Adicción y sistema cannabinoide endógeno: papel del receptor para cannabinoides CB1 en la fisiología de las neuronas dopaminérgicas mesotelencefálicas

F. Rodríguez de Fonseca, M. Navarro

Resumen


El sistema cannabinoide endogeno es un nuevo sistema de comunicación intercelular compuesto por los receptores para cannabinoides CB-1 y CB-2 y varios transmisores lipidicos, que incluyen a la anandamida y el 2-araquidonilglicerol. Los receptores para cannabinoides CB1 y CB2 son la diana farmacológica de los cannabinoides naturales, los compuestos psicoactivos presentes en la preparaciones de Cannabis sativa. que se consumen como droga ilegal. La investigacion en modelos animales ha constatado que los cannabinoides inducen cambios en los sistemas cerebrales de recompensa, en especial sobre las neuronas dopaminérgicas mesotelencefálicas, equiparables a los que inducen otras drogas como los opiáceos y el etanol. El presente trabajo analiza las evidencias anatómicas, bioquímicas y farmacológicas que apoyan el papel del sistema cannabinoide endógeno en la modulación de la transmisión dopaminérgica. El receptor CB1 no sólo se localiza en las neuronas que expresan receptores para dopamina, sino que se expresa también en células dopaminéricas del mesencéfalo y el hipotálamo. La estimulación de los receptores para dopamina D2 es, además, el estímulo más potente capaz de liberar anandamida que se ha descrito hasta la fecha. La liberación de anandamida bloquearía la hiperactividad comportamental asociada a un exceso de señal dopaminergica. Estos hallazgos permiten esperar que fármacos capaces de interferir con el sistema cannabinoide endógeno puedan ser útiles en la terapéutica de procesos con participación dopaminérgica como la adicción a drogas. 


Palabras clave


cannabis; sistema cannabinoide; receptores cannabinoides; sistema dopaminérgico; adicción

Texto completo:

PDF

Referencias


Anderson LA, Anderson JJ, Chase TN and Walters JR (1995) The cannabinoid agonist WIN 55,212-2 and CP 55,940 attenuate rotational behaviour induced by a dopamine D1 but not a D2 agonist in rats with unilateral lesions of the nigrostriatal pathway. Brain Res., 691, 106-114.

Andreàsson S, Allebeck P, Engström A, Rydberg V (1987) Cannabis and Schizophrenia: a longitudinal study of Swedish conscripts. Lancet, ii, 1483-1486.

Beltramo M, Rodríguez de Fonseca F, Navarro M, Calignano A, Gorriti MA, Sadile AG, Giuffrida A, Piomelli D. (2000) Reversal of dopamine D-2 receptor-mediated responses by an anandamide transport inhibitor. J. Neuroscience (En prensa)

Beltramo M, Stella N, Calignano A, Lin SY, Makriyannis A and Piomelli D (1997) Functional role of high-affinity anandamide transport as revealed by selective inhibition. Science, 277, 1094-1097.

Cadogan AK, Alexander SPH, Boyd EA and Kendall DA (1997) Influence of cannabinoids on electrically evoked dopamine release and cAMP generation in the rat striatum. J. Neurochem., 69, 1131-1137

Chen J, Paredes W, Li J, Smith D, Lowinson J and Gardner EL (1990) Delta-9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freelymoving rats as measured by intracerebral microdialysis. Psychopharmacol., 102, 156-162.

Clifford DB (1983) Tetrahydrocannabinol for tremor in multiple sclerosis. Ann. Neurol., 13, 669-671.

Devane WA, Dysarz FA III, Johnson MR, Melvin LS and Howlett AC (1988) Determination and characterization of a cannabinoid receptor in rat brain. Mol. Pharmacol., 34, 605-613.

Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A and Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Nature, 258, 1946-1949.

Dewey WL (1986) Cannabinoid Pharmacology. Pharmacol. Rev., 38, 151-178.

Diana M, Melis M, Gessa GL (1998) Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. Eur. J. Pharmacol. 341, 39-44.

Diana M, Melis M, Muntoni AL, Gessa GL. (1998) Mesolimbic dopaminergic decline after cannabinoid withdrawal. Proc Natl. Acad. Sci. USA, 95, 10269-10273

Diana M, Muntoni AL, Pistis M, Melis M, Gessa GL. (1999) Lasting reduction in mesolimbic dopamine neuronal activity after morphine withdrawal. Eur. J. Neurosci., 11, 1037-1041.

