Dopamine mediation of positive reinforcing effects of amphetamine in stimulant naı̈ve healthy volunteers: results from a large cohort

https://doi.org/10.1016/j.euroneuro.2003.08.007Get rights and content

Abstract

A positive experience during a first encounter with a drug of abuse is predictive of subsequent use and might represent a vulnerability factor to develop addiction. This paper presents a meta-analysis of data acquired in 60 healthy volunteers who underwent a low-dose amphetamine challenge (0.3 mg/kg, i.v.) during imaging of dopamine D2 receptor availability with SPECT and the D2/D3 radiotracer [123I]IBZM. Amphetamine-stimulated DA release induced a small, significant and highly variable decrease in striatal D2 receptor availability (−8.3±6.7%). The magnitude of the decrease in D2 receptor availability was significantly associated with the positive reinforcing effects of the drug reported by the subject (r2=0.14, p=0.003). Age was associated with decreased potency of dopamine to elicit positive reinforcing effects. This study indicates that both a large dopaminergic response and young age during a first encounter with a drug of abuse potential contribute to higher positive reinforcing effects.

Introduction

The positive reinforcement provided by psychostimulants plays a considerable role in stimulant-seeking behavior and in the development of addiction to stimulants such as cocaine and amphetamine Wise, 1988, Markou et al., 1993. Considerable between-subject heterogeneity has been observed in the subjective response to psychostimulants van Kammen and Murphy, 1975, Post et al., 1988, and it has been suggested that the intensity and quality of positive reinforcing experience during initial exposure to psychostimulants increase the vulnerability to develop psychostimulant abuse Newcomb et al., 1987, O'Brien et al., 1992, Childress et al., 1993.

In rodents, the vulnerability to experience the positive reinforcement effects of the drug during the initial exposure appears to be at least partially under genetic control. For example, compared to Fisher rats, Lewis rats show greater behavioral responses to psychoactive drugs and a faster rate of cocaine self-administration acquisitions Kosten et al., 1994, Kosten et al., 1997, Simar et al., 1996, Ward et al., 1996. A large body of literature suggests that the positive reinforcing effects of cocaine are, at least partly, mediated by the mesolimbic dopamine (DA) systems Wise and Romprè, 1989, Kuhar et al., 1991, Le Moal and Simon, 1991, Koob, 1992, Di Chiara, 1995, Self and Nestler, 1995, Nestler et al., 1996. The difference between Lewis and Fisher strains has been attributed to differences in the mesolimbic DA system reactivity to psychostimulant exposure Camp et al., 1994, Ortiz et al., 1995, Strecker et al., 1995. A first exposure to cocaine leads to a greater (Camp et al., 1994) and prolonged (Strecker et al., 1995) elevation of extracellular DA as measured with microdialysis in Lewis compared to Fisher rats. Until recently, the relevance of these preclinical observations to humans was unknown due to the difficulty in obtaining a direct measurement of DA transmission in the living human brain.

Neuroreceptor imaging with PET and SPECT are classically aimed at measuring neuroreceptor parameters in the living human brain. More recently, several groups have demonstrated that under specific conditions, in vivo neuroreceptor binding techniques can also be used to measure acute fluctuations in the concentration of the endogenous transmitters in the vicinity of radiolabeled receptors (for review, see Laruelle, 2000). For example, the administration of psychostimulants such as amphetamine or methylphenidate is associated with an acute reduction in the binding potential (BP) of the radiotracers [11C]raclopride or [123I]IBZM Volkow et al., 1994, Laruelle et al., 1995, Breier et al., 1997. In nonhuman primates, the magnitude of this reduction is related to the amphetamine-induced increase in extracellular DA measured with microdialysis Breier et al., 1997, Laruelle et al., 1997. Therefore, the decrease in [11C]raclopride BP can be used as a noninvasive measure of the change in DA induced by the challenge. Binding competition between the endogenous transmitter and the radioligand is believed to be the critical mechanism underlying this interaction, although other phenomena, such as receptor affinity state, internalization or polymerization have also been implicated Laruelle, 2000, Logan et al., 2001.

Laruelle et al. (1995) reported that in a small group of healthy volunteers never previously exposed to psychostimulants (n=8), the increase in euphoria produced by acute amphetamine administration was related to the decrease in striatal [123I]IBZM BP induced by the challenge. This observation suggested that the between subject variability in the positive effects of stimulants might result from between-subject variability in the magnitude of the dopaminergic response. This observation was confirmed in three additional cohorts, by Volkow et al. (1999a), using methylphenidate and [11C]raclopride in 14 subjects, by Drevets et al. (1999) in 7 subjects, using amphetamine and [11C]raclopride, and by Martinez et al. (2003), using amphetamine and [11C]raclopride in 14 subjects. Thus, to date, four studies from three different laboratories have observed a relationship between the intensity of the positive response reported by the subjects and the magnitude of DA release, as measured by the acute reduction in D2 receptor availability to the radiotracer. However, differences between these studies were noted in the strength of this association, as well as in the localization of these effects. Three studies observed this association at the level of the whole striatum Laruelle et al., 1995, Volkow et al., 1999a, Martinez et al., 2003, and one study observed it only in the ventral striatum (Drevets et al., 1999).

