Binky
08-30-2005, 11:09 AM
Nature Medicine 7, 1099 - 1100 (2001)
doi:10.1038/nm1001-1099
Cannabinoid activity curtails cocaine craving
Daniele Piomelli
Department of Pharmacology University of California, Irvine Irvine, California, USA
piomelli@uci.edu
Behavioral studies demonstrate that the central mechanism involved in cocaine relapse is closely linked to the sites where marijuana has its effect, suggesting that cannabinoid receptor antagonists may be used as anti-craving agents. (pages 1151-1154)
Although the use of psychoactive drugs begins as a voluntary behavior, in addicted individuals it becomes as uncontrollable as the compulsive, ritualized acts that afflict obsessive-compulsive disorder patients. The overpowering nature of drug addiction and the associated changes in brain structure and function have led to conceptualization of this condition as a chronic disease of the central nervous system. Like other chronic brain diseases, drug addiction goes through recurrent cycles of remission and relapse, which can be readily triggered when abstinent addicts are confronted with reminders of their drug habit ('conditioned cues') or with emotional distress. The prevention of such relapses is thus one of the primary goals of addiction treatment1.
Relapse to drug taking can be modeled in laboratory animals. In one such model, the 'reinstatement paradigm', cocaine self-administration is first induced in rats and then extinguished by subjecting the animals to a period of abstinence. After drug taking has stopped, exposure to stress, administration of low doses of cocaine or presentation of cocaine-associated cues will cause the behavior to reappear. Regardless of the stimulus, relapses are accompanied by increased activity of the mesolimbic dopamine system—a neural pathway comprising a small group of dopamine-releasing cells in the midbrain connected to a much larger field of dopamine-responsive neurons in the forebrain's nucleus accumbens and prefrontal cortex (Fig. 1). This pathway is thought to be activated in behaviors such as eating and mating, and to underlie the rewarding properties of many psychoactive drugs, but its exact role in drug craving and relapse is only partially understood. One key question is what neurotransmitter systems interact with this mesolimbic dopamine pathway during relapse. In this issue, a study by De Vries et al. may provide an answer2. In doing so, the study opens up an unexpected avenue for the preventive therapy of cocaine relapse2.
Figure 1. Cocaine craving is thought to be associated with activation of the mesolimbic dopamine system.
Figure 1 thumbnail
This neuromodulatory pathway projects from the ventral tegmental area (VTA) in the midbrain to the nucleus accumbens and the prefrontal cortex. Stress and drug-associated cues may activate the mesolimbic dopamine system by engaging two distinct brain regions, the prefrontal cortex and the amygdala, respectively, that send excitatory projections to the VTA. Presynaptic cannabinoid receptors are present in these brain areas, where their primary role may be to modulate gamma-aminobutyric acid (GABA) and glutamate release.
Full FigureFull Figure and legend (26K)
De Vries et al. used the rat reinstatement model to test whether cannabinoid receptors—the target of the marijuana constituent Delta9-tetrahydrocannabinol—have a role in cocaine relapse. They show that the cannabinoid agonist HU-210 precipitates relapse, whereas the cannabinoid antagonist SR141716A prevents relapse induced by cocaine or cocaine-associated cues, but not relapse induced by stress. Because SR141716A has no effect on cocaine self-administration3, these findings suggest that cannabinoid receptors may be selectively involved in triggering cocaine craving during abstinence, rather than in mediating the primary effects of the drug. That cannabinoid receptors should be implicated in reward is intuitive—millions of marijuana users can testify to that—but that these receptors should also gate cocaine relapse is more surprising. How might it occur?
Cannabinoid receptors present in the brain belong largely to the CB1 subtype, although evidence for the existence of other subtypes is accumulating4. CB1 receptors are coupled to Gi/o proteins and are normally activated by a small group of endogenous lipids called endocannabinoids, of which anandamide and 2-arachidonylglycerol are two well-studied examples. Unlike neurotransmitters and neuropeptides, endo-cannabinoids are not stored in synaptic vesicles but are produced on demand and released from neurons5.
