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

“…release of neurotransmitters and neuropeptides that play a key role in the control of emotionality, such as serotonin, dopamine (Tsou et al., 1998; Katona et al., 2001; Schlicker and Kathmann, 2001; Hermann et al., 2002) and the anxiogenic neuropeptides, CCK and CRF (Rodriguez de Fonseca et al.,…”

“Many investigations have focused on the effects of cannabinoids on basal synaptic transmission recorded by FPs or EPSCs (Misner and Sullivan 1999; Auclair et al. 2000; Katona et al. 2001; Robbe et al. 2002; Freund et al. 2003), which reflect combined excitatory and inhibitory synaptic responses.”

“Amygdala, hippocampus, and cortex that are involved in the regulation of emotional responses have a high expression of CB1 receptors (Katona et al., 2001; Hàjos and Freund, 2002; Tzavara et al., 2003; Pistis et al., 2004; Viveros et al., 2007).”

“CB1R are on interneurons in the amygdala and act via retrograde signalling to suppress GABA release, functionally disinhibiting neurons (Katona et al., 2001).”

“This is achieved through noradrenergic hormones and glucocorticoids, which release as part of the stress response and inhibit BLA GABAergic signalling to produce an emotional and salient charge in response to the experience (Roozendaal et al., 2008, 2009; Roozendaal and McGaugh, 1997, 2011).”

“CB1R is present in high concentrations throughout the central nervous system, including higher-order regions such as the amygdala (Katona et al., 2001).”

“For each mouse, cells were counted manually in Fiji (NIH) using at least 5 images from separate sections and averaged. cFos+, TRAP2+, RAM+ neurons were counted, and counts were normalized against the number of DAPI + cells in that LA. Chance of colocalization of population A and B was calculated as follows: Coloc chan…”

“In the amygdala, large somata CCK BCs (CCKL) represent the sole amygdala IN type expressing CB1Rs and form a population distinct from calretinin and/or vasoactive intestinal peptide (VIP)-expressing small CCK INs (CCKS) (Katona et al., 2001; Mascagni and McDonald, 2003).”

“CB1R also modulates synaptic inhibition in the amygdala (16, 17); hence, we examined the impact of FAAH inhibition on stress-induced alterations in GABAergic synaptic transmission.”

“In the BLA, CCK/CB1 basket cells are also present both in the rodent (Katona et al., 2001; McDonald and Mascagni, 2001; Vereczki et al., 2016; Rovira-Esteban et al., 2017) and in the monkey (McDonald, 2021), giving rise to 0.”

“We expected to observe a reduction in cue-induced reinstatement by blocking CB1 receptors in the BLA since these receptors are highly expressed by CCK-positive GABAergic interneurons in the BLA (Katona et al, 2001) that control the excitation of BLA output neurons (Collins and Pare, 1999).”

“…and cannabinoids alter the expression of glucocorticoid receptors (GRs) and cannabinoid CB1 receptors (CB1r) in the brain’s stress circuit where these receptors are highly abundant (Ahima and Harlan 1990; Herkenham et al. 1990; Katona et al. 2001; Marsicano and Kuner 2008; Sivukhina et al. 2013).”

“…neurons, Katona et al. demonstrated that the amplitude of evoked GABA-A receptor-mediated inhibitory postsynaptic currents (eIPSC) are depressed by application of the CB1 agonists Win 55212-2 and CP 55940; effects that were reversed by the CB1 receptor antagonist SR141716 (Katona et al., 2001).”

“…other hand, recent findings have suggested that CB1 receptors have been localized presynaptically on GABAergic interneurons (Hoffman & Lupica, 2000; Katona et al., 2001; Freund et al., 2003) and glutamatergic terminals, albeit at much lower levels than on GABAergic terminals (Freund et al., 2003;…”

“…pre-synaptic terminals of GABAergic cells in the substantia nigra pars reticulata (Chan et al., 1998; Wallmichrath and Szabo, 2002), hippocampus (Wilson and Nicoll, 2001), amygdala (Katona et al., 2001) and in the VTA (Szabo et al., 2002) where they exert inhibitory effects on transmitter release.”

“In light of the fact that CB1 receptors are expressed predominantly by CCK interneurons in the BLA (Katona et al. 2001; McDonald and Mascagni 2001b), these data would further suggest that Type I and Type II CCK interneurons may preferentially express CB1 receptors.”

“…the inhibitory efficacy of these two cell populations was similar, which can be, at least partially, explained by the fact that the presence of multiple release sites at the axon terminals of CCKBCs in the BA (as in other cortical regions) is typical (Katona et al., 2001; Yoshida et al., 2011).”

“, 2016) through activation of CB1R expressed on GABAergic interneurons (Katona et al., 2001) and glutamatergic neurons impinging on BLA pyramidal cells (Domenici et al.”

