The Dopaminergic System
The reinforcement and reward models of drug addiction have suggested that dopamine neurotransmission plays a key role in the motivation to use drugs. Dopamine appears to be at least partially responsible for the stimulus-reward association that is involved in addiction, and abnormal dopamine levels have even been correlated with schizophrenic and psychotic symptoms as well.
Similar to cannabinoids and the endocannabinoid system, dopamine binds to dopaminergic receptors D2 and D3. Studies conducted in 2001 and 2011 indicated that chronic cannabis use may dull these receptors, but better designed, peer-reviewed studies conducted in 2008, 2011, 2012, 2013 and 2014 have failed to replicate these findings. There are no differences in D2 and D3 dopamine receptors in those who do and do not consume cannabis.
Studies
In numerous preclinical studies, dopamine and cannabinoids were found to have inconsistently reported interactions with one another. Five studies from 1991 and 1997 indicated an increase in dopamine levels following the administration of THC, but 17 further studies conducted in between 1998 and 2015 seemed to either find difficulty replicating the same results, or producing data that contradicts those initial studies, with Jentsch 1998’s work demonstrating decreased dopamine levels in chronic THC administration. It should be noted that many of these studies did not test THC itself, and instead used synthetic cannabinoids WIN55212-2 and HU-210, both of which have been found in the dangerous designer drug Spice, and CP55940, which was developed for the treatment of brain cancer. In human trials, no consistent relationship has been found between cannabinoids and dopamine. Studies in 2013 and 2015 conducted positron-emission tomography (PET) scans on volunteers who inhaled 8 mg of THC or a placebo, and both found no effect of THC on dopamine levels.
Citations
- Wise, RA. Rompre, PP. Brain dopamine and reward. Annual Review of Psychology. (1989)
- Gardner, EL. Lowinson, JH. Marijuana’s interaction with brain reward systems: update 1991. Pharmacology, Biochemistry and Behavior. (1991)
- Schultz, W. Dayan, P. Montague, PR. A neural substrate of prediction and reward. Science. (1997)
- Gurevich, VV. Pals-Rylaarsdam, R. Benovic, JL. Hosey, MM. Onorato, JJ. Agonist-receptor-arrestin, an alternative ternary complex with high agonist affinity. Journal of Biological Chemistry. (1997)
- Tanda, G. Pontieri, FE. Di Chiara, G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. (1997)
- Cadogan, AK. Alexander, SP. Boyd, EA. Kendall, DA. Influence of cannabinoids on electrically evoked dopamine release and cyclic AMP generation in the rat striatum. Journal of Neurochemistry. (1997)
- Berridge, KC. Robinson, TE. What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience? Brain Research Reviews. (1998)
- Jentsch, JD. Verrico, CD. Le, D. Roth, RH. Repeated exposure to delta 9-tetrahydrocannabinol reduces prefrontal cortical dopamine metabolism in the rat. Neuroscience Letters. (1998)
- Diana, M. Melis, M. Muntoni, AL. Gessa, GL. Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proceedings of the National Academy of Sciences of the USA. (1998)
- Spanagel, R. Weiss, F. The dopamine hypothesis of reward: past and current status. Trends in Neuroscience. (1999)
- Szabo, B. Muller, T. Koch, H. Effects of cannabinoids on dopamine release in the corpus striatum and the nucleus accumbens in vitro. Journal of Neurochemistry. (1999)
- Sell, LA. Morris, J. Bearn, J. Frackowiak, RS. Friston, KJ. Dolan, RJ. Activation of reward circuitry in human opiate addicts. European Journal of Neuroscience. (1999)
- Volkow, ND. Chang, L. Wang, GJ. Fowler, JS. Ding, YS. Sedler, M. Logan, J. Franceschi, D. Gatley, J. Hitzemann, R. Gifford, A. Wong, C. Pappas, N. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. American Journal of Psychiatry. (2001)
- Manzoni, OJ. Bockaert, J. Cannabinoids inhibit GABAergic synaptic transmission in mice nucleus accumbens. European Journal of Pharmacology. (2001)
