Effect of delta-9-tetrahydrocannabinol on behavioral despair and on pre- and postsynaptic serotonergic transmission Francis Rodriguez Bambico, Patrick R. Hattan, Jean-Philippe Garant, Gabriella Gobbi ⁎ Neurobiological Psychiatry Unit, Dept. Psychiatry, McGill University, Montréal, Québec, Canada abstract article info Article history: Received 9 November 2011 Received in revised form 2 February 2012 Accepted 13 February 2012 Available online 22 February 2012 Keywords: Behavioral despair Cannabinoids CB 1 receptor Delta-9-THC Serotonin Preclinical and clinical studies suggest that direct and indirect cannabinoid agonists, including enhancers of endocannabinoids, engender stress-relieving, anxiolytic and antidepressant effects, mediated by central CB 1 receptors (CB 1 Rs). The effect of the main pharmacologically active principle in cannabis, (-)-trans-Δ 9 - tetrahydrocannabinol (delta-9-THC), on depressive behavior and on the serotonin (5-HT) system, which is implicated in the mechanism of action of antidepressants, has not been extensively clarified. Here, we showed that repeated (5 days), but not single (acute) intraperitoneal (ip) treatment with delta-9-THC (1 mg/kg) exerts antidepressant-like properties in the rat forced swim test (FST). This effect was CB 1 R-de- pendent because it was blocked by the CB 1 R antagonist rimonabant (1 mg/kg, ip). Using in vivo electrophys- iology, we demonstrated that delta-9-THC modulated dorsal raphe (DR) 5-HT neuronal activity through a CB 1 R-dependent mechanism. Acute intravenous delta-9-THC administration (0.1–1.5 mg/kg) elicited a com- plex response profile, producing excitatory, inhibitory and inert responses of 5-HT neurons. Only excitatory responses were blocked by rimonabant. Finally, repeated but not single delta-9-THC administration (1 mg/ kg, ip) enhanced tonic 5-HT 1A receptor activity in the hippocampus, a postsynaptic event commonly elicited by standard antidepressants. These results suggest that delta-9-THC, like other CB 1 R agonists and endocanna- binoid enhancers, may possess antidepressant properties at low doses, and could modulate 5-HT transmis- sion in the DR and hippocampus as standard antidepressants such as selective serotonin reuptake inhibitors. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Major depression is one of the most prevalent and debilitating psychi- atric afflictions. It is characterized by pervasive and recurrent episodes of low mood and motivation, despair and anhedonia. Despite the availability of several classes of antidepressants, more than a third of patients are either unremitting or relapsing (Bambico and Gobbi, 2008; Zisook et al., 2008). Antidepressants that are known to act on the brain's monoamine systems are limited by a delayed onset of therapeutic action. Moreover, the pathophysiology of depression is far from being fully elucidated. Multiple levels of dysfunction have been proposed, including impaired synaptic transmission of the monoamine 5-hydroxytryptamine (5-HT or serotonin) (Bambico et al., 2009a), which is produced by the midbrain raphe 5-HT neurons (Dahlström and Fuxe, 1964; Descarries et al., 1982), and known to regulate emotional, vegetative and neuroendocrine functions (Holmes, 2008). Not surprisingly, drugs that augment 5-HT transmission, such as selective serotonin reuptake inhibitors (SSRIs), are most preferred first-line treatments (Vaswani et al., 2003). Their chronic application facilitates exocytosis of 5-HT and/or increases 5-HT synaptic availability in corticolimbic regions extensively innervated by the raphe. Many of these forebrain structures, including the prefrontal cortex, hippocampus and amygdala are implicated in mood regulation and stress adaptation (Holmes, 2008). On the other hand, chronic stress that is known to be a risk factor for depression impairs presynaptic and postsyn- aptic 5-HT transmission (Bambico et al., 2009b). Also, acute or repeated 5- HT or tryptophan depletion precipitates anxiety/depression-like behav- iors in animals (Blokland et al., 2002) and mood-lowering effects in humans (for review, Young and Leyton, 2002), exacerbates anxiogenic re- sponses in human subjects (Miller et al., 2000), and triggers relapse in de- pressive patients (for review, Van der Does, 2001). The role of the 5-HT 1A receptor in the antidepressant response is well established. The therapeutic onset of many antidepressants has been attributed to gradual neuroplastic adaptations of these receptors, such as to the desensitization of presynaptic dorsal raphe (DR) 5-HT 1A auto-inhibitory receptors and to the enhancement of the tonic activity of postsynaptic hippocampal 5-HT 1A receptors (for review, Bambico and Gobbi, 2008; Bambico et al., 2009a). Such has been hypothesized to result from the progressive augmentation in 5-HT activity, and that could be linked to the neurogenic effects on hippocampal cells, Progress in Neuro-Psychopharmacology & Biological Psychiatry 38 (2012) 88–96 Abbreviations: 5-HT, 5-hydroxytryptamine, serotonin; CB1R, cannabinoid CB1 receptor; Delta-9-THC, (-)-trans-delta(9)-tetrahydrocannabinol; DR, dorsal raphe; FAAH, fatty acid amide hydrolase; MAGL, monoacylglycerol lipase; FST, forced swim test; OFT, open field test; WAY100, 635, N-[2-[4-(2-methoxyphenyl-1-piperazinyl] ethyl]-N-(2-pyridyl)cyclohexanecarboxamide. ⁎ Corresponding author at: 1033 Pine Avenue West, Neurobiological Psychiatry Unit, Department of Psychiatry Research and Training Building, McGill University, Montréal, Québec, Canada H3A 1A1. Tel.: +1 514 398 1290; fax: +1 514 398 4866. E-mail address: gabriella.gobbi@mcgill.ca (G. Gobbi). 0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2012.02.006 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp