Elsevier

Brain Research

Volume 852, Issue 1, 3 January 2000, Pages 198-207
Brain Research

Research report
Behavioral responses to cocaine and amphetamine administration in mice lacking the dopamine D1 receptor

https://doi.org/10.1016/S0006-8993(99)02258-1Get rights and content

Abstract

Cocaine and amphetamine can induce both short-term and long-term behavioral changes in rodents. The major target for these psychostimulants is thought to be the brain dopamine system. To determine whether the dopamine D1 receptor plays a crucial role in the behavioral effects of psychostimulants, we tested both the locomotor and stereotyped behaviors in D1 receptor mutant and wild-type control mice after cocaine and amphetamine treatments. We found that the overall locomotor responses of D1 receptor mutant mice to repeated cocaine administration were significantly reduced compared to those of the wild-type mice and the responses of the D1 receptor mutant mice to cocaine injections were never significantly higher than their responses to saline injections. D1 receptor mutant mice were less sensitive than the wild-type mice to acute amphetamine stimulation over a dose range even though they exhibited apparently similar behavioral responses as those of the wild-type mice after repeated amphetamine administration at the 5 mg/kg dose. Immunostaining experiments indicated that there was no detectable neurotoxicity in the nucleus accumbens in both D1 receptor mutant and wild-type mice after repeated amphetamine administration. The data suggest that the D1 receptor plays an essential role in mediating cocaine-induced behavioral changes in mice. Moreover, the D1 receptor also participates in behavioral responses induced by amphetamine administration.

Introduction

Cocaine and amphetamine are potent psychostimulants. Acute administration of these drugs produces locomotor hyperactivity and stereotypy in rodents. Repeated exposure with adequate dose and frequency of these drugs leads to significant behavioral changes, such as sensitization and tolerance. Psychostimulants could also produce addiction in rodents. The cellular and molecular mechanisms that mediate the development and progression of these behavioral responses in animal models have been the object of many recent studies 7, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 28, 32, 33, 34, 35, 36.

The neurobiological mechanisms underlying psychostimulant-induced behavioral changes are thought to be associated with the brain mesolimbic dopamine (DA) pathway that projects from the midbrain ventral tegmental area to the nucleus accumbens (NAc) 5, 19, 30, 31. Both cocaine and amphetamine increase synaptic levels of DA and potentiate DA neurotransmission in the NAc. However, the molecular actions of these drugs are not identical. Whereas both block DA uptake through binding to the DA transporter 13, 15, 16, 23, 28, 29, amphetamine also induces DA release 13, 39. Anatomically, cocaine induces immediate early gene (IEG) c-fos expression in both the striosome and matrix compartments of the striatum, whereas amphetamine induces c-fos expression primarily in striosomes [9], suggesting that different compartments of the striatum may contribute to the functional differences between these two stimulants.

DA D1 receptors are thought to play central roles in mediating both acute and chronic effects of psychostimulants in rodents. Pharmacological studies have shown that D1 receptor agonists and antagonists can influence locomotor and stereotyped responses to cocaine and amphetamine, cocaine self-administration and conditioned place preference to an amphetamine paired environment 2, 11, 17, 25. Moreover, D1 receptor antagonists can prevent or attenuate the development of behavioral sensitization by psychostimulants 15, 24, 40. Repeated cocaine administration also leads to persistent increases in D1 receptor sensitivity within the NAc in rats [10].

Although pharmacological agents have been widely used to study the actions of psychostimulants, they generally lack sufficient selectivity for the D1 receptor subtype 3, 8, 37. Therefore, it has been difficult to pinpoint the role of the D1 receptor in various behavioral responses after psychostimulant administration. Successful generation of the D1 receptor mutant mice by gene targeting provides a useful alternative approach to assess the role of the D1 receptor in the actions of psychostimulants 6, 44, 45. We previously reported that the D1 receptor is essential for mediating the acute cocaine-induced locomotor responses and stereotyped behaviors in mice [45]. The present study examined whether the D1 receptor plays a crucial role in responses to repeated administration of cocaine and to both acute and repeated amphetamine administration using the D1 receptor mutant mice.

Section snippets

Mice

The D1 receptor mutant mice were generated and their genotypes identified by Southern blotting as described by Xu et al. [44]. The genetic background of both D1 receptor mutant and wild-type control mice are 129Sv×C57BL6. Adult mice 6 to 10 weeks of age were individually housed in a behavioral testing room in the University of Cincinnati animal facility on a 12-h light/dark cycle with food and water available ad libitum. The temperature and humidity of the room were controlled. All experiments

Behavioral responses to repeated cocaine treatment in D1 receptor mutant mice

To determine the role of the D1 receptor in behavioral changes induced by repeated cocaine administration, we injected both D1 receptor mutant and control mice twice daily with 20 mg/kg of cocaine or saline for seven consecutive days and recorded their behavioral responses. Wild-type mice did not show significant change in pre-treatment motor activity after saline treatment across days (Fig. 1, upper left, open circles; p>0.05), but they exhibited a significant decline in pre-treatment motor

Discussion

We have previously shown that the D1 receptor mutation eliminated both the acute locomotor stimulating effects and stereotyped responses to cocaine in the mutant mice [45]. This study focused on the behavioral responses of these mutant mice to repeated cocaine, as well as to acute and repeated amphetamine treatments.

Acknowledgements

We thank Ms. Mary Moran for statistical analyses; Dr. Heiko Jansen for advice on the histological experiment and Dr. Dana Beitner-Johnson for the TH antiserum; and members of the Xu laboratory for their helpful discussions. Jianhua Zhang is an Effie D. Beeman National Alliance for Research on Schizophrenia and Depression investigator and is supported by NIDA (DA11284). Ming Xu is a National Alliance for Research on Schizophrenia and Depression investigator and is supported by a startup fund

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