Distribution of CB1 Cannabinoid Receptors in the Amygdala and their Role in the Control of GABAergic Transmission

“…and anterior cingular cortex, key regions in the regulation of anxiety, may suggest that the endocannabinoid system plays a role in the control of anxiety (Herkenham et al., 1990, 1991a,b; Glass et al., 1997b; Katona et al., 2001; Hájos and Freund, 2002; Tzavara et al., 2003; Pistis et al., 2004).”

“In support of this idea, correlated light and electron microscopy using high-resolution immunogold technique provide clear-cut evidence that the CB1 immunostaining visualizing cell bodies and proximal dendrites of interneurons at the light microscopical level is always associated with intracellular organelles, but nev…”

“(SOM), vasoactive intestinal peptide, or cholecystokinin (CCK; Refs.”

“Although previous research has mostly focused on the role of glutamatergic transmission and plasticity, there is accumulating evidence indicating that local inhibitory circuits in the amygdala contribute to, or even mediate, important aspects of fear conditioning and extinction.”

“Indeed, CB1 receptors are only found on the axon terminals of a specific subpopulation of BLA interneurons, which express the peptide cholecystokinin (CCK) (Katona et al., 2001).”

“The second is that double label immunostaining experiments demonstrated that in forebrain there is a striking correlation between CCK and CB1 receptor expression (Katona et al. 1999; Tsou et al. 1999; Katona et al. 2001).”

“For example, Katona et al. (2001) reported that CB1 receptors were expressed in high densities in lateral and basal nuclei in the rat amygdala.”

“some amygdala nuclei (356), and in hippocampus (13,”

“Combined with electron microscopy and electrophysiology studies, CB 1 receptors have been shown to be localized presynaptically on GABAergic interneurons (Katona et al., 1999, 2001).”

“The presence of CB1 receptors in other structures related to motivation and reward, such as the basolateral amygdala and the hippocampus, also contributes to this function of the endocannabinoid system [ 16 ].”

“Neurochemical mechanisms contributing to the memory-impairing effects of cannabinoids In the hippocampus, CB1R are located primarily on cholecystokinin containing GABAergic interneurons (Hajos et al. 2001; Katona et al. 2000, 2001).”

“The CB1 receptor is expressed almost exclusively on presynaptic terminals in striatum and other brain regions (Katona et al., 2001, 2006; Matyas et al., 2006; Uchigashima et al., 2007), and is known to inhibit glutamate release when activated (Gerdeman and Lovinger, 2001; Huang et al., 2001;…”

“However, CB1-positive signals have not been detected at cannabinoid-sensitive excitatory synapses in most of other brain regions such as the hippocampus (Katona et al., 1999; Hajos et al., 2000), amygdala (Katona et al., 2001), and somatosensory cortex (Bodor et al., 2005).”

“Pretreatment of mice with two doses of AM404 produced a significant effect on restraint-induced CORT release [by one-way ANOVA: F(3,24) 23.”

“…emotion and motivation [i.e., the prefrontal cortex, nucleus accumbens, amygdala, and hypothalamus (Tsou et al., 1998a,b; Marsicano and Lutz, 1999; Katona et al., 2001; McDonald and Mascagni, 2001; Gulyas et al., 2004)] is also consistent with a role for this system in the regulation of emotional…”

“…by the dense expression of the CB1 receptor in regions known to be important for anxiety and emotional learning, including the amygdala, hippocampus, and throughout the mesolimbic dopamine reward system (Katona et al, 1999, 2000, 2001; Freund et al, 2003; van der Stelt and Di Marzo, 2003).”

“Intense perikaryal labeling was reported for CCK-positive interneurons in the hippocampus, cerebral cortex, and amygdala (Katona et al., 1999, 2001; Hajos et al., 2000; Fukudome et al., 2004; Bodor et al., 2005) but has never been seen in the striatum (Julian et al., 2003; Matyas et al., 2006) (Fig.”

“The terminals of CCK-positive GABAergic basket cells in hippocampus and amygdala contain CB1-cannabinoid receptors (Katona et al. 1999, 2001).”

“Accordingly , several recent studies indicate that endocannabinoids also act as retrograde synaptic signaling molecules in these regions of the forebrain (Katona et al., 2001; Trettel and Levine, 2002).”

