Review
Sensitization to the reinforcing effects of cocaine following binge-abstinent self-administration

https://doi.org/10.1016/j.neubiorev.2003.11.004Get rights and content

Abstract

The process of addiction in humans involves a transition from recreational drug use to compulsive drug-taking. To understand or study this behavioral phenomenon from a neurobiological perspective, behavioral models that reflect this process are necessary. Data from typical (restricted access) self-administration procedures demonstrate a stable pattern of responding over time, and thus fail to capture the transitional phases of this process. Here we describe the development of a model that incorporates self-administration-induced changes in the reinforcing efficacy of cocaine, assessed using a progressive ratio schedule of reinforcement to probe the ‘motivational’ state of the animal. To date we have identified two necessary conditions for the development of this sensitization: extended access to cocaine and a deprivation period. This model, in conjunction with recently developed tools to characterize neurochemical and epigenetic changes, will provide a better understanding of the neurobiological bases of the addiction process.

Section snippets

Reinforcement versus addiction

The dynamic process of cocaine addiction generally starts with recreational use and deteriorates over time into a compulsive drug taking disorder [1]. Our goal is to understand this process from a neurobiological perspective, the premise being that if we understood what changes occurred in the brain, we might be better equipped to design appropriate therapies and develop suitable medications. A secondary benefit is that we might gain some insight into basic mechanisms of neural plasticity.

Modeling addiction

The past few years have seen significant shifts in the way cocaine addiction has been studied. Traditionally, research into the neurobiology of drugs of abuse has focused on the sites and mechanisms of action of specific drugs (i.e. receptor pharmacology) and has emphasized tolerance and physical dependence as major contributors to drug reinforcement.

In a seminal paper [1], Gawin wrote that “addiction to cocaine does not cause gross physiological withdrawal symptoms”, and at the same time

Role of sensitization—do the reinforcing effects of cocaine sensitize?

Most generally, sensitization (or reverse tolerance) refers to an augmentation (generally, progressively increasing and enduring) of a particular drug response as a consequence of repeated drug administration. A vast literature has examined sensitization of psychostimulant-induced locomotor or stereotyped activity, and the anatomical and pharmacological details of both amphetamine- and cocaine-induced sensitization have been widely described [19], [20], [21], [22], [23], [24]. Sensitization to

Repeated cycles of ‘binge’ self-administration and withdrawal

Initially we tested whether animals given access to cocaine on a FR1 schedule for a 24 h ‘binge’ would affect responding on a PR schedule. Break points determined 24 h after the binge (to allow the cocaine to clear from the body) were found to be significantly decreased (see Fig. 2), consistent with an interpretation of tolerance to the reinforcing effects of cocaine. We hypothesized that over repeated cycles of these access conditions, tolerance would begin to dissipate and breakpoints would

What do we know about the requirements for self-administration to produce changes in break point?

The data can be summarized as follows

  • Round-the-clock access to cocaine on a DT4 schedule (1.5 mg/kg/inj) produced an increase in cocaine-reinforced break points after 7 days of drug deprivation. This effect is robust and has been replicated a number of times.

  • The increase in break points is only seen after a 7 day drug free period. Testing 2–3 days after the DT4 exposure does not produce changes significantly different from baseline.

  • Interestingly, daily testing on the PR prevents the increase in

Are the neural substrates of locomotor sensitization the same as those that underlie sensitization to the reinforcing effects?

It is unclear at this stage whether the neural adaptations that underlie locomotor sensitization are identical to those which mediate the increased reinforcing efficacy of cocaine. It should be noted that Phillips et al. [35] showed that cocaine self-administration produced sensitization to the locomotor effects. However, the schedule used in that study (limited access on an FR 1 schedule) would not be expected to produce a change in cocaine-reinforced break points on a PR schedule. These data

Concluding remarks

There are a number of unanswered questions regarding sensitization to various effects of cocaine, the neurobiological substrates involved, and the significance of these changes (both behavioral and neurobiological) to humans. It is still unclear how administering several non-contingent injections can produce such profound effects weeks later, whereas cocaine self-administration for relatively long periods of time (weeks to months) fails to appreciably alter subsequent self-administration. It is

Acknowledgements

This work was supported by NIH grants P50DA06643, RO1DA14030 to DCSR, and K01DA13957 to DM.

