The genetic versus pharmacological invalidation of the cannabinoid CB1 receptor results in differential effects on ‘non-associative’ memory and forebrain monoamine concentrations in mice

Abstract

The endocannabinoid CB1 receptor has been implicated in the inhibitory control of learning and memory. In the present experiment, we compared the behavioral response of CB1 receptor knockout mice (CB1R-/-) with animals administered CB1 receptor antagonist/inverse agonist SR141716A (rimonabant; 3 mg/kg IP, 30 min pre-trial) in terms of acquisition and retention of a habituation task and changes in cerebral monoamines. The results can be summarized as follows: (i.) The acute and chronic invalidation of the CB1 receptor resulted in an increase of behavioral habituation during the first exposure to an open field, indicative of enhanced acquisition of the task; (ii.) CB1R-/-mice, but not rimonabant-treated animals, showed enhanced long-term retention of the habituation task when tested 48 hours and 1 week subsequent to the first exposure to the open field, respectively; (iii.) The facilitation of long-term retention of the habituation task in CB1R-/-mice was accompanied by a selective and site-specific increase in serotonin activity in hippocampus; and (iv.) Rimonabant-treated animals displayed 'antidepressant-like' alterations of cerebral monoamines, that is, most parameters of monoaminergic activity were increased especially in dorsal striatum and hippocampus. Taken together, the present findings demonstrate that the genetic disruption of the CB1 receptor gene can cause an improvement of behavioral habituation, which is considered to represent a form of 'non-associative' learning. Furthermore, the data support our assumption of a rimonabant-sensitive cannabinoid receptive site that is different from the 'classical' CB1 receptor and which, under physiological conditions, might be involved in the inhibitory control of the acquisition but not retention of non-associative learning tasks. Furthermore, the data support our assumption of a rimonabant-sensitive cannabinoid receptive site that is different from the 'classical' CB 1 receptor and which, under physiological conditions, might be involved in the inhibitory control of the acquisition but not retention of non-associative learning tasks. U nive r s it y o f H e r t f o r d s hir e S C H O O L O F P S Y C H O L O G Y

The Dopamine and Cannabinoid Interaction in the Modulation of Emotions and Cognition: Assessing the Role of Cannabinoid CB1 Receptor in Neurons Expressing Dopamine D1 Receptors

“…Several studies reported increased anxiety-related behaviors after impaired CB1R signaling only when aversive stimulus cannot be avoided (Haller et al, 2004, 2009; Thiemann et al, 2007; Kamprath et al, 2009). However, little is known about how ECS modulation of the DAergic system could be involved in this effect.…”

Endocannabinoids render exploratory behaviour largely independent of the test aversiveness: role of glutamatergic transmission

“…Consequently, there is the option that endocannabinoids modulate one-trial sensitization via their influence on memory processes (Riedel & Davies 2005). Attenuated CB1 signalling seems to coincide, among others, with increased short-term (Degroot et al 2005) and long-term habituation (Thiemann et al 2007) to an open field. Our data partially support these observations: Total-CB1-KO showed pronounced within-exposure habituation in the open field under bright light, but no differences to wild-type controls Genes, Brain and Behavior (2009) 8: 685-698 in between-exposure habituation.…”

“…Experiments were performed with mice lacking CB1 expression in the entire body (Total‐CB1‐KO; Marsicano et al 2002) or specifically in glutamatergic cortical neurons (CB 1 f/f;Nex−Cre = Glu‐CB1‐KO; Monory et al 2006). Because the endocannabinoid system was shown to mediate habituation to homotypic stressors (Patel et al 2005; Patel & Hillard 2008), including adaptation to aversive tones (Kamprath et al 2006), and to play a particular role during re‐exposure to exploration‐based anxiety tests, such as the elevated plus‐maze test (Rodgers et al 2005) and the open field test (Thiemann et al 2007), we additionally studied the consequences of repeated testing (i.e. familiarity) for test situations with avoidable (elevated plus‐maze) or unavoidable (open field) light exposure.…”

Synaptic plasticity alterations associated with memory impairment induced by deletion of CB2 cannabinoid receptors

“…The fact that these effects were blocked by the administration of CB 1 r-antagonist, SR141716A, supports CB 1 r as being the target involved in the acute effects of cannabinoids on memory impairments (Da and Takahashi, 2002;Pamplona and Takahashi, 2006). Interestingly, pharmacological or genetic disruption of CB 1 r signaling enhances learning and memory in a variety of spatial and operant paradigms (Thiemann et al, 2007). Further studies revealed the modulation of GABA neurotransmission through the activation of CB 1 r located on GABA interneurons, the indirect activation of the mammalian target of rapamycin (mTOR)/70-kDa ribosomal protein S6 kinase (p70S6K) signaling cascade and NMDA receptors as the main mechanisms underlying the cognitive impairments produced by cannabinoids (Puighermanal et al, 2009).…”