CB1 receptor stimulation in specific brain areas differently modulate anxiety-related behaviour T. Rubino, C. Guidali, D. Vigano, N. Realini, M. Valenti, P. Massi, D. Parolaro * DBSF, Pharmacology Section and Center of Neuroscience, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy Received 29 March 2007; received in revised form 21 June 2007; accepted 22 June 2007 Abstract There is a general consensus that the effects of cannabinoid agonists on anxiety seem to be biphasic, with low doses being anxiolytic and high doses ineffective or possibly anxiogenic. Besides the behavioural effects of cannabinoids on anxiety, very few papers have dealt with the neu- roanatomical sites of these effects. We investigated the effect on rat anxiety behavior of local administration of THC in the prefrontal cortex, basolateral amygdala and ventral hippocampus, brain regions belonging to the emotional circuit and containing high levels of CB1 receptors. THC microinjected at low doses in the prefrontal cortex (10 mg) and ventral hippocampus (5 mg) induced in rats an anxiolytic-like response tested in the elevated plus-maze, whilst higher doses lost the anxiolytic effect and even seemed to switch into an anxiogenic profile. Low THC doses (1 mg) in the basolateral amygdala produced an anxiogenic-like response whereas higher doses were ineffective. All these effects were CB1-dependent and closely linked to modulation of CREB activation. Specifically, THC anxiolytic activity in the prefrontal cortex and ventral hippocampus was paralleled by an increase in CREB activation, whilst THC anxiogenic response in the basolateral amygdala was paral- leled by a decrease in CREB activation. Our results suggest that while a mild activation of CB1 receptors in the prefrontal cortex and ventral hippocampus attenuates anxiety, a slight CB1 receptor stimulation in the amygdala results in an anxiogenic-like response. The molecular un- derpinnings of these effects involve a direct stimulation of CB1 receptors ending in pCREB modulation and/or a possible alteration in the fine tuning of local neuromodulator release. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: THC; Anxiety behaviour; Prefrontal cortex; Hippocampus; Amygdala; CREB activation 1. Introduction The complex and contradictory picture resulting from the data present in literature supports the hypothesis that cannabi- noids may be involved in responses to emotional stress and anxiety. In humans the main feature of cannabis use is that it could promote both an euphoriant and relaxing effect, thus relieving anxious states, or anxiety and panic attacks, depend- ing on subjects and on the emotional state prior to use (Iversen, 2003). Similarly, animal experiments with different cannabinoid agonists revealed both anxiolytic-like and anxiogenic-like responses as a function of, administered dose, test conditions, familiarity of the environment and ge- netic strain (for a review, see Viveros et al., 2005). Although with all these limitations and variables, there is a general con- sensus that the effects of cannabinoid agonists on anxiety seem to be biphasic, with low doses being anxiolytic and high doses ineffective or possibly anxiogenic (Viveros et al., 2005; Patel and Hillard, 2006). Periferically administered low doses of cannabinoid receptor agonists, nabilone (Onaivi et al., 1990), CP-55,940 (Marco et al., 2004) and D 9 -tetrahydrocannabinol (THC) (Valjent et al., 2002; Berrendero and Maldonado, 2002; Rubino et al., 2007) induced an anxiolytic-like effect in the elevated plus-maze and light-dark crossing test. In con- trast, higher doses of cannabinoid receptor agonists HU-210 * Corresponding author. Tel.: þ39 0331 339 417; fax: þ39 0331 339 459. E-mail address: daniela.parolaro@uninsubria.it (D. Parolaro). 0028-3908/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2007.06.024 Neuropharmacology 54 (2008) 151e160 www.elsevier.com/locate/neuropharm