Evidence for bidirectional cues as a function of time following treatment with amphetamine: implications for understanding tolerance and withdrawal

https://doi.org/10.1016/j.pbb.2004.10.005Get rights and content

Abstract

Rationale

Previous drug-discrimination studies have focused on characterizing the cue properties associated with amphetamine's (AMPH) primary effect. Results from recent experiments indicate that equally prominent cues are associated with AMPH withdrawal.

Objectives

The purpose of the present study was to investigate the extent to which AMPH-induced withdrawal cues, opposite to those associated with AMPH's primary effect are observed.

Methods

Since dopamine (DA) has been implicated in mediating the AMPH cue, rats were trained to discriminate between 0.25 mg/kg AMPH, an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) providing a behavioral baseline sensitive to assessing AMPH-related bidirectional changes in cue state. Following acquisition of the discrimination, rats were tested for choice of responding on the AMPH and HAL levers at intervals from 6 to 72 h following treatment with a single dose of 3.0 mg/AMPH. Also, in order to investigate the relationship between withdrawal and tolerance to AMPH's cue properties, AMPH dose–response curves were determined 24 h following treatment with SAL, 1.5 and 3.0 mg/kg AMPH.

Results

At short intervals after treatment with 3.0 mg/kg AMPH, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16–30 h post-treatment, before returning to predrug levels. Treatment with 1.5 and 3.0 mg/kg AMPH produced parallel dose–response curve shifts to the right.

Conclusions

Following a single dose of AMPH, robust cues associated with AMPH withdrawal were observed that lasted approximately three times longer than the cues associated with the drug's primary effects. Furthermore, results from the tolerance tests indicate that tolerance reflects a baseline shift rather than a loss in drug efficacy.

Introduction

The drug-discrimination procedure has proven to be a valuable tool in characterizing the interoceptive cue properties of drugs in both animals and people. In animals, the procedure has been used to identify drugs with similar cue properties, characterize the neurotransmitter–receptor interactions responsible for mediating a drug's cue properties and to help identify the neuroanatomical sites where these interactions are thought to occur. A drug that has received considerable attention in the drug-discrimination literature is the CNS stimulant amphetamine (AMPH), a drug with a long history documenting its potential for abuse (Ellinwood, 1973). Drug-discrimination studies have comprehensively investigated the mechanisms mediating amphetamine's primary cue properties and the results converge on an important role for the neurotransmitter dopamine (DA). For example, other drugs thought to activate DA function such as cocaine (D'Mello and Stolerman, 1977), methylphenidate (Rush and Pazzaglia, 1997) and l-cathinone (Huang and Wilson, 1986) generalize to the amphetamine cue. More specifically, results from studies that have evaluated DA agonists have shown that D2 agonists including quinpirole, pergolide and piribedil all generalize to amphetamine (Evans and Johanson, 1987, Arnt, 1988, Nielsen et al., 1989, Callahan et al., 1991). Likewise, D2 antagonists including haloperidol (HAL), pimozide, raclopride, sulpiride, spiroperidol and sulpiride have been shown to block the amphetamine cue (Jarbe, 1982, Nielsen and Jepsen, 1985, Arnt, 1988, Nielsen et al., 1989, Callahan et al., 1991). Evidence that the specific DA reuptake inhibitor GBR 12909 completely generalizes to amphetamine (Van Groll and Appel, 1992) is also consistent with a role for DA. Results from experiments with D1 agonists and antagonists are less clear. Several studies reported that neither the full D1 agonist SKF 81297 nor the partial D1 agonist SKF 38393 generalize to amphetamine (Arnt, 1988, Kamien and Woolverton, 1989, Nielsen et al., 1989, Callahan et al., 1991, Reavill et al., 1993), although a number of experiments found that the D1 antagonists SCH 23390 and SCH 39166 block the amphetamine cue (Nielsen and Jepsen, 1985, Arnt, 1988, Kamien and Woolverton, 1989, Van Groll and Appel, 1992). Taken together, the literature clearly suggests that DA is involved in mediating the amphetamine cue at D2 receptors although a role for D1 receptors is less clear. Studies aimed at identifying the neuroanatomical locus of the amphetamine cue have found that rats trained to discriminate systemically administered amphetamine will generalize to amphetamine injected directly into the nucleus accumbens (Nielsen and Scheel-Kruger, 1986), while 6-OHDA lesions of the nucleus accumbens disrupt amphetamine generalization (Dworkin and Bimle, 1989). Studies have described the conditions that produce chronic tolerance to the amphetamine cue (Barrett and Leith, 1981, Young et al., 1992) and have characterized its temporal properties (Jones et al., 1976, Silverman and Ho, 1980). In all of the studies cited above, rats were trained on a conventional, saline (SAL)–amphetamine discrimination, which provides a unidirectional measure of the interoceptive cues associated with amphetamine's primary effects. Results from several recent studies (Barrett et al., 1992, Barrett and Smith, 1988, Michaelis et al., 1988, Smith et al., 1995), specifically designed to provide a behavioral measure sensitive to bidirectional changes in cue state, have discovered that the gradual dissipation and eventual disappearance of a drug's primary cue is often accompanied by the gradual development and eventual appearance of robust and long lasting withdrawal cues that previously had gone undetected. Initial findings suggest that the withdrawal cues are qualitatively opposite to those associated with the primary cue and account for a significant percent of the overall change in cue state induced by drug administration (Barrett et al., 1992, Barrett and Smith, 1988, Barrett and Steranka, 1983, Smith et al., 1995). The purpose of the present experiment was to use the bidirectional measure previously described (Barrett et al., 1992) to characterize the intensity and duration of the rebound cues as a function of treatment dose of amphetamine and to investigate the relationship between withdrawal and the observation of rapid tolerance. Rapid tolerance is defined here as the diminished response to a drug upon administration of a second dose 24 h after the first dose (Silveri and Spear, 2001).