Two neurotransmitter systems have been linked to the generation of endocannabinoids: dopamine elicits anandamide release in the dorsal striatum by stimulating D2-type receptors6, while glutamate causes 2-arachidonylglycerol formation in the cortex by engaging NMDA (N-methyl-d-aspartate) receptors6, 7.
To explain their results, De Vries et al. outline two possible scenarios that are based on a dopamine-endocannabinoid connection. In one model, elevated dopamine levels produced by cocaine or cocaine-associated cues elicit the release of endocannabinoids, which cause relapse. Alternatively, cocaine or cocaine-associated cues elevate endocannabinoid levels, which cause relapse by enhancing dopamine release. Because the brain's cannabinergic pathways are still uncharted, we lack hard evidence to support either scenario. Yet, the latter hypothesis—that of a disinhibitory role for the endocannabinoids on dopamine transmission—is supported by three observations: CB1 receptors are found in high numbers on axon terminals of gamma-aminobutyric acid (GABA)-ergic interneurons throughout the central nervous system; activation of these receptors inhibits GABA release8; and GABA-ergic interneurons strongly influence the activity of dopaminergic projection neurons.
Irrespective of the cellular mechanism, the finding that blockade of cannabinoid receptors prevents cue-mediated relapses to cocaine seeking is of obvious therapeutic significance. There is no pharmacological treatment for cocaine relapse at present, and even though there are many social and psychological factors that can facilitate relapse, an agent that 'takes the edge off' craving would provide an invaluable complement to behavioral therapy and psychotherapy. Moreover, as commonality emerges in the mechanism by which these drugs are addictive, the therapeutic range of cannabinoid antagonists may be expanded to include other abused substances, such as opiates and alcohol. Animal studies suggest that cannabinoid receptor blockade may alleviate both heroin and alcohol craving2, 9, 10. One possible reservation to the use of cannabinoid antagonists in relapse therapy is that these molecules may not be able to prevent stress-induced relapse, as shown by De Vries et al. However, other agents such as non-peptide antagonists of corticotropin-releasing factor receptors may adequately control this condition11. As with other chronic diseases, it is reasonable to expect that treatment of drug craving and relapse will involve the use of more than one drug.
Top
REFERENCES
1. O'Brien, C.P. A range of research based pharmacotherapies for addiction. Science 278, 66–70 (1997). | Article | PubMed | ChemPort |
2. De Vries, T.C. et al. A cannabinoid mechanism in relapse to cocaine seeking. Nature Med. 7, 1151–1154 (2001). | Article | PubMed | ISI | ChemPort |
3. Fattore, L., Martellotta, M.C., Cossu, G., Mascia, M.S. & Fratta, W. CB1 cannabinoid receptor agonist WIN 55,212–2 decreases intravenous cocaine self-administration in rats. Behav. Brain Res. 104, 141–146 (1999). | Article | PubMed | ISI | ChemPort |
4. Hajos, N., Ledent, C. & Freund, T.F. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience (in press).
5. Piomelli, D., Giuffrida, A., Rodríguez de Fonseca, F. & Calignano, A. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21, 218–224 (2000). | Article | PubMed | ISI | ChemPort |
6. Giuffrida, A. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci. 2, 358–363 (1999). | Article | PubMed | ISI | ChemPort |
7. Stella, N. & Piomelli, D. Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196 (2001). | Article | PubMed | ISI | ChemPort |
8. Kátona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999). | PubMed | ISI | ChemPort |
9. Gallate, J.E. & McGregor, I.S. The motivation for beer in rats: effects of ritanserin, naloxone and SR141716. Psychopharmacology 142, 302–308 (1997). | Article |
10. Colombo, G. et al. Reduction of voluntary ethanol intake in ethanol-preferring SP rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol. 33, 126–130 (1998). | PubMed | ISI | ChemPort |
11. Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: A review. Brain Res. Rev. 33, 13–33 (2000). | Article | PubMed | ISI | ChemPort |
http://www.nature.com/nm/journal/v7/n10/full/nm1001-1099.html
doi:10.1038/nm1001-1099
Cannabinoid activity curtails cocaine craving
Daniele Piomelli
Department of Pharmacology University of California, Irvine Irvine, California, USA
piomelli@uci.edu
Behavioral studies demonstrate that the central mechanism involved in cocaine relapse is closely linked to the sites where marijuana has its effect, suggesting that cannabinoid receptor antagonists may be used as anti-craving agents. (pages 1151-1154)
Although the use of psychoactive drugs begins as a voluntary behavior, in addicted individuals it becomes as uncontrollable as the compulsive, ritualized acts that afflict obsessive-compulsive disorder patients. The overpowering nature of drug addiction and the associated changes in brain structure and function have led to conceptualization of this condition as a chronic disease of the central nervous system. Like other chronic brain diseases, drug addiction goes through recurrent cycles of remission and relapse, which can be readily triggered when abstinent addicts are confronted with reminders of their drug habit ('conditioned cues') or with emotional distress. The prevention of such relapses is thus one of the primary goals of addiction treatment1.