“…there was no change in the laminar localization of labeled cell bodies which are characteristic to the CB1R-expressing interneuron subtypes described previously (Katona et al. 1999, 2001; Tsou et al. 1999; Egertova and Elphick, 2000; Morozov and Freund 2003; Bodor et al. 2005; Matyas et al. 2006).”

“The ability of endocannabinoids to act as retrograde neurotransmitters (44) allows them to attenuate the activity of external afferents (pre-synaptic neurons) (42) and allows dopamine neurons (post-synaptic neurons) to regulate their own function (43).”

“This result agrees with an immunohistochemical study showing that CB1 receptors are undetectable in the intermediate capsule in contrast to other amygdaloid nuclei (Katona et al. 2001), and indicates that their negative result was not due to a low sensitivity of the antibody used.”

“The localization of CB1 in GABAergic and glutamatergic presynaptic terminals is well documented [36,38–43], and many studies in different brain regions have demonstrated that”

“Cannabinoid CB1 receptors are abundantly expressed on GABAergic nerve terminals in the brain, where they reduce transmitter release (79,80).”

“Our findings are in agreement with previously published studies showing that activation of CB1 receptors presynaptically modulates release of neurotransmitters [16,18,19,22,26,34,44].”

“The actions of THC are mediated by activation of CB1 receptors that are found predominately on presynaptic axon terminals of glutamatergic and GABAergic fibers (Katona et al. 2001; Kofalvi et al. 2005).”

“Furthermore, an important regulating role of CB1 receptor in the basolateral nucleus of amygdala has been described, that could explain the implication of the cannabinoid system both in addiction and psychopathic personality (Katona et al., 2001).”

“Although most research has focused on GABA and GABAergic plasticity as the mechanism by which Cnr1 mediates fear inhibition (Katona et al, 2001; Marsicano et al, 2002; Azad et al, 2003, 2004; Kamprath et al, 2011; Lin et al, 2011; Uriguen et al, 2011), we hypothesize that the anatomical…”

“…to the well established role of CB1 receptor transmission in inhibiting feedforward, GABAergic inhibitory inputs to principal output neurons (Katona et al., 2001; Freund et al., 2003), CB1 receptors also control presynaptic GLUTergic release in various neural regions, including the…”

“CB1Rs are distributed extensively throughout the brain, including the amygdala (Katona et al., 2001; Mackie, 2005).”

“At the ultrastructural level, CB1 receptors have been located on axonal terminals forming symmetrical synapses, regarded as GABAergic, in the hippocampus (Hajos et al., 2000; Katona et al., 1999) and amygdala (Katona et al., 2001).”

“In BLA, CB1 receptors are abundant on cholecystokinin (CCK)-positive GABAergic interneurons and moderately expressed on glutamatergic terminals (Bodor et al., 2005; Katona et al., 2001; Kawamura et al., 2006; Marsicano and Lutz, 1999).”

“The presence of CB1 receptors in other structures related to motivation and reward, such as amygdala, hippocampus, orbitofrontal cortex and aspects of the prefrontal cortex, contributes to this function of the eCB system (Katona et al., 2001).”

“…of the same layer, but not L2/3 (Fortin and Levine 2007); it affects neurotransmission in the BLA complex, but not in central and medial nuclei (Katona et al. 2001; Azad et al. 2003; Chevaleyre et al. 2007); AM-251 does not affect the baseline EPSPs' magnitude , but blocks long-term depression…”

“As endocannabinoids are hypothesized to regulate GABAergic signaling within the BLA (Azad et al , 2004), particularly at the GABA A -subtype of receptor (Katona et al , 2001), we also investigated whether antagonism at GABAergic receptors could rescue any memory deficit induced by CB1R blockade.”

“[20] Katona I, Rancz EA, Acsady L, Ledent C, Mackie K, Hajos N, Freund TF.”

“, nucleus accumbens, cortex, amygdale, and hippocampus), and they have been suggested to participate in memory modulation (Katona et al. 2001; Li et al. 2008a, b; Tsou et al. 1998; Wilson and Nicoll 2002).”

“The CB1 subtype occurs in high density in several regions of the CNS including the neocortex, hippocampus, amygdala, cerebellar cortex and the extrapyramidal motor control system (Herkenham et al., 1991; Matsuda et al., 1993; Tsou et al., 1998; Katona et al., 2001 ).”

“In the brain, endocannabinoids (eCBs) are released postsynaptically and diffuse back to presynaptic CB1 receptors, densely localized within AMYG, vmPFC, and HPC [86-89], thereby inhibiting presynaptic neurotransmitter release [90, 91].”

“The neurochemical mechanism and substrates mediating this biphasic effect of cannabinoids on emotionality is not entirely understood at this time; however, CB1 receptors do exist in moderate densities in amygdalar nuclei (Herkenham et al., 1991; Katona et al., 2001; McDonald and Mascagni, 2001).”

