Parametric evaluation of the development of sensitization to the effects of morphine on locomotor activity

https://doi.org/10.1016/S0376-8716(00)00167-8Get rights and content

Abstract

Animals repeatedly administered drugs of abuse often become more sensitive to their effects. It has been proposed that this behavioral sensitization may serve as a useful model for changes that may underlie the etiology and maintenance of drug-seeking behavior. This study was designed to determine systematically some of the conditions of drug exposure under which sensitization occurs to morphine-induced stimulation of locomotor activity. Groups of rats (n=8 per group) were exposed to a regimen of intermittent morphine or saline injections for 1–4 days and tested at later time points with morphine or saline. The amount of behavioral sensitization observed was related to the number of drug exposures, but not to the dose of morphine used during drug exposures. Sensitization to morphine persisted for as long as 3 months and was completely blocked when naltrexone was administered with the test dose of morphine after the final morphine exposure. Administration of naltrexone with morphine during the exposure regimen did not alter the development of behavioral sensitization. These results indicate a robust behavioral sensitization to morphine that appears to be influenced in an orderly manner within a narrow window of the drug exposure conditions.

Introduction

Over the past 30 years, there has been a growing body of evidence suggesting that repeated administration of opioid agonists or psychomotor stimulants can result in enhancement of some of the behavioral effects of these drugs (Babbini and Davis, 1972, Bartoletti et al., 1983, Stewart and Badiani, 1993). This enhanced behavioral response to repeated drug administration is typically referred to as behavioral sensitization. The importance of drug-induced behavioral sensitization has been recognized in the field of drug abuse research. It has been proposed that sensitization plays an important role in the etiology and maintenance of drug-seeking behavior as well as in relapse to this behavior after a period of drug abstinence (Stewart and Eikelborn, 1987, Robinson and Berridge, 1993, Stewart and Badiani, 1993); however, there is still little or no understanding about the role sensitization might play in drug-seeking behavior. In fact, very little is understood about the conditions under which sensitization (as opposed to tolerance) occurs with repeated drug administration. This second point is the primary focus of the present study.

Several studies have shown that behavioral sensitization can result from repeated administration of μ opioid agonists, such as morphine (Babbini and Davis, 1972, Brady and Holtzman, 1981, Kalivas and Duffy, 1987), as well as from repeated administration of psychomotor stimulants, such as amphetamine (Segal and Mandell, 1974, Segal and Kuczenski, 1992a) and cocaine (Kalivas et al., 1988, Segal and Kuczenski, 1992b). Drug-induced sensitization develops not only to the effects of these drugs on locomotor activity (Babbini and Davis, 1972, Segal and Mandell, 1974, Robinson and Becker, 1986), but also to their effects on behavioral measures of drug reward, such as self-administration (Piazza et al., 1989, Piazza et al., 1990, Horger et al., 1990), conditioned place preference (Lett, 1989, Gaiardi et al., 1991, Shippenberg et al., 1993, Shippenberg et al., 1996), and intracranial self-stimulation (Kokkinnidis and Zacharko, 1980). Furthermore, cross-sensitization has been observed between morphine and amphetamine or cocaine (Lett, 1989, Vezina et al., 1989). Based on these studies, behavioral sensitization to all of these drugs is presumed to be mediated by the mesolimbic dopaminergic system (Joyce and Iverson, 1979, Vezina and Stewart, 1984), the same neuronal system thought to mediate the rewarding effects of these drugs (Koob and Bloom, 1989, Koob, 1992, Giros et al., 1996). Thus, the study of behavioral sensitization to these abused drugs could shed light on the neurobiological mechanisms that underlie the development of drug dependence and addiction.

The development of drug-induced behavioral sensitization appears to depend upon several factors, including total number of exposures to the drug, time between drug exposures, dose of the drug during exposures, and other environmental conditioning factors. The importance of these factors has been observed and reported, but has not been studied systematically. Thus, the purpose of the present study was to conduct a systematic evaluation of the role of several factors in the development of behavioral sensitization to morphine. Locomotor behavior in rats was measured under different conditions determined by varying number of exposures to morphine, dose of morphine during exposures and time between morphine exposures. The results confirm that behavioral sensitization to morphine does occur and that the degree of this sensitization is influenced in an orderly manner by each of these factors.

Section snippets

Subjects

This study required the use of 192 male, Sprague–Dawley (Charles River, Raleigh, NC) rats weighing approximately 325–350 g at the beginning of the study. Rats were maintained on continuous access to food and water, except during daily testing sessions, and on a 12-h light, 12-h dark cycle. Care of the animals conformed to the National Institutes of Health Guide for the Care and Use of Laboratory Animals and the protocol of the study was approved by the Institutional Animal Care and Use

Morphine sensitization

Fig. 1 illustrates the effects of 3.0 mg/kg of morphine on the locomotor activity of rats tested at 48 h after exposure to drug regimen A (morphine) or regimen E (saline only). There was a significantly greater increase in locomotor activity in response to morphine in rats previously exposed to morphine (regimen A) compared to rats previously exposed only to saline (regimen E). This significant difference was observed from 30 min to approximately 2.5 h over the 6-h test session, peaking between