Relapse to drug taking can be modeled in laboratory animals. In one such model, the 'reinstatement paradigm', cocaine self-administration is first induced in rats and then extinguished by subjecting the animals to a period of abstinence. After drug taking has stopped, exposure to stress, administration of low doses of cocaine or presentation of cocaine-associated cues will cause the behavior to reappear. Regardless of the stimulus, relapses are accompanied by increased activity of the mesolimbic dopamine system—a neural pathway comprising a small group of dopamine-releasing cells in the midbrain connected to a much larger field of dopamine-responsive neurons in the forebrain's nucleus accumbens and prefrontal cortex (Fig. 1). This pathway is thought to be activated in behaviors such as eating and mating, and to underlie the rewarding properties of many psychoactive drugs, but its exact role in drug craving and relapse is only partially understood. One key question is what neurotransmitter systems interact with this mesolimbic dopamine pathway during relapse. In this issue, a study by De Vries et al. may provide an answer2. In doing so, the study opens up an unexpected avenue for the preventive therapy of cocaine relapse2.
Figure 1. Cocaine craving is thought to be associated with activation of the mesolimbic dopamine system.
Figure 1 thumbnail
This neuromodulatory pathway projects from the ventral tegmental area (VTA) in the midbrain to the nucleus accumbens and the prefrontal cortex. Stress and drug-associated cues may activate the mesolimbic dopamine system by engaging two distinct brain regions, the prefrontal cortex and the amygdala, respectively, that send excitatory projections to the VTA. Presynaptic cannabinoid receptors are present in these brain areas, where their primary role may be to modulate gamma-aminobutyric acid (GABA) and glutamate release.
Full FigureFull Figure and legend (26K)
De Vries et al. used the rat reinstatement model to test whether cannabinoid receptors—the target of the marijuana constituent Delta9-tetrahydrocannabinol—have a role in cocaine relapse. They show that the cannabinoid agonist HU-210 precipitates relapse, whereas the cannabinoid antagonist SR141716A prevents relapse induced by cocaine or cocaine-associated cues, but not relapse induced by stress. Because SR141716A has no effect on cocaine self-administration3, these findings suggest that cannabinoid receptors may be selectively involved in triggering cocaine craving during abstinence, rather than in mediating the primary effects of the drug. That cannabinoid receptors should be implicated in reward is intuitive—millions of marijuana users can testify to that—but that these receptors should also gate cocaine relapse is more surprising. How might it occur?
Cannabinoid receptors present in the brain belong largely to the CB1 subtype, although evidence for the existence of other subtypes is accumulating4. CB1 receptors are coupled to Gi/o proteins and are normally activated by a small group of endogenous lipids called endocannabinoids, of which anandamide and 2-arachidonylglycerol are two well-studied examples. Unlike neurotransmitters and neuropeptides, endo-cannabinoids are not stored in synaptic vesicles but are produced on demand and released from neurons5.
Two neurotransmitter systems have been linked to the generation of endocannabinoids: dopamine elicits anandamide release in the dorsal striatum by stimulating D2-type receptors6, while glutamate causes 2-arachidonylglycerol formation in the cortex by engaging NMDA (N-methyl-d-aspartate) receptors6, 7.
