A ‘crash’ course on psychostimulant withdrawal as a model of depression

doi:10.1016/S0165-6147(02)02086-2

Trends in Pharmacological Sciences

Volume 23, Issue 10, 1 October 2002, Pages 475-482

https://doi.org/10.1016/S0165-6147(02)02086-2 Get rights and content

Abstract

Most drugs of abuse generate diverse behavioral and neurochemical effects in mammals. However, one feature common to many such drugs is the phenomenon of the withdrawal syndrome that results from termination of drug administration. Early drug withdrawal, often referred to as the ‘crash’ phase in humans, is characterized by adverse psychological and/or somatic symptoms. Withdrawal from psychostimulant drugs precipitates a transient and primarily psychological condition that bears remarkable similarity to the symptoms of major depressive disorder in humans. Rodent paradigms of psychostimulant withdrawal faithfully model the human condition. Associated behavioral deficits in these animals can be reversed by treatments with antidepressant properties, suggesting that psychostimulant withdrawal might provide the basis for an animal model of depression. Current advances and limitations in the development of this model, together with recent evidence that psychostimulant withdrawal in rodents can be used to screen for novel, rapidly acting antidepressant treatments, are discussed.

Section snippets

Psychostimulant withdrawal in humans

In general, both cocaine and amphetamines increase alertness, concentration and energy when taken in lower doses, whereas higher doses of these compounds produce additional euphorigenic effects that often are described as a ‘high’ or ‘rush’ [9]. These pleasurable effects decline rapidly, within minutes in the case of cocaine [10] or over a period of several hours in the case of d-amphetamine [11], depending partly on the route of self-administration. As the rewarding properties of the drug

Psychostimulant withdrawal and ‘depressive-like’ symptoms

The features of psychostimulant withdrawal bear remarkable similarity to the symptoms of unipolar depression; indeed, the semblance can be so great that the clinician might have to differentiate between the two based solely on the suspected etiology of the condition [20]. A comparison of the effects of psychostimulant withdrawal with the DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnostic criteria for MDD, independent of symptom duration, shows that almost

Psychostimulant withdrawal as a model of depression

The similarity of psychostimulant withdrawal and depressive symptoms evident in MDD in humans provides the foundation for the development of an animal model of depressive symptomatology, in which valid comparisons can be made between the behavioral, physiological and pharmacological aspects of psychostimulant withdrawal in animals and humans. Rodents self-administer similar drugs of abuse as do humans [21]. Through the use of sophisticated behavioral paradigms, it has been shown that rodents

Physiological effects of psychostimulant withdrawal

In addition to the behavioral similarities between psychostimulant withdrawal in rodents and symptoms of MDD in humans, there are also significant physiological parallels between the two situations. Numerous studies examining the neurochemical alterations associated with cocaine withdrawal, using in vivo techniques, have shown reduced extracellular levels of dopamine in limbic nuclei, such as the NAcc, during cocaine withdrawal [41], although equivocal findings in this region have been reported

Pharmacological treatment of psychostimulant withdrawal

One of the primary purposes of animal models of depression, particularly for the pharmaceutical industry, is the identification of compounds with antidepressant properties. For a model to serve this function successfully, it must respond to drugs that exhibit antidepressant effects in humans, and hence display ‘pharmacological validity’ 22., 23., 40.. The model ideally should respond to all classes of compounds [such as tricyclic drugs, monoamine oxidase inhibitors and selective 5-HT reuptake

Limitations of the model

Although recent advances in the development of the psychostimulant withdrawal model indicate substantial scientific potential for this paradigm, this model also has several inherent limitations. It should be noted that the transient nature of psychostimulant withdrawal in rodents, with effects typically observable for less than one week (and hence a narrow window for therapeutic intervention), might pose a theoretical challenge to the detection of novel antidepressant compounds because of the

Concluding remarks

The withdrawal from large doses of psychostimulant drugs in humans generates a syndrome with striking behavioral and physiological parallels to MDD. These effects have been modeled successfully in rodent paradigms, in which animals display reliable and highly reproducible behavioral and physiological alterations following withdrawal from both cocaine and amphetamines, although the effects on affective indices of withdrawal from other psychostimulants, such as MDMA, remain to be determined.

Acknowledgements

This work is supported by NIDA grant DA11946, NIMH grant MHS62527 and a Novartis Pharma AG Research grant to A.M., and a grant from the Canadian Institutes for Health Research to A.G.P. We would like to thank John F. Cryan, Novartis Pharma AG for his helpful comments on the manuscript. We would also like to thank Patricia Di Ciano, Dept of Experimental Psychology, University of Cambridge, and Pornnarin Taepavarapruk, Dept of Psychiatry, University of British Columbia for their contribution of

References (61)

A.S. Christophersen
Amphetamine designer drugs – an overview and epidemiology
Toxicol. Lett.
(2000)
W.C. Drevets
Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria
Biol. Psychiatry
(2001)
N.D. Volkow
Effects of route of administration on cocaine induced dopamine transporter blockade in the human brain
Life Sci.
(2000)
H.C. Breiter
Acute effects of cocaine on human brain activity and emotion
Neuron
(1997)
A.J. Justice et al.
Acute effects of d-amphetamine during the early and late follicular phases of the menstrual cycle in women
Pharmacol. Biochem. Behav.
(2000)
G.F. Koob
Opponent process model and psychostimulant addiction
Pharmacol. Biochem. Behav.
(1997)
K.M. Kampman
The combination of phentermine and fenfluramine reduced cocaine withdrawal symptoms in an open trial
J. Subst. Abuse Treat.
(2000)
P. Willner
Animal models as simulations of depression
Trends Pharmacol. Sci.
(1991)
A. Ettenberg
Evidence for opponent-process actions of intravenous cocaine
Pharmacol. Biochem. Behav.
(1999)
A.M. Barr
Effects of withdrawal from an escalating dose schedule of d-amphetamine on sexual behavior in the male rat
Pharmacol. Biochem. Behav.
(1999)

A.M. Barr et al.

