Strengthening the Accumbal Indirect Pathway Promotes Resilience to Compulsive Cocaine Use

Overview

Journal Nat Neurosci

Date 2013 Apr 2

PMID 23542690

Citations 184

Authors

Roland Bock

J Hoon Shin

Alanna R Kaplan

Alice Dobi

Eric Markey

Paul F Kramer

Christina M Gremel

Christine H Christensen

Martin F Adrover

Veronica A Alvarez

Affiliations

Soon will be listed here.

Abstract

A hallmark of addiction is the loss of control over drug intake, which is seen in only a fraction of those exposed to stimulant drugs such as cocaine. The cellular mechanisms underlying vulnerability or resistance to compulsive drug use remain unknown. We found that individual variability in the development of highly motivated and perseverative behavior toward cocaine is associated with synaptic plasticity in medium spiny neurons expressing dopamine D2 receptors (D2-MSNs) in the nucleus accumbens (NAc) of mice. Potentiation of glutamatergic inputs onto indirect pathway D2-MSNs was associated with resilience toward compulsive cocaine seeking. Inhibition of D2-MSNs using a chemicogenetic approach enhanced the motivation to obtain cocaine, whereas optogenetic activation of D2-MSNs suppressed cocaine self-administration. These results indicate that recruitment of D2-MSNs in NAc functions to restrain cocaine self-administration and serves as a natural protective mechanism in drug-exposed individuals.

Citing Articles

Formation of an Enduring Ensemble of Accumbens Neurons Leads to Prepotent Seeking for Cocaine Over Natural Reward Cues.

Chalhoub R, Testen A, Hopkins J, Carthy C, Kalivas P bioRxiv. 2024; .

PMID: 39149274 PMC: 11326163. DOI: 10.1101/2024.08.05.606522.

NPAS4 supports cocaine-conditioned cues in rodents by controlling the cell type-specific activation balance in the nucleus accumbens.

Hughes B, Huebschman J, Tsvetkov E, Siemsen B, Snyder K, Akiki R Nat Commun. 2024; 15(1):5971.

PMID: 39117647 PMC: 11310321. DOI: 10.1038/s41467-024-50099-1.

Selenoprotein P in a Rodent Model of Exercise; Theorizing Its Interaction with Brain Reward Dysregulation, Addictive Behavior, and Aging.

Mohr P, Hanna C, Powell A, Penman S, Blum K, Sharafshah A J Pers Med. 2024; 14(5).

PMID: 38793071 PMC: 11122084. DOI: 10.3390/jpm14050489.

Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior.

Piantadosi S, Manning E, Chamberlain B, Hyde J, LaPalombara Z, Bannon N Nat Commun. 2024; 15(1):4434.

PMID: 38789416 PMC: 11126597. DOI: 10.1038/s41467-024-48331-z.

D1 and D2 medium spiny neurons in the nucleus accumbens core have distinct and valence-independent roles in learning.

Zachry J, Kutlu M, Yoon H, Leonard M, Chevee M, Patel D Neuron. 2023; 112(5):835-849.e7.

PMID: 38134921 PMC: 10939818. DOI: 10.1016/j.neuron.2023.11.023.

References

Root D, Ma S, Barker D, Megehee L, Striano B, Ralston C . Differential roles of ventral pallidum subregions during cocaine self-administration behaviors. J Comp Neurol. 2012; 521(3):558-88. PMC: 3525731. DOI: 10.1002/cne.23191. View

Dobi A, Seabold G, Christensen C, Bock R, Alvarez V . Cocaine-induced plasticity in the nucleus accumbens is cell specific and develops without prolonged withdrawal. J Neurosci. 2011; 31(5):1895-904. PMC: 3040105. DOI: 10.1523/JNEUROSCI.5375-10.2011. View

Ersche K, Barnes A, Jones P, Morein-Zamir S, Robbins T, Bullmore E . Abnormal structure of frontostriatal brain systems is associated with aspects of impulsivity and compulsivity in cocaine dependence. Brain. 2011; 134(Pt 7):2013-24. PMC: 3122375. DOI: 10.1093/brain/awr138. View