To explain their results, De Vries et al. outline two possible scenarios that are based on a dopamine-endocannabinoid connection. In one model, elevated dopamine levels produced by cocaine or cocaine-associated cues elicit the release of endocannabinoids, which cause relapse. Alternatively, cocaine or cocaine-associated cues elevate endocannabinoid levels, which cause relapse by enhancing dopamine release. Because the brain's cannabinergic pathways are still uncharted, we lack hard evidence to support either scenario. Yet, the latter hypothesis—that of a disinhibitory role for the endocannabinoids on dopamine transmission—is supported by three observations: CB1 receptors are found in high numbers on axon terminals of gamma-aminobutyric acid (GABA)-ergic interneurons throughout the central nervous system; activation of these receptors inhibits GABA release8; and GABA-ergic interneurons strongly influence the activity of dopaminergic projection neurons.
Irrespective of the cellular mechanism, the finding that blockade of cannabinoid receptors prevents cue-mediated relapses to cocaine seeking is of obvious therapeutic significance. There is no pharmacological treatment for cocaine relapse at present, and even though there are many social and psychological factors that can facilitate relapse, an agent that 'takes the edge off' craving would provide an invaluable complement to behavioral therapy and psychotherapy. Moreover, as commonality emerges in the mechanism by which these drugs are addictive, the therapeutic range of cannabinoid antagonists may be expanded to include other abused substances, such as opiates and alcohol. Animal studies suggest that cannabinoid receptor blockade may alleviate both heroin and alcohol craving2, 9, 10. One possible reservation to the use of cannabinoid antagonists in relapse therapy is that these molecules may not be able to prevent stress-induced relapse, as shown by De Vries et al. However, other agents such as non-peptide antagonists of corticotropin-releasing factor receptors may adequately control this condition11. As with other chronic diseases, it is reasonable to expect that treatment of drug craving and relapse will involve the use of more than one drug.
Top
REFERENCES
1. O'Brien, C.P. A range of research based pharmacotherapies for addiction. Science 278, 66–70 (1997). | Article | PubMed | ChemPort |
2. De Vries, T.C. et al. A cannabinoid mechanism in relapse to cocaine seeking. Nature Med. 7, 1151–1154 (2001). | Article | PubMed | ISI | ChemPort |
3. Fattore, L., Martellotta, M.C., Cossu, G., Mascia, M.S. & Fratta, W. CB1 cannabinoid receptor agonist WIN 55,212–2 decreases intravenous cocaine self-administration in rats. Behav. Brain Res. 104, 141–146 (1999). | Article | PubMed | ISI | ChemPort |
4. Hajos, N., Ledent, C. & Freund, T.F. Novel cannabinoid-sensitive receptor mediates inhibition of glutamatergic synaptic transmission in the hippocampus. Neuroscience (in press).
5. Piomelli, D., Giuffrida, A., Rodríguez de Fonseca, F. & Calignano, A. The endocannabinoid system as a target for therapeutic drugs. Trends Pharmacol. Sci. 21, 218–224 (2000). | Article | PubMed | ISI | ChemPort |
6. Giuffrida, A. et al. Dopamine activation of endogenous cannabinoid signaling in dorsal striatum. Nature Neurosci. 2, 358–363 (1999). | Article | PubMed | ISI | ChemPort |
7. Stella, N. & Piomelli, D. Receptor-dependent formation of endogenous cannabinoids in cortical neurons. Eur. J. Pharmacol. 425, 189–196 (2001). | Article | PubMed | ISI | ChemPort |
8. Kátona, I. et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J. Neurosci. 19, 4544–4558 (1999). | PubMed | ISI | ChemPort |
9. Gallate, J.E. & McGregor, I.S. The motivation for beer in rats: effects of ritanserin, naloxone and SR141716. Psychopharmacology 142, 302–308 (1997). | Article |
10. Colombo, G. et al. Reduction of voluntary ethanol intake in ethanol-preferring SP rats by the cannabinoid antagonist SR-141716. Alcohol Alcohol. 33, 126–130 (1998). | PubMed | ISI | ChemPort |
11. Shaham, Y., Erb, S. & Stewart, J. Stress-induced relapse to heroin and cocaine seeking in rats: A review. Brain Res. Rev. 33, 13–33 (2000). | Article | PubMed | ISI | ChemPort |
http://www.nature.com/nm/journal/v7/n10/full/nm1001-1099.html