The effect of CB1 receptor antagonism in the right basolateral amygdala on conditioned fear and associated analgesia in rats

The endocannabinoid system mediates analgesia expressed following exposure to conditioned or unconditioned aversive stimuli, and controls the extinction of conditioned aversive behaviour. The present study investigated the effects of administration of the cannabinoid(1) (CB1) receptor antagonist SR141716A into the right basolateral amygdala (BLA) on expression of conditioned fear, formalin-evoked nociceptive behaviour, fear-conditioned analgesia and associated alterations in monoamine levels in discrete rat brain areas. Re-exposure to a context previously paired with footshock significantly reduced formalin-evoked nociceptive behaviour. Intra-BLA administration of SR141716A did not attenuate fear-conditioned analgesia, but reduced formalin-evoked nociceptive behaviour and attenuated the formalin-induced decrease in freezing and 22-kHz ultrasonic vocalizations in the early part of the trial. Furthermore, intra-BLA SR141716A significantly prolonged the duration of these fear-related behaviours in fear-conditioned rats not receiving formalin. Fear-conditioned analgesia was accompanied by increased homovanillic acid (HVA) : dopamine (DA) ratio and reduced serotonin (5-HT) in the cerebellum, an effect not altered by SR141716A. SR141716A-induced analgesia was accompanied by reduced DA, increased HVA : DA ratio and reduced 5-HT levels in the cerebellum, increased hippocampal HVA levels and increased 5-hydroxyindole-3-acetic acid (5-HIAA) in the amygdaloid cortex. The SR141716A-induced prolongation of contextually induced aversive behaviour was accompanied by reduced DA and 3,4-dihyroxyphenylacetic acid (DOPAC), levels in the hippocampus, and increased DA and 5-HIAA in the periaqueductal grey. These data suggest an important role for CB1 receptors in the right BLA in mediating short-term extinction of conditioned aversive behaviour but not fear-conditioned analgesia. The results also enhance our understanding of endocannabinoid-monoamine interactions of relevance to conditioned fear and associated analgesia.