“Similarly, large CCK-positive cells were found to express CB 1 receptors in both the basolateral amygdala (Katona et al., 2001; McDonald and Mascagni, 2001) and hippocampus (Katona et al., 1999).”

“, 2005), cannabinoids (Katona et al., 2001; McDonald and Mascagni, 2001; Marsicano et al., 2002) and dopamine (Brinley-Reed and McDonald, 1999; Bissiere et al.”

“…mice have provided evidence that CB1 is the major presynaptic cannabinoid receptor at inhibitory and excitatory synapses in various brain regions (Katona et al., 1999, 2001; Farquhar-Smith et al., 2000; Hajos et al., 2000, 2001; Wilson and Received Jan. 6, 2006; revised March 18, 2006; accepted…”

“Numerous studies described the expression of cannabinoid 1 receptors in animal and human brain tissue [2,35—39].”

“…European Journal of Neuroscience, 21, 1057–1069 within subregions of the amygdala (Patel et al., 2004a) and the known cellular and functional effects of eCB signalling previously observed in this region (Alonso et al., 1999; Katona et al., 2001; Marsicano et al., 2002; Azad et al., 2003).”

“CB1 receptors are expressed at high levels in the rat amygdala, particularly the BLA (4, 13, 28).”

“Their distribution has been mapped by autoradiographic studies, immunohistochemical techniques, in situ histochemistry, and electrophysiological studies [53, 78, 140].”

“Abbreviations: PN: principal neuron, CS: conditioned stimulus, US: unconditioned stimulus, IL: infralimbic, PL: prelimbic, CB1R: cannabinoid receptor type 1, DGLα: diacylglycerol lipase α, DSI: depolarization-induced suppression of inhibition.”

“In the other method, the release of endogenous or radiolabelled neurotransmitters from presynaptic axon terminals is determined chemically.”

“CB1 receptors are densely localized to a distinct population of GABAergic interneurons in the lateral and basal (BLA), but not central (CeA), nuclei of the amygdala (Katona et al., 2001).”

“, 2001) but also in the amygdala (Azad et al., 2003;Katona et al., 2001).”

“Such effects of eCB signaling on anxiety-like behaviors are likely mediated through the amygdala, where CB1 receptors are densely expressed (47; 48), and both AEA and 2-AG concentrations are markedly elevated during the presentation of anxiogenic stimuli (49).”

“or other properties of miniature synaptic responses, indicating that the receptor has little effect on mechanisms downstream from VGCCs (Hoffman and Lupica 2001; Katona et al. 2001; Zhu and Lovinger 2005).”

“The specificity of CB1 receptor antibody has been confirmed by the laboratory of origin and by the lack of immunostaining in the CB1 receptor knock-out mice (Katona et al., 2001).”

“Similarly, studies employing exogenous CB1 receptor agonists have also found that activation of CB1 receptors can suppress both glutamatergic and GABAergic synaptic transmission (Azad et al, 2003; Domenici et al, 2006; Katona et al, 2001).”

“No significant change Ford et al. (2014) fMRI 15 [cannabis users]/15 [MDD]/14 [cannabis users with MDD]/17 [healthy controls] - Music Listening Paradigm (Neutral and Preferred Music) 20.2 (1.3) [cannabis users], 19.9 (1.7) [MDD + cannabis users] 6.8 (0.4) [cannabis users] 6.9 (0.4) [cannabis users + MDD] - 22.0 (6.2)…”

“Within amygdala subnuclei, FAAH is highly expressed on pyramidal neurons in the BLA, and to a significantly lesser extent in the central nucleus (CeA) [19,20,46,47].”

“Endocannabinoids are considered to be retrograde messengers released by neurons to modulate release of neurotransmitters (Kreitzer and Regehr 2001; Ohno-Shosaku et al. 2001; Wilson and Nicoll 2001).”

“CB1Rs have been shown to be localized presynaptically on GABAergic interneurons and glutamatergic neurons (Katona et al. 1999, 2001, 2006), and this localization of CB1Rs is consistent with the proposed role of ECs in modulating GABA and glutamate neurotransmission (Ohno-Shosaku et al. 1998, 2000,…”

“…with somata and dendrites as well as presynaptic terminals of CCKþ interneurons where it’s activation produces a short duration reduction of the action potential evoked release of GABA and the subsequent inhibitory post-synaptic current (Katona et al., 2001; McDonald and Mascagni, 2001b).”