French ED, Dillon K and Wu X (1997) Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. NeuroReport, 8, 649-652.

Gaoni Y and Mechoulam R (1964) Isolation, structure and partial synthesis on an active constituent of hashish. J Am. Chem. Soc., 86, 1646-1654.

Gardner EL, Paredes W, Smith D, Donner A, Milling C, Cohen D and Morrison D (1988) Facilitation of brain stimulation reward by Δ9-tetrahydrocannabinol . Psychopharmacol., 96, 142-144.

Gardner EL and Vorel, RH (1998) Cannabinoid transmission and reward-related events.Neurobiology of Disease. 5, 502-533.

Gessa, GL, Melis, M, Muntoni AL, Diana M (1998) Cannabinoids activate mesolimbic dopamineneurons by an action on cannabinoid CB1 receptors.Eur. J. Pharmacol. 341, 39-44.

Giuffrida, A., Parsons, L.H., Kehrr, A., Rodríguez de Fonseca, F., Navarro, M., Piomelli, D.(1999) Dopamine activation of endogenous cannabinoid signalling in dorsal striatum. Nature Neuroscience 2, 358-363.

Glass M, Brotchie JM and MAneuf YP (1997a) Modulation of neurotransmission by cannabinoids in the basal ganglia. Eur. J. Neurosci., 9, 199-203.

Glass M and Felder C (1997b) Concurrent stimulation of cannabinoid CB1 and dopamine D2 receptors augments cAMP accumulation in striatal neurons: evidence for a Gs linkage to the CB1 receptor. J. Neurosci., 17, 5327-5333.

Gorriti, M.A., Rodriguez de Fonseca, F.A., Navarro, M., Palomo, M.(1999) Chronic treatment with (-)- delta-9-tetrahydrocannabinol results in sensitization to the psychomotor effects of amphetamine. Eur. J. Pharmacol. 365, 133-142.

Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience, 41, 1-24.

Gueudet C, Santucci V, Rinaldi-Carmona M, Soubrié P and Le Fur G (1995) The CB1 cannabinoid receptor antagonist SR 141716A affects A9 dopamine neuronal activity in the rat. NeuroReport, 6, 1293-1297.

Halikas JA, Weller RA, Mouse CL and Hoffman RA (1985) A longitudinal study of marijuana effects. Int. J. Addiction, 20, 701-711.

Hampson RE, Evans GJO, Mu J, Zhuang S, King VC, Childers SR and Deadwyler SA (1995) Role of cyclic AMP dependent protein kinase in cannabinoid receptor modulation of potassium “Acurrent” in cultured hippocampal neurons. Life Sci., 56, 2081-2087

Herkenham M, Lynn AB, de Costa BR and Richfield EK (1991) Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res, 547, 267-274.

Herkenham M, Lynn AB, Little MD, Johnson MR, Melvin LS, de Costa BR and Rice (1990) Cannabinoid receptor localization in brain. Proc. Natl. Acad. Sci. USA., 87, 1932-1936.

Howlett AC (1995) Pharmacology of cannabinoid receptors. Ann. Rev. Pharmacol. Toxicol. 35, 607-634.

Knudsen P and Vilmar P (1984) Cannabis and neuroleptics agents in schizophrenia. Acta Psychiatr. Scand., 69, 162-174.

Landfield PW, Cadwallader LB and Vinsant S (1988) Quantitative changes in hippocampal structure following chronic exposure to Δ9-tetrahydrocannabinol: possible mediation by glucocorticoid systems.Brain . Res., 443, 47-62.

Le Moal M and Simon H (1991) Mesocorticolimbic dopaminergic network: functional and regulatory roles. Physiol. Rev., 71, 155-234.

Leweke, FM, Giuffrida, A, Wurster, U, Emrich, HM and Piomelli, D (1999) Elevated endogenous cannabinoids in schizophrenia. NeurReport 10, 1665-1669.

Mackie K, and Hille B (1992) Cannabinoids inhibit Ntype calcium channels in neuroblastoma-glioma cells. Proc. Natl. Acad. Sci. USA, 89, 3825-3829.

Mailleux P and Vanderhaeghen JJ (1992) Distribution of neuronal cannabinoid receptor in the adult rat brain: a comparative receptor binding radioautoagraphy and in situ hybridization histochemistry. Neuroscience, 48, 655-688.