Discussion

The present results extend previous findings demonstrating morphine-induced behavioral sensitization (Babbini and Davis, 1972, Brady and Holtzman, 1981, Kalivas and Duffy, 1987, Shippenberg et al., 1996). In this study, acute morphine administration increased locomotor activity in a dose-dependent manner. In rats exposed to at least 2 days of intermittent morphine administration, the effects of morphine on locomotor activity were significantly enhanced compared to rats that had no prior

Acknowledgements

This study was supported in part by Grant DA 00541, individual postdoctoral fellowship F32 DA05709 (K.R. Powell) and Research Scientist Award KO5 DA00008 (S.G. Holtzman) from the National Institute on Drug Abuse, NIH.

References (42)

  • R.T. Livezey et al.

    The effect of MK-801 and SCH23390 on the expression and sensitization of morphine-induced oral stereotypy

    Brain Res.

    (1995)
  • P.V. Piazza et al.

    Stress- and pharmacologically-induced behavioral sensitization increases vulnerability to acquisition of amphetamine self-administration

    Brain Res.

    (1990)
  • J. Pollock et al.

    Reexpression of morphine-induced oral stereotypy six months after last morphine sensitizing dose

    Pharmacol. Biochem. Behav.

    (1996)
  • T.E. Robinson et al.

    Enduring changes in brain and behavior produced by chronic amphetamine administration: a review and evaluation of animal models of amphetamine psychosis

    Brain Res. Rev.

    (1986)
  • T.E. Robinson et al.

    The neural basis of drug craving: An incentive-sensitization theory of addiction

    Brain Res. Rev.

    (1993)
  • T.E. Robinson et al.

    Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by prior experience with (+)-amphetamine: a microdialysis study in freely moving rats

    Brain Res.

    (1988)
  • D.S. Segal et al.

    Repeated cocaine administration induces behavioral sensitization and corresponding decreased extracellular dopamine responses in caudate and accumbens

    Brain Res.

    (1992)
  • D.S. Segal et al.

    In vivo microdialysis reveals a diminished amphetamine-induced DA response corresponding to behavioral sensitization produced by repeated amphetamine pretreatment

    Brain Res.

    (1992)
  • D.S. Segal et al.

    Long-term administration of d-amphetamine: Progressive augmentation of motor activity and stereotypy

    Pharmacol. Biochem. Behav.

    (1974)
  • T.S. Shippenberg et al.

    Sensitization to the conditioned rewarding effects of morphine: pharmacology and temporal characteristics

    Eur. J. Pharmacol.

    (1996)
  • R. Spanagel

    Modulation of drug-induced sensitization processes by endogenous opioid systems

    Behav. Brain Sci.

    (1995)
  • Cited by (49)

    • Context evoked morphine conditioned effects can be equivalent to morphine induced drug effects in terms of behavioral response and ERK activation in reward associated subcortical brain structures

      2022, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      It has been extensively demonstrated in rodents that repeated morphine treatments produce potent stimulant effects manifested in spontaneous motor activity behavior as hyperactivity (Vezina and Stewart, 1984; Neisewander and Bardo, 1987; Vanderschuren et al., 1999; Powell and Holtzman, 2001; Tzschentke and Schmidt, 1995; Leite Júnior et al., 2019).

    • A new method to study learning and memory using spontaneous locomotor activity in an open-field arena

      2022, Journal of Neuroscience Methods
      Citation Excerpt :

      Certainly, a unique feature of using the present post-trial drug treatment method to investigate effects on acquisition of a new behavior is that the effects of the post-trial treatment can be observed in terms of direct effects on behavior instead of only indirect effects such as on the acquisition of a complex behavior such as maze learning. The present results show that the increase in total activity by the post-trial morphine treatment essentially mirrors the direct effects of increased activity induced by morphine administered in a conventional pre-test morphine protocol (Vanderschuren et al., 1999; Powell and Holtzman, 2001; Li et al., 2010; Liu et al., 2014). This similarity in pre- and post-trial morphine effects on locomotor activity suggests that the morphine drug response is incorporated into the memory consolidation of the environmental experience and the morphine drug response is expressed in behavior during the subsequent non-drug test one day later.

    • Morphine reward effects and morphine behavioral sensitization: The adventitious association of morphine activation of brain reward effects with ongoing spontaneous activity

      2021, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      Fig. 6D shows examples of the sections used for counting phosphorylated-ERK-immunoreactive cells in the VTA and NAc following VEH and MOR administration. In line with previous studies (Vezina and Stewart, 1984; Neisewander and Bardo, 1987; Powell and Holtzman, 2001; Lu et al., 2002; Sharf et al., 2010), we found that repeated morphine treatments in rats induced a behavioral locomotor sensitization effect. This effect was context selective in that similar morphine treatments administered unpaired to the test arena did not result in locomotor stimulant effects.

    View all citing articles on Scopus
    View full text