Addictive potential of cannabinoids: the underlying neurobiology

doi:10.1016/S0009-3084(02)00162-7

Chemistry and Physics of Lipids

Volume 121, Issues 1–2, 31 December 2002, Pages 267-290

https://doi.org/10.1016/S0009-3084(02)00162-7 Get rights and content

Abstract

Drugs that are addictive in humans have a number of commonalities in animal model systems—(1) they enhance electrical brain-stimulation reward in the core meso-accumbens reward circuitry of the brain, a circuit encompassing that portion of the medial forebrain bundle (MFB) which links the ventral tegmental area (VTA) of the mesencephalic midbrain with the nucleus accumbens (Acb) of the ventral limbic forebrain; (2) they enhance neural firing of a core dopamine (DA) component of this meso-accumbens reward circuit; (3) they enhance DA tone in this reward-relevant meso-accumbens DA circuit, with resultant enhancement of extracellular Acb DA; (4) they produce conditioned place preference (CPP), a behavioral model of incentive motivation; (5) they are self-administered; and (6) they trigger reinstatement of drug-seeking behavior in animals behaviorally extinguished from intravenous drug self-administration behavior and, perforce, pharmacologically detoxified from their self-administered drug. Cannabinoids were long considered ‘anomalous’, in that they were believed to not interact with these brain reward processes or support drug-seeking and drug-taking behavior in these animal model systems. However, it is now clear—from the published data of several research groups over the last 15 years—that this view of cannabinoid action on brain reward processes and reward-related behaviors is untenable. This paper reviews those data, and concludes that cannabinoids act on brain reward processes and reward-related behaviors in strikingly similar fashion to other addictive drugs.

Introduction

The reward circuitry of the mammalian brain consists of synaptically interconnected neurons which link the ventral tegmental area (VTA), nucleus accumbens (Acb), ventral pallidum (VP), and medial prefrontal cortex (MPFC). Laboratory animals avidly self-administer mild electrical stimulation to these loci, and to the medial forebrain bundle (MFB) which interconnects the VTA, Acb, and MPFC. Mild electrical stimulation of this circuit is intensely pleasurable in humans. This circuit is strongly implicated in the neural processes underlying drug addiction, and inhibition of this circuit is implicated in such phenomena as withdrawal dysphoria and dysphoria-mediated drug craving. These brain processes are believed to have evolved to subserve biologically essential natural rewards, such as the seeking and consumption of food and water, the seeking of and mating with sexual partners, and the performance of parenting behaviors. These brain processes are also believed to subserve drug-seeking and drug-taking behaviors supported by addictive drugs. Cannabinoids are euphorigenic in humans and have addictive liability, but were long considered to be devoid of pharmacological action on these brain reward processes or on drug-seeking and drug-taking behaviors. Work with cannabinoids over the last 15 years, however, makes it clear that they interact with these brain processes and influence drug-seeking and drug-taking behaviors in a manner strikingly similar to that of other addictive drugs.

Section snippets

Neuroanatomy, neurophysiology, and neurochemistry of brain reward

The neuroanatomy, neurophysiology, and neurochemistry of brain reward processes is known to involve a series of neural links associated with the MFB and located in the ventral limbic midbrain/forebrain (Gardner, 1997). Neuroanatomically, this system appears to consist of ‘first-stage’, ‘second-stage’, and ‘third-stage’ reward-related neurons ‘in series’ with one another (Wise and Bozarth, 1984, Gardner, 1997). From anatomical tracing studies and electrophysiological studies which allow

Modeling addiction with animal behavioral models

A number of salient features of addictive behavior at the human level have been successfully modeled at the animal level, with seemingly good face validity and predictive validity to the human situation (Gardner, 2000, Wise and Gardner, 2002a). These models include conditioned place preference (CPP), drug self-administration, and reinstatement.

Cannabinoid effects on brain reward processes

Although cannabinoids have clear addictive potential at the human level (Kozel and Adams, 1986, Kleber, 1988, Goldstein and Kalant, 1990, Anthony et al., 1994, Hall et al., 1994, MacCoun and Reuter, 1997, Crowley et al., 1998), they have been labeled by some (e.g. Felder and Glass, 1998) as ‘anomalous’, i.e. having no action on brain reward processes. Simply stated, this is an untenable position. Over the last 15 years, a large body of research has made it clear that marijuana and other

Cannabinoid actions on CPP

As noted above, CPP is a widely used behavioral model for studying drug-seeking behavior, and inferring the incentive motivational value and strength of addictive drugs. Fundamentally, CPP is the learned approach to a previously neutral set of environmental stimuli which have been paired with administration of a rewarding treatment (van der Kooy, 1987, Tzschentke, 1998). When used to assess drug-induced reward, animals are given drug injections while confined in one of two cue-distinctive

Neural models of cannabinoid actions on brain reward processes

From the evidence cited above, and from additional available data, hypotheses may be generated regarding where and how cannabinoids act to alter brain reward processes, and in turn, reward-related behaviors.