Over the last few years, we acquired a relatively large sample of healthy controls who underwent an amphetamine challenge coupled with [123I]IBZM imaging. None of the study participants had a prior history of exposure to psychostimulants. The experimental procedure was kept constant, enabling us to pool the data to better characterize the relationship between subjective effects of amphetamine and parameters of DA transmission, as well as the effect of age on this association.

Section snippets

Subjects

A total of 60 healthy volunteers were included in this analysis (age: 35±11 years old, age range 19–53 years old, 43 males and 17 females, 42 Caucasians, 7 Hispanics and 11 Afro-American subjects). Inclusion criteria for study participation were: (1) absence of past or present neurological or psychiatric illness (including substance abuse), (2) no concomitant or past cardiovascular conditions, (3) no present or prior exposure to psychostimulants and (4) absence of pregnancy. Participants were

Subjective response to amphetamine challenge

Amphetamine-induced changes in the four subjective analog scales are shown in Fig. 1. “Happiness” and “Energy” showed similar time course of changes: a rapid raise, a peak at about 10 min, followed by a rapid decline and a stabilization above baseline from 30 to 60 min. Typically, subjects reported that the effects began to diminish between 20 and 30 min, corresponding to the decline in self-rating of happiness and energy. Restlessness followed a different pattern, with a similar but more

Discussion

Functional brain imaging techniques are important tools to study the neurobiological mechanisms mediating acute and chronic effects of drugs of abuse in the human brain. Until recently, functional imaging techniques used in this context were based on measurements of glucose metabolism London et al., 1990, Stapleton et al., 1995 or blood flow Pearlson et al., 1993, Breiter et al., 1997. Here, a new method providing unique insight on changes into DA neurotransmission was applied to study the

Conclusion

In conclusion, this study examined the relationship between the magnitude of DA release following a single dose d-amphetamine challenge and the intensity of positive reinforcement effect experienced by subjects never previously exposed to psychostimulants. A significant association was observed between the reinforcing effects of the drug and the magnitude of decrease in striatal D2 receptor availability. While an association does not necessarily imply a causal relationship, the results suggest

Acknowledgments

The authors would like to thank the collaborators at Yale and Columbia who were involved in collecting the primary data included in this analysis: Christopher H. van Dyck, Sami S. Zoghbi, Ronald M. Baldwin, John P. Seibyl, Dennis S. Charney, Paul Hoffer, Janine Rodenhiser, PhD, Yolanda Zea-Ponce, Ronald L. Van Heertum, J. John Mann, Ramin V. Parsey, Jack M. Gorman and Thomas B. Cooper. The authors acknowledge the support of the National Alliance for Research on Schizophrenia and Depression

References (82)

  • G.F. Koob et al.

    The D1 dopamine receptor antagonist SCH 23390 increases cocaine self-administration in the rat

    Neurosci. Lett.

    (1987)
  • C. Kornetsky et al.

    Reward and detection thresholds for brain stimulation: dissociative effects of cocaine

    Brain Res.

    (1981)
  • T.A. Kosten et al.

    Acquisition and maintenance of intravenous cocaine self-administration in Lewis and Fischer inbred rat strains

    Brain Res.

    (1997)
  • M.J. Kuhar et al.

    The dopamine hypothesis of the reinforcing properties of cocaine

    Trends Neurosci.

    (1991)
  • M. Laruelle et al.

    In vivo quantification of dopamine D2 receptors parameters in nonhuman primates with [123I]iodobenzofuran and single photon emission computerized tomography

    Eur. J. Pharmacol.

    (1994)
  • R.R. Luedtke et al.

    Comparison of the expression, transcription and genomic organization of D2 dopamine receptors in outbred and inbred strains of rat

    Brain Res.

    (1992)
  • W.H. Lyness et al.

    Destruction of dopaminergic nerve terminals in nucleus accumbens: effect on d-amphetamine self-administration

    Pharmacol. Biochem. Behav.

    (1979)
  • R. Maldonado et al.

    D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat

    Pharmacol. Biochem. Behav.

    (1993)
  • J. Ortiz et al.

    Strain-selective effects of corticosterone on locomotor sensitization to cocaine and on levels of tyrosine hydroxylase and glucocorticoid receptor in the ventral tegmental area

    Neuroscience

    (1995)
  • R.V. Parsey et al.

