Electrophysiological effects of cocaine in the mesoaccumbens dopamine system: repeated administration

DJ Henry, MA Greene and FJ White

Wayne State University School of Medicine, Department of Psychiatry, Lafayette Clinic, Detroit, Michigan.

Behavioral evidence indicates that the potent rewarding effects of cocaine are mediated, in part, by the mesoaccumbens dopamine (DA) system projecting from A10 DA cells in the ventral tegmental area (VTA) to the nucleus accumbens (NAc). Previous electrophysiological studies from our laboratory have indicated that cocaine (i.v.) exerts inhibitory effects on A10 DA neurons, due to enhanced stimulation by DA at DA autoreceptors are well as by activation of NAc-VTA feedback pathways. In the present experiments, extracellular single-unit recording and microiontophoretic techniques were used to determine the possible alterations in the mesoaccumbens DA system after repeated cocaine administration. Twice daily injections of cocaine (10 mg/kg i.p., 14 days) caused significant subsensitivity to the inhibitory effects of low i.v. doses of the DA agonist apomorphine in comparison to rats receiving similar treatments with saline or procaine. Iontophoretic application of DA to A10 DA neurons in rats treated repeatedly with cocaine (2X10 mg/kg, 14 days) also produced significantly less inhibition as compared to control rats. Cell population analysis of the VTA revealed that autoreceptor subsensitivity in cocaine-treated rats resulted in a significantly greater number of spontaneously active A10 DA neurons, and a significantly higher firing rate as compared to A10 DA neurons in control rats. In striking contrast to A10 DA cells, recordings from NAc neurons in cocaine-treated rats (2X10 mg/kg, 14 days) indicated that these cells were supersensitive to the inhibitory effects of iontophoretic DA. Although the mechanism underlying such supersensitivity remains unclear, the increased sensitivity of postsynaptic NAc DA receptors combined with the subsensitivity of A10 DA autoreceptors could lead to greatly enhanced DA transmission and may help to explain some aspects of cocaine-induced behavioral sensitization.

Volume 251, Issue 3, pp. 833-839, 12/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				D. J. Lodge and A. A. Grace Amphetamine Activation of Hippocampal Drive of Mesolimbic Dopamine Neurons: A Mechanism of Behavioral Sensitization J. Neurosci., July 30, 2008; 28(31): 7876 - 7882. [Abstract] [Full Text] [PDF]

				C. A. McClung, K. Sidiropoulou, M. Vitaterna, J. S. Takahashi, F. J. White, D. C. Cooper, and E. J. Nestler Regulation of dopaminergic transmission and cocaine reward by the Clock gene PNAS, June 28, 2005; 102(26): 9377 - 9381. [Abstract] [Full Text] [PDF]

				J. McDaid, J. E. Dallimore, A. R. Mackie, A. L. Mickiewicz, and T. C. Napier Cross-Sensitization to Morphine in Cocaine-Sensitized Rats: Behavioral Assessments Correlate with Enhanced Responding of Ventral Pallidal Neurons to Morphine and Glutamate, with Diminished Effects of GABA J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1182 - 1193. [Abstract] [Full Text] [PDF]

				X.-T. Hu, S. Basu, and F. J. White Repeated Cocaine Administration Suppresses HVA-Ca2+ Potentials and Enhances Activity of K+ Channels in Rat Nucleus Accumbens Neurons J Neurophysiol, September 1, 2004; 92(3): 1597 - 1607. [Abstract] [Full Text] [PDF]

				S. L. Borgland, R. C. Malenka, and A. Bonci Acute and Chronic Cocaine-Induced Potentiation of Synaptic Strength in the Ventral Tegmental Area: Electrophysiological and Behavioral Correlates in Individual Rats J. Neurosci., August 25, 2004; 24(34): 7482 - 7490. [Abstract] [Full Text] [PDF]

				R. Reeves, M. Thiruchelvam, and D. A. Cory-Slechta Development of Behavioral Sensitization to the Cocaine-Like Fungicide Triadimefon Is Prevented by AMPA, NMDa, DA D1 but Not DA D2 RECEPTOR Antagonists Toxicol. Sci., May 1, 2004; 79(1): 123 - 136. [Abstract] [Full Text] [PDF]

				K. McFarland and P. W. Kalivas The Circuitry Mediating Cocaine-Induced Reinstatement of Drug-Seeking Behavior J. Neurosci., November 1, 2001; 21(21): 8655 - 8663. [Abstract] [Full Text] [PDF]

				M. Marinelli and F. J. White Enhanced Vulnerability to Cocaine Self-Administration Is Associated with Elevated Impulse Activity of Midbrain Dopamine Neurons J. Neurosci., December 1, 2000; 20(23): 8876 - 8885. [Abstract] [Full Text] [PDF]

				R. C. Pierce, A. F. Pierce-Bancroft, and B. M. Prasad Neurotrophin-3 Contributes to the Initiation of Behavioral Sensitization to Cocaine by Activating the Ras/Mitogen-Activated Protein Kinase Signal Transduction Cascade J. Neurosci., October 1, 1999; 19(19): 8685 - 8695. [Abstract] [Full Text] [PDF]

				X.-F. Zhang, X.-T. Hu, and F. J. White Whole-Cell Plasticity in Cocaine Withdrawal: Reduced Sodium Currents in Nucleus Accumbens Neurons J. Neurosci., January 1, 1998; 18(1): 488 - 498. [Abstract] [Full Text] [PDF]

				R. Kuczenski and D. S. Segal An Escalating Dose/Multiple High-Dose Binge Pattern of Amphetamine Administration Results in Differential Changes in the Extracellular Dopamine Response Profiles in Caudate-Putamen and Nucleus Accumbens J. Neurosci., June 1, 1997; 17(11): 4441 - 4447. [Abstract] [Full Text] [PDF]

				X.-F. Zhang, X.-T. Hu, F. J. White, and M. E. Wolf Increased Responsiveness of Ventral Tegmental Area Dopamine Neurons to Glutamate after Repeated Administration of Cocaine or Amphetamine Is Transient and Selectively Involves AMPA Receptors J. Pharmacol. Exp. Ther., May 1, 1997; 281(2): 699 - 706. [Abstract] [Full Text]

				M. T. Berhow, N. Hiroi, L. A. Kobierski, S. E. Hyman, and E. J. Nestler Influence of Cocaine on the JAK-STAT Pathway in the Mesolimbic Dopamine System J. Neurosci., December 15, 1996; 16(24): 8019 - 8026. [Abstract] [Full Text] [PDF]

				M. T. Berhow, N. Hiroi, and E. J. Nestler Regulation of ERK (Extracellular Signal Regulated Kinase), Part of the Neurotrophin Signal Transduction Cascade, in the Rat Mesolimbic Dopamine System by Chronic Exposure to Morphine or Cocaine J. Neurosci., August 1, 1996; 16(15): 4707 - 4715. [Abstract] [Full Text] [PDF]

				E. J. Nestler Review : Molecular Basis of Addictive States Neuroscientist, July 1, 1995; 1(4): 212 - 220. [Abstract] [PDF]