Mailleux P and Vanderhaeghen JJ (1993) Dopaminergic regulation of cannabinoid receptor mRNA levels in the rat caudate-putamen: An in situ hybridization study. J. Neurochem., 61, 1705-1712.

Maneuf YP and Brotchie JM (1997) Paradoxical action of the cannabinod WIN 55,212-2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices. Br. J. Pharmacol., 120, 1397-1398.

Maneuf YP, Crossman AR and Brotchie JM (1996) Modulation of GABAergic transmission in the globus pallidus by the synthetic canabinoid WIN 55,212-2. Synapse, 22, 383-385.

Maneuf YP, Crossman AR and Brotchie JM (1997) The cannabinoid receptor agonist WIN 55,212-2 reduces D2, but not D1, dopamine receptormediated alleviation of akinesia in the reserpinetreated rat model of Parkinson’s disease.Exp. Neurol., 148, 265-270

Martín-Calderón JL, Muñoz RM, Villanúa, del Arco I, Moren JL, Rodríguez de Fonseca F and Navarro M (1998) Characterization of the acute endocrine actions of HU-210, a potent synthetic cannabinoid in rats. Eur. J. Pharmacol. 344, 77-86.

Matsuda LA, Bonner TI and Lolait SJ (1993) Localization of Cannabinoid Receptor mRNA in rat brain. J . Comp. Neurol., 327, 535-550

Matsuda LA, Lolait SJ, Brownstein MJ, Young AC and Bonner TI (1990) Structure of a brain cannabinoid receptor and functional expression of the cloned cDNA. Nature, 346, 561-564.

Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Comton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J and Vogel Z (1995) Identification of an endogenous 2-monoglyceride present in canine gut that binds to cannabinoid receptor. Biochem. Pharmacol., 50, 83-90.

Nagayama, T., Sinor, A.D., Simon, R.P., Cheen, J., Graham, S.H., Jin, K., Greenberg, D.A. (1999) Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J.Neurosci. 19, 2987-95.

Navarro, M, Cowen, J, Carrera, MRA, del Arco, I., Villanúa, MA, Martin Y, Roberts, AJ, Koob, GF and Rodriguez de Fonseca, F (1998) CB1 cannabinoid receptor antagonist-induced opiate withdrawal in morphine-dependent rats. Neuro-Report, 9, 3397-3402.

Navarro M, Fernandez-Ruiz JJ, de Miguel R, Hernandez ML, Cebeira M and Ramos JA (1993) Motor disturbances induced by an acute dose of delta-9-tetrahydrocannabinol: possible involvement of nigrostriatal dopaminergic alterations. Pharmacol. Biochem. Behav., 45, 291-298.

Navarro M, Hernández E, Muñoz RM, Del Arco I, Villanúa MA, Carrera MRA and Rodríguez de Fonseca F (1997) Acute administration of the CB1 receptor antagonist SR 141716A induces anxiety-like responses in the rat. NeuroReport, 8, 491-496.

Ng Cheong Ton JM, Gerhardt SA, Freidman M, Etgen A, Rose GM, Sharlegg NS and Gardner EL (1988) The effect of delta-9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study. Brain Res., 451, 59-68.

Nuñez-Domínguez LA and Gurpegui-Fernández de Legaria M (1997) Cannabis psychosis: a five year follow-up study. International Meeting on Interactive Monoaminergic Brain Disorders. October 8-12, 1997, P3.5, pp 76.

Ong, W.Y. and Mackie, K. (1999) A light and electron microscopic study of the CB1 cannabinoid receptor in primate brain. Neuroscience 92, 1177-1191.

Pertwee RG and Greentree SG (1988) Delta-9-tetrahydrocannabinol-induced catalepsy in mice is enhanced by pretreatment with flurazepam or chlordiazepoxide. Neuropharmacol., 27, 485-491.

Piazza PV and Le Moal M (1996b) Pathophysiological basis of vulnerability to drug abuse: role of an interaction between stress, glucocorticoids and dopaminergic neurons. Ann. Rev. Pharmacol. Toxicol., 36, 359-378.

Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, Martinez S, Maruani J, Néliat G, Caput D, Ferrara P, Soubrié, Breliére JC and Le Fur G (1994) SR 141716A a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett., 350, 240-244.

Rodríguez de Fonseca F, Carrera MRA, Navarro M, Koob GF and Weiss F (1997) Activation of corticotropinreleasing factor in the limbic system during cannabinoid withdrawal. Science, 276, 2050-2054.

