Involvement of 5-HT1A serotonergic receptor on Δ9-Tetrahydrocannabinol (Δ9-THC)-induced emotional response in rats

The major psychoactive constituent of cannabis, Δ9-THC, affects emotional reactivity in humans (Porter and Felder, 2001) and laboratory animals by activating brain cannabinoid receptors (Onaivi et al. 1990; Berrendero and Maldonado 2002). The 5HT system plays a key modulatory role in CNS processes that appear to be dysregulated in psychiatric disorders such as anxiety, fear, depression or aggression (Griebel, 1995). The role of 5HT1A serotonergic receptor, located in serotonergic patways projecting from mid-brain raphe nuclei to limbic areas, in the modulation of anxious states has been particularly well studied (Handley, 1995; Barnes and Sharp, 1999). To date, there is only one report on the involvement of 5HT1A serotonergic receptor in anxiogenic-like response induced by CP 55,940 (Marco et al., 2004). The aim of the present work was to further elucidate the role of 5-HT1A serotonergic receptor on emotional reactivity induced by cannabinoids in rats using the elevated plus-maze (EPM) and forced swimming test (FST). D9–THC (0.015-3 mg/kg), was studied in a EPM apparatus according to Pellow et al. (1985). The test length was 5 min, the total time spent in each arm and the number of arm entries were scored by trained observers in male Sprague-Dawley rats, 30 min after treatment. The FST, evaluated according to Porsolt et al., (1977), consisted in two swimming sessions where the time of immobility during the 2nd 5-min session was an indicator of antidepressant activity. D9–THC showed a biphasic effect being anxiolytic at a low (0.75 mg/kg) and anxiogenic at a high (3 mg/kg) dose. Lower doses as 0.015 and 0.075 mg/kg significantly reduced the immobility time in the FST, showing an antidepressant activity. Pre-treatment with the 5-HT1A serotonergic receptor antagonist, WAY 100635 (0.3 mg/kg) given s.c. 1h before D9–THC, significantly reversed its anxiolytic effect. A synergistic action on anxiolytic effect, when the 5-HT1A serotonergic receptor agonist 8-OH-DPAT (0.0075 mg/kg) was given in combination with D9–THC, was observed. These findings support a key role of 5-HT1A serotonergic receptor in the regulation of D9–THC-induced emotional states.