Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine

doi:10.1016/S0306-4522(03)00378-6

Neuroscience

Volume 120, Issue 4, 15 September 2003, Pages 1149-1156

https://doi.org/10.1016/S0306-4522(03)00378-6 Get rights and content

Abstract

The nucleus accumbens, a major component of the ventral striatum, and the dorsal striatum are primary targets of the mesolimbic dopamine pathway, which is a pathway that plays a critical role in reward and addiction. The shell compartment of the nucleus accumbens and the ventromedial striatum, in particular, receive extensive afferent projections from the ventral tegmental area, which is the major afferent source of the mesolimbic pathway [Prog Brain Res 99 (1993) 209; J Neurosci 7 (1987) 3915]. The present study focused on striatal cholinergic interneurons as potential key neurons involved in the neural basis of drug reinforcement. The main finding of this study is that cholinergic interneurons located in the shell compartment of the nucleus accumbens and the ventromedial striatum were activated, as measured by Fos labeling, following a 1 h session of the self-administration of cocaine in rats. A direct correlation existed between the percent of cholinergic interneurons that were activated and the amount of cocaine that was self-administered. The greatest amount of administered cocaine (approximately 10 mg/kg) resulted in the activation of approximately 80% of the cholinergic neurons. No such correlation existed in the group of animals that self-administered saline. In addition, activation was not found in the core compartment of the nucleus accumbens or the dorsolateral striatum, which receive extensive innervation from the substantia nigra and thus are more closely tied to the motor effects of the drug.

In conclusion, cocaine-driven neuronal activation was specific to the shell compartment of the nucleus accumbens (R²=0.9365) and the ventromedial striatum (R²=0.9059). These findings demonstrate that cholinergic interneurons are involved in the initial stage of cocaine intake and that these neurons are located in areas of the nucleus accumbens and dorsal striatum that are more closely tied to the rewarding and hedonic effects rather than the motor effects of cocaine intake.

Section snippets

Subjects

Thirty-two male Sprague–Dawley rats were obtained from the Animal Resource Center at the University of Texas at Austin. All experimental procedures conformed to National Institutes of Health guidelines and were carried out under an institutionally reviewed and approved research protocol. Animals were group housed and handled for 2 weeks, and then trained to lever press for sugar pellets on a fixed ratio 1 (FR1) schedule for 1 week before receiving surgery. All efforts were made to minimize

Results

Cholinergic interneurons of the dorsal and ventral striatum of the rat were identified using immunocytochemistry procedures and an antibody against ChAT. Fig. 1A illustrates ChAT-immunolabeled neurons of the striatum. Cholinergic cells that were activated were determined by dual immunolabeling for ChAT and Fos protein. A representative photomicrograph of Fos-labeled cholinergic cells is shown in Fig. 1B. The percent of neurons activated were calculated from samples taken from specific regions

Discussion

The main finding of this study is that the cholinergic interneurons of the NAcc and dorsal striatum were activated in a dose dependent manner following a 1 h session of the self-administration of cocaine in rats. Specifically, the neurons activated were cholinergic interneurons located in the shell compartment of the NAcc and the ventromedial striatum. These brain areas receive direct innervation from the dopaminergic mesolimbic pathway, which plays an important role in reward and addiction

Acknowledgements

This work was supported by National Institutes of Health/National Institute of Drug Abuse grant DA12858, Waggoner Center Faculty Research Fellowship, and The University of Texas Faculty and Undergraduate Student Research Fellowships. We are grateful to Dr. Walter Wilczynski, Dr. Timothy Schallert and Dr. William T. Greenough for their encouragement and helpful comments on this manuscript. We also thank Ms Taylor K. Simpson and Ms Ginger Becker for technical assistance.

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Cholinergic interneurons of the nucleus accumbens and dorsal striatum are activated by the self-administration of cocaine

Abstract

Section snippets

Subjects

Results

Discussion

Acknowledgements

Prog Brain Res

Neuron

Neuropharmacology

Trends Neurosci

Neurobiol Learn Mem

Neuroscience

Eur J Pharmacol

Drug Alcohol Depend

Pharm Biochem Behav

Brain Res Bull

Brain Res

Neuroscience

Neuropsychopharmacology

Brain Res

Pharm Biochem Behav

Localization of dopamine D2 receptors on cholinergic interneurons of the dorsal striatum and the nucleus accumbens of the rat

Brain Res

Muscarinic m1 and m2 receptor proteins in local circuit and projection neurons of the primate striatumanatomical evidence for cholinergic modulation of glutamatergic prefronto-striatal pathways

J Comp Neurol

Memory processes governing amphetamine-induced psychomotor sensitization

Neuropsychopharmacology

Responses of tonically active neurons in the primate's striatum undergo systematic changes during behavioral sensorimotor conditioning

J Neurosci

Endogeneous dopamine facilitates striatal in vivo acetylcholine release by acting on D1 receptors localized in the striatum

J Neurochem