Abstract
The endocannabinoid (ECB) system is strongly involved in the regulation of cognitive processing and emotional behavior and evidence indicates that ECB signaling might affect these behavioral abilities by modulations of prefrontal cortical functions. The aim of the present study was to examine the role of the CB1 receptor in the medial prefrontal cortex (mPFC) on cognitive flexibility and emotional behavior. Therefore, the CB1 receptor was overexpressed by adeno-associated virus vector-mediated gene transfer specifically in the mPFC of adult Wistar rats. Animals were then tested in different anxiety-related paradigms for emotional reactivity [e.g., elevated plus maze (EPM), light/dark emergence test (EMT), social interaction] and the attentional set shift task (ASST) – an adaptation of the human Wisconsin card sorting test – for cognitive abilities and behavioral flexibility. A subtle increase in exploratory behavior was found in CB1 receptor overexpressing animals (CB1-R) compared to Empty vector injected controls (Empty) in the EMT and EPM, although general locomotor activity did not differ between the groups. During social interaction testing, social contact behavior toward the unknown conspecific was found to be decreased, whereas social withdrawal was increased in CB1-R animals and they showed an inadequate increase in exploratory behavior compared to control animals. In the ASST, impaired reversal learning abilities were detected in CB1-R animals compared to controls, indicating reduced behavioral flexibility. In conclusion, upregulation of the CB1 receptor specifically in the rat mPFC induces alterations in emotional reactivity, leads to inadequate social behavior, and impairs cognitive flexibility. These findings might be relevant for neuropsychiatric disorders, since higher cortical CB1 receptor expression levels as well as similar behavioral impairments as observed in the present study have been described in schizophrenic patients.
Highlights
The endocannabinoid (ECB) system has emerged in recent years as a key modulator of neuronal activity of various neurotransmitter systems and appears to be involved in synaptic plasticity in diverse brain structures
Upregulation of the CB1 receptor in the rat medial prefrontal cortex (mPFC) induces alterations in emotional reactivity, leads to inadequate social behavior, and impairs cognitive flexibility.These findings might be relevant for neuropsychiatric disorders, since higher cortical CB1 receptor expression levels as well as similar behavioral impairments as observed in the present study have been described in schizophrenic patients
associated virus (AAV) vector production and stereotaxic delivery The cDNA encoding the rat CB1 receptor was cloned into an AAV expression cassette containing the 1.1-kb CMV immediate early enhancer/chicken β-actin hybrid promoter (CBA), the woodchuck hepatitis virus post-transcriptional regulatory element (WPRE), and the bovine growth hormone polyadenylation sequence flanked by AAV2 inverted terminal repeats
Summary
The endocannabinoid (ECB) system has emerged in recent years as a key modulator of neuronal activity of various neurotransmitter systems and appears to be involved in synaptic plasticity in diverse brain structures. One important brain region through which cannabinoids might exert their modulatory effects on cognition and emotional behavior is the prefrontal cortex (PFC). It has been reported that systemic activation or blockade of cannabinoid CB1 receptors in the rat medial prefrontal cortex (mPFC) modulates emotional associative learning and memory formation, mainly through functional inputs from the basolateral amygdala The importance of the ECB system for cognitive flexibility – a behavior that is highly dependent on prefrontocortical functions (Owen et al, 1991; Birrell and Brown, 2000; Egerton et al, 2005) – has been indicated in various studies in humans and rodents (for review see Egerton et al, 2006; Pattij et al, 2008). It has been suggested that these cannabinoid effects might be related to the modulatory influence of ECB signaling on PFC neurotransmission (e.g., dopamine, GABA, and glutamate; Egerton et al, 2006; Pattij et al, 2008)
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