats were trained to intravenously self-administer cocaine, extinguished, and subjected to a reinstatement test session consisting of an intracranial microinfusion of either amphetamine or vehicle targeted to the NAcDMS or the NAcINT.

Results

Small amphetamine microinfusions targeted to the NAcDMS resulted in statistically significant reinstatement of lever pressing, whereas no significant difference was observed for microinfusions targeted to the NAcINT. No significant difference was found for vehicle microinfusions in either case.

Conclusion

These results suggest heterogeneity in the behavioral relevance of NAc shell subregions, a possibility that can be tested in specific neuronal populations in the future with recently developed techniques including optogenetics.

Introduction

The unrelenting desire to obtain drugs of abuse is a persistent and debilitating aspect of addiction. This feeling of motivation—commonly referred to as craving—is mediated by distinct circuits that are believed to precipitate the reinstatement of drug-seeking behavior (Kalivas and McFarland, 2003).

The nucleus accumbens (NAc) is an integral component of the neuronal circuitry underlying drug-seeking behavior in rodents and remains at the center of intense investigation after decades of interrogation. The functional and anatomical heterogeneity of the NAc revealed by past studies resulted in its division into core and shell regions (Deutch and Cameron, 1992, Zaborszky et al., 1985). Despite intense study of the NAc as only two disparate regions, a growing body of research suggests that further partitioning of the NAc shell to account for differences in gene expression, anatomy, and function may be warranted.

The NAc shell is a heterogeneous structure (Jongen-Relo et al., 1993, Meredith et al., 1992, Schilman et al., 2008, Shin et al., 2008, Wright and Groenewegen, 1995). It can be segregated into dorsomedial (NAcDMS), intermediate (NAcINT), and ventrolateral zones based on differences in gross projection patterns (Heimer et al., 1997, Moga et al., 1995, Usuda et al., 1998, Zahm and Brog, 1992) and immunoreactivity to various peptides and neurotransmitters (Heimer et al., 1997, Voorn et al., 1989, Voorn et al., 1986, Zahm and Brog, 1992, Zahm et al., 1998). Furthermore, accumulating evidence suggests that each NAc shell subregion is a module that responds to psychostimulants in a manner distinct from the others. Early evidence for this was provided by differential neurotensin immunoreactivity in response to systemic injections of amphetamine and the dopamine antagonist haloperidol (Heimer et al., 1997). Subsequent experiments revealed that locomotor activity varies in response to cocaine infusions into different NAc shell subregions (Ikemoto, 2002). More recent physiological studies showed sustained changes in neuronal activity during cocaine self-administration that varied across the NAc shell subregions (Fabbricatore et al., 2009).

To further characterize the NAc shell in an addicted state, our group previously sensitized animals to cocaine and subsequently assayed NAc shell subregions for ΔFosB immunoreactivity (Brenhouse and Stellar, 2006). ΔFosB dimerizes with cofactors to form long-lasting complexes that function like a molecular switch. This persisting switch may be involved in the long-term changes that enable reinstatement of drug-seeking behavior even after long periods of extinction (Hope et al., 1994, Nestler et al., 2001). Expression of ΔFosB in the NAcDMS following 14 days of withdrawal from cocaine was upregulated, implying that this subregion may be a site of neuronal plasticity that plays a paramount role in the persistence of addiction (Brenhouse and Stellar, 2006). In contrast, no significant change was found for ΔFosB expression in the NAcINT. The aforementioned evidence suggests a functional significance associated with NAc shell subregion segregation. However, studies measuring neurochemical immunoreactivity patterns in response to behavioral sensitization provide only indirect support for subregion-specific roles in reward and addiction. No study has yet demonstrated the consequences of manipulating particular NAc shell subregions on reward-seeking behavior.

We hypothesized a functional role for the NAcDMS in mediating reinstatement of reward-seeking behavior. We tested this with a self-administration paradigm in which rats were trained to press a lever for intravenous infusions of cocaine. Subsequently, the same lever was paired with saline infusions to extinguish lever pressing. Upon extinction, a microinfusion of amphetamine was targeted to NAc shell subregions to probe reinstatement while animals were freely behaving. To our knowledge, this is the first study to implicate a specific NAc shell subregion in the reinstatement of reward-seeking behavior.

Section snippets

Animal subjects

Male Sprague-Dawley rats (n = 13; Charles River Laboratories) were housed individually in a temperature-controlled, 12 h light:dark cycle facility. Daily food intake was restricted to maintain animal masses of 350 g or less. Water was available ad libitum. Animal care was approved by the Northeastern University Institutional Animal Care and Use Committee and performed in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996).

Behavioral apparatus and conditions

Training and test sessions

Anatomical distribution of cannula placements

A total of 13 animals completed all phases of the experiment. In this group, 8 cannula placements corresponded to the NAcDMS and 5 to the NAcINT (Fig. 1).

Operant behavior during baseline training

Each subject's responding during cocaine self-administration and extinction sessions was quantified as the total number of lever presses during the last 2 h session before progression to the next phase. On average, subjects administered 2.63 ± 0.13 mg × kg−1 of cocaine during each of the final three days of cocaine-self administration training. No

Discussion

In this study, we found that animals with placements in the NAcDMS—unlike those in the NAcINT—show significantly elevated lever-pressing behavior following an intracranial amphetamine challenge during the extinguished state. These results suggest that increasing dopamine levels in the NAcDMS subregion alone is sufficient to induce reinstatement of reward-seeking behavior. This may be due to disparities in dopamine availability caused by heterogeneous tyrosine hydroxylase expression across the

Role of funding source

Funding for this study was provided by the Whitehall Foundation and NIH grant DA019946. Neither funding source had a role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributions

M.D.R. and D.G.C.H. collected data, performed analyses, and wrote the paper. M.F. and J.R.S. provided advice, guidance, and resources. All other authors collected data. All authors approved the article.

Conflict of interest

All authors declare that they have no conflicts of interest.

Acknowledgements

We thank J.L. Morgan for discussions regarding statistical analysis.

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  • Cited by (0)

    1

    Present address: Graduate Program in Neuroscience, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, United States.

    2

    Present address: Graduate Program in Neuroscience, Division of Medical Sciences, Harvard Medical School, Boston, MA, United States.

    3

    Present address: Department of Psychiatry, University of Florida College of Medicine, McKnight Brain Institute, Gainesville, FL, United States.

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