Increased successive negative contrast in rats withdrawn from an escalating-dose schedule of D-amphetamine

Pharmacol. Biochem. Behav.

(2002)

A.A. Harrison

Fluoxetine combined with a serotonin-1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats

Neuropsychopharmacology

(2001)

P. Willner

Animal models of depression: an overview

Pharmacol. Ther.

(1990)

F. Weiss

Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration

Brain Res.

(1992)

P.E. Paulson et al.

Regional differences in the effects of amphetamine withdrawal on dopamine dynamics in the striatum. Analysis of circadian patterns using automated on-line microdialysis

Neuropsychopharmacology

(1996)

M.H. Baumann et al.

Alterations in serotonergic responsiveness during cocaine withdrawal in rats: similarities to major depression in humans

Biol. Psychiatry

(1998)

F. Holsboer

The corticosteroid receptor hypothesis of depression

Neuropsychopharmacology

(2000)

J.F. Cryan

Assessing antidepressant activity in rodents: recent developments and future needs

Trends Pharmacol. Sci.

(2002)

A. Markou

Neurobiological similarities in depression and drug-dependence: a self-medication hypothesis

Neuropsychopharmacology

(1998)

P.M. Thompson

Polygraphic sleep measures differentiate alcoholics and stimulant abusers during short-term abstinence

Biol. Psychiatry

(1995)

S.M. Evans et al.

Caffeine withdrawal: a parametric analysis of caffeine dosing conditions

J. Pharmacol. Exp. Ther.

(1999)

S. Shiffman et al.

The effect of bupropion on nicotine craving and withdrawal

Psychopharmacology (Berl.)

(2000)

M.P. Epping-Jordan

Dramatic decreases in brain reward function during nicotine withdrawal

Nature

(1998)

J.M. Brown

Regulation of the vesicular monoamine transporter-2: a novel mechanism for cocaine and other psychostimulants

J. Pharmacol. Exp. Ther.

(2001)

R.B. Rothman

Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin

Synapse

(2001)

S.M. Evans

The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women

Psychopharmacology (Berl.)

(2002)

R.L. Solomon et al.

An opponent-process theory of motivation: 1. Temporal dynamics of affect

Psychol. Rev.

(1974)

F.H. Gawin et al.

Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations

Arch. Gen. Psychiatry

(1986)

R.W. Foltin et al.

Effects of ‘binge’ use of intravenous cocaine in methadone-maintained individuals

Addiction

(1998)

K.M. Kampman

Amantadine in the treatment of cocaine-dependent patients with severe withdrawal symptoms

Am. J. Psychiatry

(2000)

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Another critical aspect that characterizes the withdrawal period is the emergence of a long phase dominated by depression-like symptoms such as dysphoria, anhedonia and anxiety, similar to those observed in animal models of depression, and all of which provide fertile ground for relapse (Koob and Le Moal, 2001; Koob and Volkow, 2010) (Barr et al., 2002). A significant negative emotional state is evident during withdrawal from drugs of abuse such as opioids and alcohol (Koob, 2021) as well as psychostimulants, tobacco, and cannabis (Barr et al., 2002; Koob, 2021). Preclinical research has provided inspiration for novel strategies to treat addiction and multiple approaches have been explored in order to counteract the withdrawal negative state and to revert the neural maladaptations underlying these symptoms.
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Trends in Pharmacological Sciences

ReviewA ‘crash’ course on psychostimulant withdrawal as a model of depression

Abstract

Section snippets

Psychostimulant withdrawal in humans

Psychostimulant withdrawal and ‘depressive-like’ symptoms

Psychostimulant withdrawal as a model of depression

Physiological effects of psychostimulant withdrawal

Pharmacological treatment of psychostimulant withdrawal

Limitations of the model

Concluding remarks

Acknowledgements

Toxicol. Lett.

Biol. Psychiatry

Life Sci.

Neuron

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

J. Subst. Abuse Treat.

Trends Pharmacol. Sci.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neuropsychopharmacology

Pharmacol. Ther.

Brain Res.

Neuropsychopharmacology

Biol. Psychiatry

Neuropsychopharmacology

Trends Pharmacol. Sci.

Neuropsychopharmacology

Biol. Psychiatry

Caffeine withdrawal: a parametric analysis of caffeine dosing conditions

J. Pharmacol. Exp. Ther.

The effect of bupropion on nicotine craving and withdrawal

Psychopharmacology (Berl.)

Dramatic decreases in brain reward function during nicotine withdrawal

Nature

Regulation of the vesicular monoamine transporter-2: a novel mechanism for cocaine and other psychostimulants

J. Pharmacol. Exp. Ther.

Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin

Synapse

The effects of smoked cocaine during the follicular and luteal phases of the menstrual cycle in women

Psychopharmacology (Berl.)

An opponent-process theory of motivation: 1. Temporal dynamics of affect

Psychol. Rev.

Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Clinical observations

Arch. Gen. Psychiatry

Effects of ‘binge’ use of intravenous cocaine in methadone-maintained individuals

Addiction

Amantadine in the treatment of cocaine-dependent patients with severe withdrawal symptoms

Am. J. Psychiatry

Review
A ‘crash’ course on psychostimulant withdrawal as a model of depression