“Modest to high CB1 receptor densities exist in structures implicated in depression, including the prefrontal cortex, hypothalamus, amygdala and hippocampus (Herkenham et al., 1991; Marsicano and Lutz, 1999; Tsou et al., 1999; Moldrich and Wenger, 2000; Katona et al., 2001).”

“CB1 cannabinoid receptors are abundant in brain areas involved in emotion and motivation, such as the nucleus accumbens (NAc) and amygdala (Tsou et al., 1998; Katona et al., 2001).”

“CB1 is highly expressed by GABAergic neurons in many brain regions, especially in the hippocampus, neocortex, cerebellum, amygdala, as well as in several nuclei of the basal ganglia (Tsou et al., 1998; Katona et al., 1999, 2001; Egertova and Elphick, 2000; Egertova et al., 2003; Freund et al., 2003; Julian et al., 200…”

“Since CB1R inhibit the release of g-aminobutyric acid (GABA) (Katona et al., 2001), these results suggest that the extinction-induced upregulation of perisomatic CB1R facilitated the persistence of a small subset of active BA fear neurons in the extinction group (Figure 1J).”

“CB1 endocannabinoid receptors have been identified in presynaptic terminals (Katona et al., 1999, 2001), enabling endocannabinoids to function as retrograde messengers (Ohno-Shosaku et al., 2001).”

“Moreover, plastic events in regions such as the NAc, PFC and other limbic structures likely participate in the formation of conditioned associations between drug reward and a variety of internal and external cues associated with drug intake.”

“At the subcellular level, CB1 has been localized to pre-synaptic terminals, and is found at significantly higher levels on GABAergic than glutamatergic neurons in various brain regions (Katona et al., 1999; Katona et al., 2001; Puighermanal et al., 2009).”

“…widely distributed in the brain but are present in relatively high concentrations in the BLA and, in particular, are present on the presynaptic terminal of CCK interneurons (Katona et al., 2001; McDonald and Mascagni, 2001b), which densely innervate principal neurons (McDonald and Pearson, 1989).”

“Although the distribution of CB1 immunoreactivity across monkey neocortical regions is broadly similar to that observed in the rat using immunocytochemical (Egertova and Elphick 2000; Hajos et al. 2000; Katona et al. 2001; Bodor et al. 2005) and autoradiographic (Herkenham et al.”

“Indeed, the potential therapeutic value of cannabinoid modulation is underscored by the dense expression of the cannabinoid CB1 receptor in regions known to be significant for anxiety and emotional learning, particularly the basolateral amygdala (BLA) (Katona et al., 2001; Haller et al., 2002).”

“Restraint increased the number of Fos-li cells within the BLA, whereas AM404 alone had no effect (Figure 7).”

“The authors conclude that CB-1 receptor activation effectively reduces the threshold at which salient sensory stimuli activate the basolateral amygdala (BLA) –CeA pathway (Katona et al., 2001).”

“We focused our electrophysiological studies on the BLA given the high level of both DAGLp and CB1 receptor expression in this subregion (Katona et al, 2001).”

“mation, and amygdala), the cerebellum and neocortex, and are expressed widely at lower levels in other brain regions (6,40,41).”

“Studies examining the functions of endocannabinoid signaling in the limbic system have shown that CB1 receptors play a key role in modulating synaptic transmission (Katona et al., 2001; Tan et al., 2011) and neuronal firing (Pistis et al.”

“Experiments testing the role of Ca2þ in LTDi of the BLA have not been reported.”

“produced by activated neurons, act presynaptically modulating the release of several neurotransmitters and neuropeptides that play a key role in anxiety (Hermann et al. 2002; Katona et al. 2001; Schlicker and Kathmann 2001; Tsou et al. 1998; Ameri 1999; Rodriguez de Fonseca et al. 1997).”

“Genetic and pharmacological approaches also support an involvement of endocannabinoids in extinction of aversive memories.”

“Decreased FAAH activity after salvinorin A, was only observed in amygdala, which is a brain region linked with the effects of cannabinoids on emotionally relevant behaviours (Katona et al., 2001) and where anatomical studies have reported the presence of k-opioid receptors (Mansour et al., 1994).”