    Dopamine D(2) receptor availability and amphetamine-induced dopamine release in unipolar depression

    Biol. Psychiatry

    (2001)
  • D.C. Roberts et al.

    Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens

    Pharmacol. Biochem. Behav.

    (1980)
  • D.W. Self et al.

    The D1 agonists SKF 82958 and SKF 77434 are self-administered by rats

    Brain Res.

    (1992)
  • J.M. Stapleton et al.

    Cerebral glucose utilization in polysubstance abuse

    Neuropsychopharmacology

    (1995)
  • S.R. Tella

    Differential blockade of chronic versus acute effects of intravenous cocaine by dopamine receptor antagonists

    Pharmacol. Biochem. Behav.

    (1994)
  • W.L. Woolverton

    Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys

    Pharmacol. Biochem. Behav.

    (1986)
  • A. Abi-Dargham et al.

    Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort

    Am. J. Psychiatry

    (1998)
  • R.L. Barrett et al.

    Effects of stimulation and blockade of dopamine receptor subtypes on the discriminative stimulus properties of cocaine

    Psychopharmacology

    (1989)
  • J. Bergman et al.

    Effects of cocaine and related drugs in nonhuman primates: III. Self-administration by squirrel monkeys

    J. Pharmacol. Exp. Ther.

    (1989)
  • J. Bergman et al.

    Agonist efficacy and the behavioral effects of dopamine D1 receptor ligands: drug interaction studies in squirrel monkeys

    J. Pharmacol. Exp. Ther.

    (1996)
  • J. Booij et al.

    Assessment of endogenous dopamine release by methylphenidate challenge using iodine-123 iodobenzamide single-photon emission tomography

    Eur. J. Nucl. Med.

    (1997)
  • A. Breier et al.

    Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • S. Cabib et al.

    D1 and D2 receptor antagonists differently affect cocaine-induced locomotor hyperactivity in the mouse

    Psychopharmacology

    (1991)
  • S.B. Caine et al.

    Modulation of cocaine self-administration in the rat through D-3 dopamine receptors

    Science

    (1993)
  • S.B. Caine et al.

    Effects of the dopamine D-1 antagonist SCH 23390 microinjected into the accumbens, amygdala or striatum on cocaine self-administration in the rat

    Brain Res.

    (1995)
  • P.M. Callahan et al.

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

    Psychopharmacology

    (1991)
  • A.R. Childress et al.

    Cue reactivity and cue reactivity interventions in drug dependence

    NIDA Res. Monogr.

    (1993)
  • G. Di Chiara et al.

    Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of freely moving rats

    Proc. Natl. Acad. Sci. U. S. A.

    (1988)
  • D.M. Grech et al.

    Self-administration of D1 receptor agonists by squirrel monkeys

    Psychopharmacology

    (1996)
  • C.B. Hubner et al.

    Effects of selective D1 and D2 dopamine antagonists on cocaine self-administration in the rat

    Psychopharmacology

    (1991)
  • H.F. Kaiser

    The varimax criterion for varimax rotation in factor analysis

    Psychometrika

    (1958)
  • L.S. Kegeles et al.

    Stability of [123I]IBZM SPECT measurement of amphetamine-induced striatal dopamine release in humans

    Synapse

    (1999)
  • Cited by (63)

    • Neurochemical imaging in addiction: How science informs practice

      2018, The Assessment and Treatment of Addiction: Best Practices and New Frontiers
    • Variability in paralimbic dopamine signaling correlates with subjective responses to d-amphetamine

      2016, Neuropharmacology
      Citation Excerpt :

      Given that dAMPH causes the release of the neurotransmitter dopamine (DA) primarily via blockade and reversal of the dopamine transporter (DAT) (Jones et al., 1998) and animal work has linked DA release in nodes of the mesocorticolimbic system with reward processes (Wise and Rompre, 1989), researchers have proposed that DA release in this system may be directly or indirectly responsible for dAMPH’s euphoric effect in humans. Indeed, previous work has found that dAMPH-induced DA release measured in the striatum with 123I-IBZM SPECT is associated with a positive reinforcement factor (Abi-Dargham et al., 2003). PET studies using 11C-raclopride have, more specifically, implicated ventral striatum (VS) dAMPH-induced DA release with self-reported dAMPH-induced euphoria (Drevets et al., 2001) or drug wanting (Leyton et al., 2002).

    • Neuronal and Behavioral Effects of Amphetamine in Caenorhabditis elegans

      2016, Neuropathology of Drug Addictions and Substance Misuse
    • Neuronal and Behavioral Effects of Amphetamine in Caenorhabditis elegans

      2016, Neuropathology of Drug Addictions and Substance Misuse Volume 2: Stimulants, Club and Dissociative Drugs, Hallucinogens, Steroids, Inhalants and International Aspects
    View all citing articles on Scopus
    View full text