Rodríguez de Fonseca F, Fernandez-Ruiz JJ, Murphy LL, Cebeira M, Steger RW, Bartke A and Ramos A (1992) Acute effects of Δ9- tetrahydrocannabinol on dopaminergic activity in several rat brain areas. Pharmacol. Biochem. Behav. 42, 269-275.

Rodríguez de Fonseca F, Gorriti MA, Fernández- Ruiz JJ, Palomo T and Ramos JA (1994a) Down regulation of rat brain cannabinoid binding sites after chronic Δ9-tetrahydrocannabinol treatment. Pharmacol. Biochem. Behav., 47, 33-40.

Rodríguez de Fonseca, F.A., Martín-Calderón, J.L., Del Arco, I., Gorriti, M.A.,Navarro, M.(1998) Role of the endogenous cannabinoid system in the regulation of motor activity.Neurobiology of Disease 5, 483-501.

Rodríguez de Fonseca F, Martín-Calderón JL, Mechoulam R and Navarro M (1994b) Repeated stimulation of D-1 dopamine receptors enhances (-)-11-hydroxy-?8-tetrahydrocannabinol-dimethylheptyl-induced catalepsy in male rats. NeuroReport, 5, 761-765. Rodríguez de Fonseca FA, Roberts AJ, Bilbao A, Koob GF, Navarro M. (2000) Cannabinoid receptor antagonist SR 141716 A decreases operant ethanol self-administration in rats exposed to ethanol-vapor chambers. Acta. Pharmacol. Sinica, 20, 1109-1114.

Rodríguez de Fonseca, F.; Wenger, T., Navarro, M.; Murphy, L.L.(1999) Effects of THC on VIP-induced prolactin secretion in pituitary cultures: evidence for the presence of functional cannabinoid receptors in pituitary cells. Brain Res. 841, 114-122.

Romero J, García-Palomero E, Fernández-Ruiz JJ, and Ramos JA (1995) Involvement of GABA-B receptors in the motor inhibition produced by agonists of brain cannabinoid receptors.Behav. Pharmacol., 7, 299-302.

Sañudo-Peña MC, Patrick SL, Patrick RL and Walker JM (1996) Effects of intranigral cannabinoids on rotational behavior in rats: interactions with the dopaminergic system. Neurosci. Lett., 206, 21-24.

Sañudo-Peña MC, and Walker JM (1997) Role of the subthalamic nucleus in cannabinoid actions in the substantia nigra of the rat.J. Neurophysiol., 77, 1635-1638.

Sañudo-Peña, M.C. and Walker, J.M. (1998). Effects of intrapallidal cannabinoids on rotational behavior in rats. Interaction with the dopaminergic system. Synapse 28, 2-32. Sim, L.J., Selley, D.E., Dworkin, S.I. and Childers,S.R.(1996) Effects of chronic morphine administration on mu opioid receptor-stimulated [35S]GTPgS autoradiography in rat brain. J. Neurosci., 16, 2684-2692 .

Steiner, H., Bonner, T.I., Zimmer, A.M., Kitai, S.T. and Zimmer, A. (1999) Altered gene expressionin striatal projection neurons in CB1 cannabinoid receptor knockout mice. Proc. Natl. Acad. Sci. 96, 5786-5790.

Stella N, Schweitzer P and Pomelli D (1997) A second endogenous cannabinoid that modulates long-term potentiation. Nature, 388, 773-777. Surmeier DJ, Song WJ and Yan Z (1996) Coordinated expression of dopamine receptors in neostriatal medium spiny neurons. J. Neurosci., 16, 6579-6591.

Tanda, G, Pontieri, FE, Di Chiara, G (1997) Cannabinoid and heroin activation of mesolimbic dopaminetransmission by a common mu1 opioid receptor mechanism. Science 76, 2048-2050.

Tersigni T and Rosemberg HC (1996) Local pressure application of cannabinoid agonists increases spontaneous activity of rat substantia nigra pars reticulata neurons without affecting response to iontophoretically-applied GABA. Brain Res., 733, 184-192

Tsou, K., Sañudo-Peña, M.C., Mackie, K., Walker, J.M. (1998) Immunohystochemical distribution.




DOI: https://doi.org/10.20882/adicciones.673

Enlaces refback

  • No hay ningún enlace refback.