ABSTRACT
Cannabinoid receptors 1 (CB1R) have been shown to be a crucial part of the neuromodulatory endocannabinoid system which is involved in emotional learning and memory. We here investigated in rats the role of CB1R in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC) in different phases of fear learning, memory and extinction. We used the fear potentiated startle paradigm to measure the effects of local microinfusion of the CB1R agonist WIN 55,212-2 (WIN) or the CB1R antagonist AM251 on acquisition, consolidation, retrieval and extinction of fear. No effects on fear acquisition of WIN or AM251 were found in the BLA or mPFC. WIN impaired fear retrieval in the BLA and in mPFC. Also, WIN reduced fear consolidation in the BLA but not in the mPFC. AM251 decreased fear consolidation after mPFC infusion. Likewise, fear extinction was impaired by AM251 infused into the mPFC. Our data indicate that fear memory consolidation and retrieval, as well as extinction are regulated differentially by amygdaloid and cortical CB1R.
Subject(s)
Amygdala/physiology , Conditioning, Psychological/physiology , Extinction, Psychological/physiology , Fear , Mental Recall/physiology , Prefrontal Cortex/physiology , Receptor, Cannabinoid, CB1/metabolism , Amygdala/drug effects , Analysis of Variance , Animals , Benzoxazines/pharmacology , Conditioning, Psychological/drug effects , Extinction, Psychological/drug effects , Male , Mental Recall/drug effects , Microinjections , Morpholines/pharmacology , Naphthalenes/pharmacology , Piperidines/pharmacology , Prefrontal Cortex/drug effects , Pyrazoles/pharmacology , Rats , Rats, WistarABSTRACT
RATIONALE: Cannabinoid CB(1) receptors in the brain are targets of both endocannabinoid signalling and the psychoactive compounds of the hemp plant. They mediate neuronal effects of their ligands in various corticolimbic and striatal circuits by presynaptic regulation of transmitter release. OBJECTIVES/METHODS: This study investigates acute systemic effects of the full CB(1) receptor agonist WIN 55,212-2 (WIN) on prepulse inhibition (PPI) of the acoustic startle response (ASR), locomotor activity and spatial memory retrieval in an eight-arm radial-maze task. Furthermore, we tested the effect of local intra-cerebral micro-infusions of WIN into the nucleus accumbens (NAc), ventral tegmental area (VTA), dorsal (dHIP) and ventral (vHIP) hippocampus and medial prefrontal cortex (mPFC). RESULTS: Systemic WIN (1.2 mg/kg) reduced PPI without affecting ASR, had no effect on locomotion in the open field, but impaired retrieval of spatial memory. Infusions of 5 microg/0.3 microl WIN into either NAc (core or shell), dHIP or VTA did not affect PPI and locomotion immediately afterwards. However, PPI was significantly reduced after intra-mPFC and intra-vHIP infusion of WIN. Furthermore, WIN infusion into dHIP increased the number of reference memory errors in the maze, suggesting impairment of memory retrieval. CONCLUSIONS: Our data support the notion that CB(1) receptor stimulation impairs sensorimotor gating most likely by modulation of neurotransmitter release in mPFC and vHIP. The lack of effects of local WIN infusions in NAc and VTA might be due to low receptor abundance in these regions. Additionally, CB(1) receptor activation in dHIP impairs spatial memory retrieval. Taken together, cortico-hippocampal cannabinoid receptors play an essential role in the regulation of cognitive and behavioural processes.
