ReviewAddictive potential of cannabinoids: the underlying neurobiology
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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2016, Journal of Steroid Biochemistry and Molecular BiologyCitation Excerpt :Furthermore, PREG has the ability to antagonize the addiction-related effects of cannabinoids [152]. A well-known consequence of the intake of Cannabis sativa and its derivatives is a positive reinforcing effect that can lead to regular use and ultimately to addiction [42]. First, we demonstrated that acute PREG decreased midbrain DA system activation that is involved in mediating addiction to most drugs of abuse, including cannabinoids [30,43,141].
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2015, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :Previously, we reported that injection of NMDA into the dorsal hippocampus potentiates morphine-CPP (Zarrindast et al., 2007). These results confirm that cannabinoids act on brain reward processes and reward-related behaviors in strikingly similar fashion to other addictive drugs (Gardner, 2002). The present results also showed that the bilateral microinjection of D-AP7, a specific NMDA receptor antagonist, into the CA1 region of dorsal hippocampus alone, did not induce a significant place preference or aversion by itself, while co-administration of the antagonist with ACPA, during the conditioning phase, inhibited the ACPA (0.02 mg/kg)-induced place preference.
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2012, Handbook of Clinical NeurologyCitation Excerpt :The brain has at least two types of cannabinoid receptor – CB1 and CB2 – and there are at least two types of endogenous cannabinoid – anandamide and 2-AG (Elphick and Egertova, 2001). Regular consumption of cannabis (marijuana) can give rise to dependence, and the same dopaminergic reward pathways that underlie the development of addiction-based pathological neuroplasticity are activated by cannabis (Gardner, 2002). Thus, cannabinoid receptors are in high density in the vicinity of midbrain dopamine neurons.
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2011, PainCitation Excerpt :CB1 is predominantly located within the CNS [57]. Here, activation is linked to hypoactivity, hypothermia, catalepsy, antinociception [38], and rewarding properties typical of addictive substances [15,16,37,43]. CB2 is expressed predominantly, but not exclusively [4,7,52], in immune cells and occurs in brain at low levels [33,52].