- Di Chiara, G. Nucleus accumbens shell and core dopamine: differential role in behavior and addiction. Behavioural Brain Research. (2002)
- Wise, RA. Dopamine, learning and motivation. Nature Reviews, Neuroscience. (2004)
- Moranta, D. Esteban, S. Garcia-Sevilla, JA. Differential effects of acute cannabinoid drug treatment, mediated by CB1 receptors, on the in vivo activity of tyrosine and tryptophan hydroxylase in the rat brain. Naunyn-Schmiedeberg’s Archives of Pharmacology. (2004)
- Everitt, BJ. Robbins, TW. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neuroscience. (2005)
- Volkow, ND. Wang, GJ. Telang, F. Fowler, JS. Logan, J. Childress, AR. Jayne, M. Ma, Y. Wong, C. Cocaine cues and dopamine in dorsal striatum: mechanism of craving in cocaine addiction. Journal of Neuroscience. (2006)
- Alcaro, A. Huber, R. Panksepp, J. Behavioral Functions of the Mesolimbic Dopaminergic System: an Affective Neuroethological Perspective. Brain Research Reviews. (2007)
- Chen, J. Downs, SM. Amp-Activated Protein Kinase is Involved in Hormone-Induced Mouse Oocyte Meiotic Maturation in Vitro. Developmental Biology. (2008)
- Sevy, S. Smith, GS. Ma, Y. Dhawan, V. Chaly, T. Kingsley, PB. Kumra, S. Abdelmessih, S. Eidelberg. D. Cerebral glucose metabolism and D2/D3 receptor availability in young adults with cannabis dependence measured with positron emission tomography. Psychopharmacology. (2008)
- Morera-Herreras, T. Ruiz-Ortega, JA. Gomez-Urquijo, S. Ugedo, L. Involvement of subthalamic nucleus in the stimulatory effect of Delta(9)-tetrahydrocannabinol on dopaminergic neurons. Neuroscience. (2008)
- Kegeles, LS. Abi-Dargham, A. Frankle, WG. Gil, R. Cooper, TB. Slifstein, M. Hwang, DR. Huang, Y. Haber, SN. Laruelle, M. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Archives of General Psychiatry. (2010)
- Wise, RA. Dopamine and Reward: The Anhedonia Hypothesis 30 years on. Neurotoxicity Research. (2011)
- Kim, SH. Baik, SH. Park, CS. Kim, SJ. Choi, SW. Kim, SE. Reduced striatal dopamine D2 receptors in people with Internet addiction. Neuroreport. (2011)
- Ginovart, N. Tournier, BB. Moulin-Sallanon, M. Steimer, T. Ibanez, V. Millet, P. Chronic Δ9-Tetrahydrocannabinol Exposure Induces a Sensitization of Dopamine D2/3 Receptors in the Mesoaccumbens and Nigrostriatal Systems. Neuropsychopharmacology. (2012)
- Morera-Herreras, T. Miguelez, C. Aristieta, A. Ruiz-Ortega, JA. Ugedo, L. Endocannabinoid modulation of dopaminergic motor circuits. Frontiers in Pharmacology. (2012)
- Urban, NB. Slifstein, M. Thompson, JL. Xu, X. Girgis, RR. Raheja, S. Dopamine release in chronic cannabis users: a [11c]raclopride positron emission tomography study. Biology Psychiatry. (2012)
- Stokes, PR. Egerton, A. Watson, B. Reid, A. Lappin, J. Howes, OD. Nutt, DJ. Lingford-Hughes, AR. History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability. Journal of Psychopharmacology. (2012)
- Kuepper, R. Ceccarini, J. Lataster, J. Van OS, J. Van Kroonenburgh, M. Van Gerven, JM. Marcelis, M. Van Laere, K. Henquet, C. Delta-9-tetrahydrocannabinol-induced dopamine release as a function of psychosis risk: 18F-fallypride positron emission tomography study. Public Library of Science. (2013)
- Albrecht, DS. Skosnik, PD. Vollmer, JM. Brumbaugh, MS. Perry, KM. Mock, BH. Yoder, KK. Striatal D2/D3 receptor availability is inversely correlated with cannabis consumption in chronic marijuana users. Drug and Alcohol Dependence. (2013)
- Volkow, ND. Baler, RD. Compton, WM. Weiss, SR. Adverse health effects of marijuana use. The New England Journal of Medicine. (2014)
- Bossong, MG. Mehta, MA. Van Berckel, BNM. Howes, OD. Kahn, RS. Stokes, PRA. Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum. Psychopharmacology. (2015)
- Fanarioti, E. Mavrikaki, M. Panagis, G. Mitsacos, A. Nomikos, GG. Giompres, P. Behavioral and Neurochemical Changes in Mesostriatal Dopaminergic Regions of the Rat after Chronic Administration of the Cannabinoid Receptor Agonist WIN55,212-2. International Journal of Neuropsychopharmacology. (2015)