Stimulation of in vivo dopamine transmission and intravenous self-administration in rats and mice by JWH-018, a Spice cannabinoid.
The synthetic cannabinoid 1-pentyl-3-(1-naphthoyl)-indole (JWH-018) has been detected in about 140 samples of a smokable herbal mixture termed "Spice". JWH-018 is a CB1 and CB2 agonist with a higher affinity than Δ9-THC. In order to investigate the neurobiological substrates of JWH-018 actions, we studied by microdialysis in freely moving rats the effect of JWH-018 on extracellular dopamine (DA) levels in the nucleus accumbens (NAc) shell and core and in the medial prefrontal cortex (mPFC). JWH-018, at the dose of 0.25 mg/kg i.p., increased DA release in the NAc shell but not in the NAc core and mPFC. Lower (0.125 mg/kg) and higher doses (0.50 mg/kg) were ineffective. These effects were blocked by CB1 receptor antagonists (SR-141716A and AM 251) and were absent in mice lacking the CB1 receptor. Ex vivo whole cell patch clamp recordings from rat ventral tegmental area (VTA) DA neurons showed that JWH-018 decreases GABAA-mediated post-synaptic currents in a dose-dependent fashion suggesting that the stimulation of DA release observed in vivo might result from disinhibition of DA neurons. In addition, on the "tetrad" paradigm for screening cannabinoid-like effects (i.e., hypothermia, analgesia, catalepsy, hypomotility), JWH-018, at doses of 1 and 3 mg/kg i.p., produced CB1 receptor-dependent behavioural effects in rats. Finally, under appropriate experimental conditions, rats (20 μg/kg/inf i.v., FR3; nose-poking) and mice (30 μg/kg/inf i.v., FR1; lever-pressing) self-administer intravenously JWH-018. In conclusion, JWH-018 shares with the active ingredient of Marijuana, Δ9-THC, CB1-dependent reinforcing and DA stimulant actions.
Department of Biomedical Sciences, University of Cagliari, Italy; INN, National Institute of Neuroscience, Italy. Electronic address: deluca@unica.it.
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MA
De Luca
Department of Biomedical Sciences, University of Cagliari, Italy.
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Z
Bimpisidis
Department of Biomedical Sciences, University of Cagliari, Italy.
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M
Melis
INN, National Institute of Neuroscience, Italy; Department of Life Sciences and Biotechnology, University of Ferrara, Italy.
M
M
Marti
Department of Life and Environmental Sciences, University of Cagliari, Italy.
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P
Caboni
Department of Biomedical Sciences, University of Cagliari, Italy; INN, National Institute of Neuroscience, Italy; Centre of Excellence "Neurobiology of Addiction", Italy.
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V
Valentini
Department of Biomedical Sciences, University of Cagliari, Italy.
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G
Margiani
Department of Biomedical Sciences, University of Cagliari, Italy.
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Pintori
The Scripps Research Institute, La Jolla, CA, USA.
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I
Polis
Neurocentre Magendie, University of Bordeaux, France.
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Marsicano
The Scripps Research Institute, La Jolla, CA, USA.
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LH
Parsons
Department of Biomedical Sciences, University of Cagliari, Italy; INN, National Institute of Neuroscience, Italy; CNR Institute of Neuroscience, Cagliari Section, Italy; Centre of Excellence "Neurobiology of Addiction", Italy.
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Di Chiara
D061605:Administration, Intravenous; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage*; D004298:Dopamine / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D007211:Indoles / Q000008:administration & dosage*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017551:Microdialysis; D009281:Naphthalenes / Q000008:administration & dosage*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000502:physiology; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000378:metabolism; D012646:Self Administration; D013045:Species Specificity; D046509:Tissue Culture Techniques; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000502:physiology
C578453:CNR1 protein, mouse; D063386:Cannabinoid Receptor Agonists; D007211:Indoles; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D011963:Receptors, GABA-A; C552597:1-pentyl-3-(1-naphthoyl)indole; D004298:Dopamine
CB1 receptor; Dopamine; Electrophysiology; JWH-018; Microdialysis; Nucleus accumbens