Summary

On the basis of more than 15 years of electrophysiological and biochemical evidence, cannabinoids appear to enhance brain reward processes in similar fashion to other addictive drugs. Also on the basis of electrophysiological and biochemical evidence, cannabinoid withdrawal appears to activate the same brain withdrawal processes as activated by withdrawal from other addictive drugs. Behaviorally, cannabinoids produce CPP, are self-administered, and trigger relapse to drug-seeking behavior in

Acknowledgements

Cannabinoid research cited in this paper from the author's laboratory was supported by research grants from the US Public Health Service, National Institutes of Health (grants AA09547, DA02089, DA03622, and RR05397); the US National Science Foundation (grant BNS-86-09351); the Natural Sciences and Engineering Research Council of Canada; the New York State Office of Alcoholism and Substance Abuse Services; the New York State Office of Mental Health; the Aaron Diamond Foundation; the Julia

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ReviewAddictive potential of cannabinoids: the underlying neurobiology

Abstract

Introduction

Section snippets

Neuroanatomy, neurophysiology, and neurochemistry of brain reward

Modeling addiction with animal behavioral models

Cannabinoid effects on brain reward processes

Cannabinoid actions on CPP

Neural models of cannabinoid actions on brain reward processes

Summary

Acknowledgements

Eur. J. Pharmacol.

Brain Res. Rev.

Neuroscience

Eur. J. Pharmacol.

Neuroscience

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Brain Res.

Brain Res.

Drug Alcohol Depend.

Drug Alcohol Depend.

Neuroscience

Pharmacol. Biochem. Behav.

Neurosci. Lett.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Semin. Neurosci.

Neurobiol. Dis.

Pharmacol. Biochem. Behav.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Neuroscience

Neuropsychopharmacology

Brain Res.

Neuropharmacology

Biochem. Pharmacol.

Brain Res.

Eur. J. Pharmacol.

Biochem. Pharmacol.

Dependence on delta 9-tetrahydrocannabinol: studies on precipitated and abrupt withdrawal

J. Pharmacol. Exp. Ther.

Oral self-administration of alcohol: a valid approach to the study of drug self-administration and human alcoholism

Comparative epidemiology of dependence on tobacco, alcohol, controlled substances and inhalants: basic findings from National Comorbidity Study

Exp. Clin. Psychopharmacol.

Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes

J. Pharmacol. Exp. Ther.

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens

Crit. Rev. Neurobiol.

Neuropsychological interpretation of the effects of drive and incentive-motivation on general activity and instrumental behavior

Psychol. Rev.

The effect of Δ9-tetrahydrocannabinol on the synthesis of dopamine and norepinephrine in mouse brain synaptosomes

J. Pharmacol. Exp. Ther.

A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse

Psychopharmacology

9-Nor-9beta-hydroxyhexahydrocannabinol, a cannabinoid with potent antinociceptive activity: comparisons with morphine

J. Pharmacol. Exp. Ther.

Reward deficiency syndrome

Am. Scientist

The D2 dopamine receptor gene as a determinant of reward deficiency syndrome

J. R. Soc. Med.

Anatomically distinct opiate receptor fields mediate reward and physical dependence

Science

Testing Drugs for Physical Dependence Potential and Abuse Liability (NIDA Res. Monogr. 52)

Assessing drugs for abuse liability and dependence potential in laboratory primates

Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum

J. Neurochem.

Rewarding actions of phencyclidine and related drugs in nucleus accumbens shell and frontal cortex

J. Neurosci.

Involvement of central cannabinoid (CB1) receptors in the establishment of place conditioning in rats

Psychopharmacology

Cannabinoid receptors and reward in the rat: a conditioned place preference study

Psychopharmacology

Review
Addictive potential of cannabinoids: the underlying neurobiology

The effect of Δ⁹-tetrahydrocannabinol on the synthesis of dopamine and norepinephrine in mouse brain synaptosomes

A comparison of some pharmacological actions of morphine and Δ⁹-tetrahydrocannabinol in the mouse

Involvement of central cannabinoid (CB₁) receptors in the establishment of place conditioning in rats