Section snippets

Subjects and apparatus

Thirty-six male Sprague–Dawley rats obtained from Harlan Laboratories, Indianapolis, IN weighing approximately 250–300 g at the start of the experiment were housed in individual cages and food deprived to 85% of their expected free-feeding weight. The rats were maintained on a 12-h light–dark cycle (lights on at 0600 h) and given enough food (Purina Lab Chow) immediately following each training session and on weekends to maintain their control weight throughout the experiments. The animals had

Training on a two-lever task to discriminate between amphetamine and haloperidol

The rats in the present experiment had received training on a three-lever, amphetamine–saline–haloperidol discrimination prior to being switched to the two-lever, amphetamine–haloperidol task used in this experiment. The three-lever training occurred during daily 20-min training sessions in the operant chambers described above with the exception that three levers were positioned on the front panel of each chamber. Reinforcement during the three-lever training was programmed on a concurrent,

Acquisition of the amphetamine–haloperidol discrimination

From the time the rats were switched from training on the three-lever procedure to training on the two-lever, AMPH-HAL task, 10 sessions with AMPH and 10 with HAL were required for the animals to reach criterion discrimination. By the conclusion of acquisition and throughout the duration of the experiment, the rats consistently averaged over 90% correct lever choice when tested on the training doses of both AMPH (0.25 mg/kg) and HAL (0.035 mg/kg). When all rats were tested on SAL following

Discussion

The results from the present study show that rats can learn to discriminate differences along a continuum of presumed DA-mediated cues. By adjusting the training doses of the indirect DA agonist AMPH and the DA, D2 receptor antagonist HAL, it was possible to obtain a discrimination baseline that was equally sensitive to detecting increases and decreases in DA mediated cues. Of particular interest is the normal distribution of the SAL test scores that were acquired throughout the experiment that

Acknowledgments

The authors would like to express their appreciation for the expertise and meticulous attention to detail provided by Ms. Barbara Gilreath in conducting this study. This research was supported by the Veterans Administration.

