Detection of cannabinoid agonist evoked increase in BOLD contrast in rats using functional magnetic resonance imaging

BOLD-contrast functional magnetic resonance imaging (fMRI) was used to investigate the effects of the synthetic cannabinoid agonist HU210 on the rat brain in order to determine potential CNS sites of action for the functional effects of cannabinoids. After obtaining basal data, rats (n=8) were given the cannabinoid agonist HU210 (10 microg/kg i.v.) and volume data sets collected for 85 mins. Significant increases in functional BOLD activity were observed in specific brain regions including those important in pain (PAG), reward (VTA and accumbens) and motor function (striatum). In order to confirm cannabinoid receptor involvement in the HU210 evoked functional BOLD activity, rats (n=8) were pre-treated with the CB1 cannabinoid receptor antagonist SR141716A (100 microg/kg i.v.) prior to HU210. Pretreatment with SR141716A abolished all significant evoked HU210 functional BOLD activity. To exclude the involvement of potential systemic effects induced by the cannabinoid agonist administration on the observed evoked functional BOLD activity a separate experiment investigated the effect of HU210 (10 microg/kg i.v.) on mean arterial pressure and showed that HU210 had no significant effect on pressure under chloral hydrate anaesthesia. In summary, this study demonstrates that the cannabinoid agonist HU210 evokes a significant increase in BOLD functional activity in specific regions and that this was cannabinoid receptor mediated. Furthermore the study indicates the potential value of fMRI in rodents to delineate pharmacologically induced changes in regional brain function.

[1]  R. Mechoulam,et al.  Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens , 1995, Neuropharmacology.

[2]  B. Rosen,et al.  Cocaine Activation Discriminates Dopaminergic Projections by Temporal Response: An fMRI Study in Rat , 2000, NeuroImage.

[3]  A. Lichtman,et al.  Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats , 1995, Psychopharmacology.

[4]  Ravi S. Menon,et al.  Intrinsic signal changes accompanying sensory stimulation: functional brain mapping with magnetic resonance imaging. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  A. Lichtman,et al.  The Selective Cannabinoid Antagonist SR 141716A Blocks Cannabinoid-Induced Antinociception in Rats , 1997, Pharmacology Biochemistry and Behavior.

[6]  M. Diana,et al.  Increase in meso‐prefrontal dopaminergic activity after stimulation of CB1 receptors by cannabinoids , 1998 .

[7]  B R Rosen,et al.  Detection of dopaminergic neurotransmitter activity using pharmacologic MRI: Correlation with PET, microdialysis, and behavioral data , 1997, Magnetic resonance in medicine.

[8]  R Bandler,et al.  Orbitomedial prefrontal cortical projections to distinct longitudinal columns of the periaqueductal gray in the rat , 2000, The Journal of comparative neurology.

[9]  P. Coffin,et al.  Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections , 1999, Brain Research.

[10]  R. Maldonado.  Study of cannabinoid dependence in animals. , 2002, Pharmacology & therapeutics.

[11]  L. Berrino,et al.  Metabotropic and NMDA glutamate receptors participate in the cannabinoid-induced antinociception , 2001, Neuropharmacology.

[12]  F. Orzi,et al.  Metabolic Mapping of the Effects of Win 55212–2 Intravenous Administration in the Rat , 1999, Neuropsychopharmacology.

[13]  C. Whitlow,et al.  Dose‐dependent effects of Δ9‐tetrahydrocannabinol on rates of local cerebral glucose utilization in rat , 2002, Synapse.

[14]  E. French,et al.  Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra , 1997, Neuroreport.

[15]  J Hennig,et al.  RARE imaging: A fast imaging method for clinical MR , 1986, Magnetic resonance in medicine.

[16]  G. Di Chiara,et al.  Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. , 1997, Science.

[17]  R. Buxton,et al.  A Model for the Coupling between Cerebral Blood Flow and Oxygen Metabolism during Neural Stimulation , 1997, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[18]  J. Cheer,et al.  Cannabinoid receptors and reward in the rat: a conditioned place preference study , 2000, Psychopharmacology.

