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.

Author Keywords: Addiction; Brain stimulation reward; Cannabis; Cannabinoids; Conditioned place preference; Dopamine; Limbic; Marijuana; Medial forebrain bundle; Meso-accumbens; Mesolimbic; Microdialysis; Nucleus accumbens; Reinforcement; Reinstatement; Relapse; Reward; Self-administration; Self-stimulation; Ventral tegmental area

Abbreviations: Acb, nucleus accumbens; BLA, basolateral amygdala; BNST, bed nucleus of stria terminalis; BSR, brain stimulation reward; CeA, central nucleus of the amygdala; CPA, conditioned place aversion; CPP, conditioned place preference; CRF, corticotropin-releasing factor; DA, dopamine; GABA, γ-aminobutyric acid; MFB, medial forebrain bundle; MPFC, medial prefrontal cortex; 3-MT, 3-methoxytyramine; PR, progressive-ratio; THC, Δ⁹-tetrahydrocannabinol; VP, ventral pallidum; VTA, ventral tegmental area

Article Outline

1. Introduction

2. Brain reward processes

2.1. Neuroanatomy, neurophysiology, and neurochemistry of brain reward

2.2. Addictive drug action on brain reward processes

2.3. Brain reward dysregulation as a cause of addiction

3. Reward-related behaviors

3.1. Modeling addiction with animal behavioral models

3.1.1. Conditioned place preference

3.1.2. Drug self-administration

3.1.3. Reinstatement

3.2. Addictive drug action on reward-related behaviors

4. Cannabinoid effects on brain reward processes

4.1. Cannabinoid effects on electrical BSR

4.2. Cannabinoid effects on DA neuronal firing in brain reward circuitry

4.3. Cannabinoid effects on DA neurochemical substrates of brain reward

4.3.1. In vitro studies

4.3.2. In vivo studies

4.4. Genetic variation in cannabinoid actions on brain reward processes

4.5. Cannabinoid withdrawal and brain reward processes

4.6. Endogenous opioid involvement in cannabinoid actions on brain reward processes

5. Cannabinoid actions on reward-related behaviors

5.1. Cannabinoid actions on CPP

5.2. Cannabinoid self-administration in animal models

5.3. Cannabinoid actions on reinstatement

6. Neural models of cannabinoid actions on brain reward processes

6.1. Neural sites of cannabinoid action on brain reward

6.2. Neural mechanisms of cannabinoid action on brain reward processes

7. Summary

Acknowledgements

References