References (67)

  • S Schenk et al.

    Sensitization to cocaine's reinforcing effects produced by various cocaine pretreatment regimens in rats

    Pharmacol Biochem Behav

    (2000)
  • D.S Lorrain et al.

    Previous exposure to amphetamine increases incentive to obtain the drug: long-lasting effects revealed by the progressive ratio schedule

    Behav Brain Res

    (2000)
  • A Le et al.

    Neurobiology of relapse to alcohol in rats

    Pharmacol Ther

    (2002)
  • C.-E Johanson et al.

    Self-administration of psychomotor stimulant drugs: The effects of unlimited access

    Pharmacol Biochem Behav

    (1976)
  • D.C.S Roberts et al.

    Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure

    Drug Alcohol Depend

    (2002)
  • T.E Fitch et al.

    The effects of dose and access restrictions on the periodicity of cocaine self-administration in the rat

    Drug Alcohol Depend

    (1993)
  • K Brebner et al.

    The GABA(B) agonist CGP 44532 decreases cocaine self-administration in rats: demonstration using a progressive ratio and a discrete trials procedure

    Neuropharmacol

    (1999)
  • R.C Pierce et al.

    A circuitry model of the expression of behavioral sensitization to amphetamine-like psychostimulants

    Brain Res Brain Res Rev

    (1997)
  • J.D Steketee

    Neurotransmitter systems of the medial prefrontal cortex: potential role in sensitization to psychostimulants

    Brain Res Brain Res Rev

    (2003)
  • M.E Wolf

    The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

    Prog Neurobiol

    (1998)
  • N Suto et al.

    Previous exposure to VTA amphetamine enhances cocaine self-administration under a progressive ratio schedule in a D1 dopamine receptor dependent manner

    Neuropsychopharmacology

    (2002)
  • F.H Gawin

    Cocaine addiction: psychology and neurophysiology

    Science

    (1991)
  • S.B Caine et al.

    Effects of dopamine D(1-like) and D(2-like) agonists in rats that self-administer cocaine

    J Pharmacol Exp Ther

    (1999)
  • D.C.S Roberts et al.

    The estrous cycle affects cocaine self-administration on a progressive ratio schedule in rats

    Psychopharm

    (1989)
  • V Deroche et al.

    Glucocorticoids and behavioral effects of psychostimulants. II: cocaine intravenous self-administration and reinstatement depend on glucocorticoid levels

    J Pharmacol Exp Ther

    (1997)
  • H De Wit et al.

    Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with noradrenergic blockers phentolamine and phenoxybenzamine

    Can J Psych

    (1977)
  • B.J Everitt et al.

    Psychomotor stimulant addiction: a neural systems perspective

    J Neurosci

    (2002)
  • E.J Nestler

    Psychogenomics: opportunities for understanding addiction

    J Neurosci

    (2001)
  • C.P O'Brien

    Recent developments in the pharmacotherapy of substance abuse

    J Consult Clin Psychol

    (1996)
  • P Willner et al.

    New advances in the understanding and treatment of addiction

    Behav Pharmacol

    (2002)
  • A.I Leshner

    National Institute on Drug Abuse's behavioral research agenda

    Exp Clin Psychopharmacol

    (2000)
  • K Brebner et al.

    Effect of baclofen on cocaine self-administration in rats reinforced under fixed-ratio 1 and progressive-ratio schedules

    Psychopharm

    (2000)
  • D.C.S Roberts et al.

    Self-administration of cocaine on a progressive ratio schedule in rats: dose-response relationship and effect of haloperidol pretreatment

    Psychopharm

    (1989)
  • Cited by (0)

    View full text