References (69)

  • G.F. Koob et al.

    Opponent process model of addiction

    Pharmacol. Biochem. Behav.

    (1997)
  • M.L. McKenna et al.

    Induced tolerance to the discriminative stimulus properties of cocaine

    Pharmacol. Biochem. Behav.

    (1977)
  • E.B. Nielsen et al.

    Antagonism of the amphetamine cue by both classical and atypical antipsychotic drugs

    Eur. J. Pharmacol.

    (1985)
  • E.B. Nielsen et al.

    Cueing effects of amphetamine and LSD: elicitation by direct microinjections of the drugs into the nucleus accumbens

    Eur. J. Pharmacol.

    (1986)
  • E.B. Nielsen et al.

    Amphetamine discrimination: effects of dopamine receptor agonists

    Eur. J. Pharmacol.

    (1989)
  • J.B. Rosen et al.

    Discriminative stimulus properties of amphetamine and other stimulants in lead-exposed and normal rats

    Pharmacol. Biochem. Behav.

    (1986)
  • M.D. Schechter

    Dopaminergic mediation of a behavioral effect of l-cathinone

    Pharmacol. Biochem. Behav.

    (1986)
  • P.B. Silverman et al.

    Amphetamine discrimination: onset of the stimulus

    Pharmacol. Biochem. Behav.

    (1980)
  • R.L. Smith et al.

    Tolerance to the anticonflict effects of diazepam: importance of methodological considerations

    Pharmacol. Biochem. Behav.

    (1997)
  • B.J. Van Groll et al.

    Stimulus effects of d-amphetamine 1: DA mechanisms

    Pharmacol. Biochem. Behav.

    (1992)
  • S.H. Ahmed et al.

    Long-lasting increases in the set point for cocaine self-administration after escalation in rats

    Psychopharmacology

    (1999)
  • E.J. Ariens

    Affinity and intrinsic activity in the theory of competitive inhibition

    Arch. Int. Pharmacodyn. Ther.

    (1954)
  • R.L. Balster

    Drug abuse potential evaluation in animals

    Br. J. Addict.

    (1991)
  • R.J. Barrett

    Behavioral approaches to individual differences in substance abuse

  • R.J. Barrett et al.

    Time dependent pentylenetetrazol-like cues subsequent to diazepam administration

    Psychopharmacology

    (1988)
  • R.J. Barrett et al.

    Tolerance, withdrawal and supersensitivity to dopamine mediated cues in a drug–drug discrimination

    Psychopharmacology

    (1992)
  • R.J. Barrett et al.

    Drug discrimination is a continuous rather than quantal process following training on a VI–TO schedule of reinforcement

    Psychopharmacology

    (1994)
  • P.M. Beardsley et al.

    Separation of the response rate and discriminative stimulus effects of phencyclidine: training dose as a factor in phencyclidine–saline discrimination

    J. Pharmacol. Exp. Ther.

    (1987)
  • P.M. Callahan et al.

    Dopamine D1 and D2 mediation of the discriminative stimulus properties of d-amphetamine and cocaine

    Psychopharmacology

    (1991)
  • W.F. Caul et al.

    Drug discrimination training during chronic drug treatment affects the development of tolerance

    Behav. Neurosci.

    (1989)
  • W.F. Caul et al.

    Rebound responding following a single dose of drug using an amphetamine–vehicle–haloperidol drug discrimination

    Psychopharmacology

    (1996)
  • F.C. Colpaert

    Drug discrimination: no evidence for tolerance to opiates

    Pharmacol. Rev.

    (1995)
  • F.C. Colpaert

    System theory of pain and of opiate analgesia: no tolerance to opiates

    Pharmacol. Rev.

    (1996)
  • F.C. Colpaert et al.

    Agonist and antagonist effects of prototype opiate drugs in fentanyl dose–dose discrimination

    Psychopharmacology

    (1986)
  • Cited by (6)

    View full text