Kravitz A, Tye L, Kreitzer A . Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat Neurosci. 2012; 15(6):816-8. PMC: 3410042. DOI: 10.1038/nn.3100. View

Ferguson S, Eskenazi D, Ishikawa M, Wanat M, Phillips P, Dong Y . Transient neuronal inhibition reveals opposing roles of indirect and direct pathways in sensitization. Nat Neurosci. 2010; 14(1):22-4. PMC: 3058296. DOI: 10.1038/nn.2703. View

Ralph R, Caine S . Dopamine D1 and D2 agonist effects on prepulse inhibition and locomotion: comparison of Sprague-Dawley rats to Swiss-Webster, 129X1/SvJ, C57BL/6J, and DBA/2J mice. J Pharmacol Exp Ther. 2004; 312(2):733-41. DOI: 10.1124/jpet.104.074468. View

Corbit L, Janak P . Posterior dorsomedial striatum is critical for both selective instrumental and Pavlovian reward learning. Eur J Neurosci. 2010; 31(7):1312-21. PMC: 2914557. DOI: 10.1111/j.1460-9568.2010.07153.x. View

Richardson N, Roberts D . Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods. 1996; 66(1):1-11. DOI: 10.1016/0165-0270(95)00153-0. View

Torregrossa M, Tang X, Kalivas P . The glutamatergic projection from the prefrontal cortex to the nucleus accumbens core is required for cocaine-induced decreases in ventral pallidal GABA. Neurosci Lett. 2008; 438(2):142-5. PMC: 2659572. DOI: 10.1016/j.neulet.2008.04.016. View

10.

Gerfen C, Surmeier D . Modulation of striatal projection systems by dopamine. Annu Rev Neurosci. 2011; 34:441-66. PMC: 3487690. DOI: 10.1146/annurev-neuro-061010-113641. View

11.

Kravitz A, Freeze B, Parker P, Kay K, Thwin M, Deisseroth K . Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry. Nature. 2010; 466(7306):622-6. PMC: 3552484. DOI: 10.1038/nature09159. View

12.

Belin D, Mar A, Dalley J, Robbins T, Everitt B . High impulsivity predicts the switch to compulsive cocaine-taking. Science. 2008; 320(5881):1352-5. PMC: 2478705. DOI: 10.1126/science.1158136. View

13.

Kasanetz F, Deroche-Gamonet V, Berson N, Balado E, Lafourcade M, Manzoni O . Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science. 2010; 328(5986):1709-12. DOI: 10.1126/science.1187801. View

14.

Saunders B, Robinson T . Individual variation in the motivational properties of cocaine. Neuropsychopharmacology. 2011; 36(8):1668-76. PMC: 3138662. DOI: 10.1038/npp.2011.48. View

15.

Durieux P, Bearzatto B, Guiducci S, Buch T, Waisman A, Zoli M . D2R striatopallidal neurons inhibit both locomotor and drug reward processes. Nat Neurosci. 2009; 12(4):393-5. DOI: 10.1038/nn.2286. View

16.

Caine S, Negus S, Mello N, Bergman J . Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine. J Pharmacol Exp Ther. 1999; 291(1):353-60. View

17.

Pologruto T, Sabatini B, Svoboda K . ScanImage: flexible software for operating laser scanning microscopes. Biomed Eng Online. 2003; 2:13. PMC: 161784. DOI: 10.1186/1475-925X-2-13. View

18.

Barrett A, Miller J, Dohrmann J, Caine S . Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats. Neuropharmacology. 2004; 47 Suppl 1:256-73. DOI: 10.1016/j.neuropharm.2004.07.007. View

19.

Alexander G, Rogan S, Abbas A, Armbruster B, Pei Y, Allen J . Remote control of neuronal activity in transgenic mice expressing evolved G protein-coupled receptors. Neuron. 2009; 63(1):27-39. PMC: 2751885. DOI: 10.1016/j.neuron.2009.06.014. View

20.

Giessel A, Sabatini B . M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels. Neuron. 2010; 68(5):936-47. PMC: 3052967. DOI: 10.1016/j.neuron.2010.09.004. View