Cannabinoid Interaction with Brain Reward Systems

  • Eliot L. Gardner


With few exceptions, addicting drugs enhance electrical brain-stimulation reward and act as direct or indirect dopamine agonists in the reward-relevant dopaminergic projections of the medial forebrain bundle. These dopaminergic projections constitute a crucial drug-sensitive link in the brain’s reward circuitry, and addictive drugs derive significant abuse liability from enhancing these circuits. Furthermore, basal aberrations in dopaminergic function within these circuits appear to constitute a major neurobiological vulnerability factor for drug addiction. Marihuana was long considered an “anomalous” addictive drug, lacking pharmacological interaction with these brain reward substrates. However, it is now clear—from more than 10 years of consistent research findings—that ∆9-tetrahydrocannabinol (THC), marihuana’s principal psychoactive constituent, acts on these brain reward substrates in strikingly similar fashion to noncannabinoid addictive drugs. Specifically, THC enhances MFB electrical brain-stimulation reward, and enhances both basal and stimulated dopamine release in reward-relevant MFB projection loci. THC’s actions on these mechanisms is tetrodotoxin-sensitive, calcium-dependent, and naloxone-blockable. Furthermore, THC modulates brain t and S opioid receptors. Also, withdrawal from THC produces neurophysiological and neurochemical sequelae that are strikingly similar to those seen in withdrawal from other addictive drugs. Mechanistically, THC appears to act on brain reward substrates by inhibiting the reuptake of dopamine from the synaptic cleft in reward-relevant synapses of the nucleus accumbens. Behaviorally, THC enhances reward-related behaviors and incentive motivation. This paper reviews these data, and suggests that marihuana’s interaction with brain reward systems is fundamentally similar to that of other addictive drugs. This paper concludes that persistent claims that cannabinoids do not interact with brain reward mechanisms must be dismissed—on the basis of more than 10 years of consistent published findings—as either uninformed or biased pleadings.


Nucleus Accumbens Conditioned Place Preference Conditioned Taste Aversion Medial Forebrain Bundle Brain Reward 
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© Springer Science+Business Media New York 1999

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  • Eliot L. Gardner

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