[19]  L. Sokoloff,et al.  RELATION BETWEEN PHYSIOLOGICAL FUNCTION AND ENERGY METABOLISM IN THE CENTRAL NERVOUS SYSTEM , 1977, Journal of neurochemistry.

[20]  A. Hohmann,et al.  Suppression of Noxious Stimulus-Evoked Activity in the Ventral Posterolateral Nucleus of the Thalamus by a Cannabinoid Agonist: Correlation between Electrophysiological and Antinociceptive Effects , 1996, The Journal of Neuroscience.

[21]  E. French.  Δ 9-Tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors , 1997, Neuroscience Letters.

[22]  Karl J. Friston,et al.  Statistical parametric maps in functional imaging: A general linear approach , 1994 .

[23]  S. L. Patrick,et al.  An examination of the central sites of action of cannabinoid-induced antinociception in the rat. , 1995, Life sciences.

[24]  Payton King,et al.  Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo , 1998, Journal of neurochemistry.

[25]  B. Martin,et al.  Cannabis: pharmacology and toxicology in animals and humans. , 1996, Addiction.

[26]  S. Batkai,et al.  Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. , 2001, European journal of pharmacology.

[27]  C. Whitlow,et al.  Metabolic mapping of the time-dependent effects of Δ9-tetrahydrocannabinol administration in the rat , 2002, Psychopharmacology.

[28]  H. Fields,et al.  Pain modulation: expectation, opioid analgesia and virtual pain. , 2000, Progress in brain research.

[29]  D. R. Compton,et al.  Cannabinoid-induced hypotension and bradycardia in rats mediated by CB1-like cannabinoid receptors. , 1997, The Journal of pharmacology and experimental therapeutics.

[30]  N. Volkow,et al.  Cerebellar metabolic activation by delta-9-tetrahydrocannabinol in human brain: A study with positron emission tomography and 18F-2-Fluoro-2-deoxyglucose , 1991, Psychiatry Research: Neuroimaging.

[31]  J. Lowinson,et al.  Marijuana's interaction with brain reward systems: Update 1991 , 1991, Pharmacology Biochemistry and Behavior.

[32]  E. Stein,et al.  Cannabinoid-Induced Alterations in Regional Cerebral Blood Flow in the Rat , 1997, Pharmacology Biochemistry and Behavior.

[33]  J. Lowe,et al.  In vivo characterization of a specific cannabinoid receptor antagonist (SR141716A): inhibition of delta 9-tetrahydrocannabinol-induced responses and apparent agonist activity. , 1996, The Journal of pharmacology and experimental therapeutics.

[34]  J. Cheer,et al.  Differential cannabinoid-induced electrophysiological effects in rat ventral tegmentum , 2003, Neuropharmacology.

[35]  E. Gardner,et al.  Ventral tegmental microinjection of Δ9-tetrahydrocannabinol enhances ventral tegmental somatodendritic dopamine levels but not forebrain dopamine levels: evidence for local neural action by marijuana's psychoactive ingredient , 1993, Brain Research.

[36]  K. Mackie,et al.  Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system , 1998, Neuroscience.

[37]  A. Hohmann,et al.  Suppression of noxious stimulus-evoked expression of fos protein-like immunoreactivity in rat spinal cord by a selective cannabinoid agonist , 1996, Neuroscience.

[38]  S. McAllister,et al.  Evaluation of the cannabinoid CB2 receptor-selective antagonist, SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. , 1999, European journal of pharmacology.

[39]  J. Walker,et al.  Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjection into the rostral ventromedial medulla , 1998, Neuroscience Letters.

[40]  P. Soubrié,et al.  SR141716A, a potent and selective antagonist of the brain cannabinoid receptor , 1994, FEBS letters.

[41]  T. Freund,et al.  The effects of genetic and pharmacological blockade of the CB1 cannabinoid receptor on anxiety , 2002, The European journal of neuroscience.