“Concerning the role of amygdalar PKA activity in consolidation and extinction, two papers from the same laboratory suggest that in conditioned-taste aversion, things may be different from what has been described in one-trial avoidance in the rat, both concerning extinction (which is enhanced by Rp-cAMPS) and short-ter…”

“2009) including prefrontal cortex, hippocampus and basolateral amygdala, express a moderate to high density of CB1 receptor protein (Chhatwal et al. 2008; Herkenham et al. 1991; Katona et al. 2001; McDonald and Mascagni 2001).”

“…to the cannabinergic system and hippocampal (Deadwyler et al., 1996; Sullivan, 1999; Wilson and Nicoll, 2001; Robbe et al., 2006), amygdala (Katona et al., 2001; Marsicano et al., 2002; Azad et al., 2005; Zhu and Lovinger, 2005), and striatal activity (Gerdeman et al., 2002; Kreitzer and…”

“Their stimulation reduced the inhibitory tone of GABA which leads to an imbalance of the excitatory/inhibitory input (Katona et al., 1999, 2001), a phenomenon that may interfere with cannabinoid-mediated neuroprotection.”

“, 2007), the reports indicating the presence of both CB1 receptors (Katona et al., 2001; McDonald and Mascagni, 001; Kamprath et al., 2011) and Sim1-expressing neurons (Balthasar et al.”

“In the rat BLA, CCK basket cells, identified by their expression of cannabinoid (CB) 1 receptors, also coexpress VIP (Katona et al., 2001; Mascagni and McDonald, 2003).”

“2003), it is unlikely that the effects of rimonabant, which could have diffused into this nucleus, are mediated by the CeA because no CB1 receptors have been found in this area (Katona et al. 2001).”

“All rights reserved. amygdala, hippocampus, and the PFC (Ahima and Harlan, 1990; Herkenham et al., 1990; Katona et al., 2001; Marsicano and Kuner, 2008).”

“More specifically, the large majority of GABAergic CB1-containing neurons is cholecystokininergic (Marsicano and Lutz 1999; McDonald and Mascagni 2001; Katona et al. 2001).”

“The amygdala is a forebrain structure that has a high density of CB1 receptors; that is, the cannabinoid receptor subtype predominantly found in the central nervous system (CNS).(18,19) In addition to being a key region involved in the modulation of emotional and defensive responses, the amygdala is also associated wi…”

“The latter notion is com- patible with the fact that mGluR5 blockade shortens the duration of DSI in the BLA (Zhu and Lovinger, 2005) and abolishes CB1mediated short-tem synaptic depression in the hippocampus (Sheinin et al., 2008).”

“CB1 receptors have been found to be primarily localized presynaptically on GABAergic neurons as determined by electrophysiological analyses (15, 16).”

“Immunohistochemical studies have confirmed a dense expression of cannabinoid1 (CB1) receptors on GABAergic interneurons [34,45,50,61,83,84], and on glutamatergic pyramidal projection”

“Yet, CB1 receptors are expressed at high levels in the BLA but their expression in the central amygdala is less clear (Herkenham et al. 1990; Tsou et al. 1998; Katona et al. 2001; Cota et al. 2007).”

“CB1Rs are highly expressed in brain regions involved in stress and fear responding, including the amygdala, hippocampus, mPFC, and anterior cingulate cortex (Glass et al., 1997; Herkenham et al., 1990; Katona et al., 2001).”

“The very same neurons express CB1 receptors on their axon terminals suggesting that the 5-HT3 receptor-mediated GABA release is controlled by CB1 receptors (Katona et al., 1999, 2001; Marsicano and Lutz, 1999; Hajos et al., 2000; Bodor et al., 2005).”

“…(Hoffman and Lupica, 2000; Hájos et al., 2000; Diana et al, 2002; Wilson and Nicoll, 2002), including the hippocampus (Kawamura et al., 2006), ventral tegmental area (Szabo et al, 2004; Melis et al., 2004), amygdala (Katona et al, 2001; Azad et al., 2003), and cerebellum (Kawamura et al, 2006).”

“This receptor is localized in excitatory and inhibitory neurons (Katona et al., 2001; Wilson et al., 2001; Kawamura, 2006) and also in astrocytes (Hoffman et al., 2010; Han et al., 2012).”

“It has been demonstrated that dopaminergic, glutamatergic and GABAergic axon terminals in the amygdala express cannabinoid CB1 receptors (Katona et al., 2001).”

“Endogenous cannabinoids (endocannabinoids) and their receptor CB1 are found in many places in the brain (Marsicano et al., 2002, Wilson and Nicoll, 2002), including the BLA ( Katona et al., 2001 ) and the hippocampus (see Barros et al., 2003).”

“Hence, the reduction in inhibitory tone may in turn indirectly reduce the effects of stress by enhancing the activity of intercalated GABAergic cells that inhibit activation of the central amygdala (Katona et al., 2001).”

“In many brain regions CB1 receptor actions and CB1 expression are especially strong on GABAergic synapses (Adermark and Lovinger, 2009; Katona et al., 2001; Katona et al., 1999; Yoshida et al., 2002).”