| Abstract No.: | C-B3058 |
| Country: | Canada |
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| Title: | CANNABINOIDS MODIFY HIPPOCAMPAL SEROTONERGIC TRANSMISSION |
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| Authors/Affiliations: | 2 Patrick Hattan; 2 Francis Bambico*; 5 Andrea Duranti; 5 Andrea Tontini; 5 Giorgio Tarzia; 4 Marco Mor; 1 Claire Dominique Walker; 3 Gabriella Gobbi;
1 Douglas Mental Health Institute and McGill University, Montreal, QC, Canada; 2 McGill University, Montreal, QC, Canada; 3 McGill University and Université de Montréal, Montreal, QC, Canada; 4 University of Parma, Italy; 5 University of Urbino, Italy
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| Content: | Objectives: Cannabis is the most abused illicit substance. Its main pharmacologically active principle, (−)-trans-delta(9)-tetrahydrocannabinal (THC) likely mediates most of its psychoactive by binding brain cannabinoid CB1 receptors. CB1 agonism has been demonstrated to elicit antidepressant/anxiolytic-like effects (Bambico et al., 2007, J. Neurosci.). Likewise, amplifying the intrinsic levels of the endogenous cannabinoid anandamide by inhibiting the enzyme fatty acid amide hydrolase (FAAH) that degrades it, thereby increasing anandamide-CB1 signalling, leads to anxiolytic/antidepressant behavioural effects paralleled by a modulation in monoaminergic neuronal activity (Kathuria et al., 2003, Nat. Med.; Gobbi et al., 2005, PNAS). Since chronic antidepressant treatment have been shown to increase the tonic activity of hippocampal 5-HT1A receptors (Haddjeri et al., 1998, J. Neurosci.) and downregulate 5-HT1A and 5-HT2A/C receptors (Stahl, 1994, Psychopharmacol. Bull.), we therefore sought to determine whether the FAAH inhibitor URB597 and THC modify 5-HT1A and 5-HT2A/C receptor sensitivity/activity in the dorsal hippocampus.
Materials and Methods: In vivo single-unit extracellular recordings and microiontophoretic drug applications were employed to examine the changes in the sensitivity of hippocampal CA3 5-HT2A/C and 5-HT1A, and and the tonic activity of CA3 5-HT1A receptors following subchronic (4 days o.d.) intraperitoneal administration of URB597 (0.1 mg/kg) and THC (1.0 mg/kg). 5-HT1A sensitivity was assessed through the inhibitory response of CA3 pyramidal neuron to iontophoretically-applied 5-HT1A agonist 8-OH-DPAT (1-10 nA); 5-HT2A/C sensitivity through the excitatory response to iontophoretically-applied 5-HT2A/C agonist DOI (10-100 nA); and tonic 5-HT1A activity through the disinhibitory (excitatory) response to intravenously applied 5-HT1A antagonist WAY100635 (25-100 μg/kg).
Results: Subchronic treatment with THC decreased the inhibitory response of pyramidal neurons to iontophoretically applied 8-OH-DPAT (AUC, 779.97% vs. vehicle, p<0.001) and attenuated the excitatory response of these neurons to iontophoretically applied DOI (AUC, 176.54% vs. vehicle, p<0.05). These results indicate desensitization of both 5-HT1A and 5-HT2A/C following treatment. Subchronic treatment with THC increased the disinhibitory response to intravenously administered WAY100635 (AUC, 106.10% vs. vehicle, p<0.05), indicating an increase of tonic 5-HT1A activity.
Subchronic treatment with URB597 also decreased the inhibitory response of pyramidal neurons to iontophoretically applied 8-OH-DPAT (AUC, 846.42% vs. vehicle, p<0.001) and attenuated the excitatory response to iontophoretically applied DOI (AUC, 117.23% vs. vehicle, p<0.05). These results indicate desensitization of both 5-HT1A and 5-HT2A/C following treatment. Subchronic treatment with URB597 increased the disinhibitory response to intravenously administered WAY100635 (AUC 0-50 mg/kg, 139.08% vs. vehicle, p<0.05), indicating an increase of tonic 5-HT1A activity.
Conclusion: These data indicate that THC and URB597 modify the sensitivity of 5-HT1A and 5-HT2A/C receptors and increase the tonic activity of 5-HT1A receptors, effects similar to those of conventional antidepressant treatments. |
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