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

“GABAB and CB1 receptors show overlapping anatomical localization in some brain areas, e.g. the hippocampus (Katona et al., 1999, 2001; Hajos et al., 2000; Nyiri et al., 2005).”

“CB1 receptors are present in the presynaptic terminals of both GABAergic and glutamatergic neurons in the amygdala (Katona et al., 2001; Marsicano and Lutz, 1999).”

“For example, subsets of GABAergic cells in the basolateral nucleus complex express somatostatin, neuropeptide Y, cholecystokinin, or vasoactive intestinal peptide (McDonald and Pearson, 1989; Katona et al., 2001).”

“endocannabinoids) ligands leads to a profound suppression of inhibitory transmission (Katona et al. 2001; Azad 2003; Zhu and Lovinger 2005).”

“CB1 receptors were first described on neuronal elements in the rat brain, including postsynaptic sites in specific cell populations, such as pyramidal neurons in the hippocampus [45], and at presynaptic sites in γ-aminobutyric acid (GABA)-ergic interneurons [46, 47] and GABAergic projection neurons [48].”

“Especially in the limbic system CB1 receptors show high densities, where agonists inhibit -amino butyric acid (GABA) release and modulate glutamate release [23,24,36].”

“CB1 receptors are predominantly expressed in the nervous system (Herkenham et al., 1991; Tsou et al., 1998; Katona et al., 2001; Wilson and Nicoll, 2002) while CB2 receptors are primarily found in immune cells.”

“There are two main types of neurons in the BLA (reviewed in McDonald, 1992a): (1) multipolar projection cells with spiny dendrites and highly collateralized axons and (2) GABAergic local-circuit neurons (McDonald, 1985; Mc-Donald and Augustine, 1993; Pare and Smith, 1993) that are aspiny (or sparsely spiny) and expres…”

“The ability of natural and synthetic cannabinoids to influence anxiety responses is mostly mediated by the cannabinoid CB1 receptor (CB1R), a G-protein coupled receptor abundantly expressed in all the major brain regions implicated in emotional regulation, including the prefrontal cortex (PFC), amygdaloid complex, sep…”

“Indeed, a detailed examination of CB1 receptor expression in the amygdala using immunohistochemistry has identified high concentrations of this receptor type within the BLA, whereas the receptor appears to be absent within the central and medial nuclei of the amygdala (Katona et al., 2001).”

“The cannabinoid CB1 receptor (CB1R) is localized to neural regions responsible for emotional processing, including the basolateral amygdala (BLA) and mesolimbic pathway (Katona et al. 2001).”

“Targeted neurons express functional CB1R Based on earlier reports that CCK-containing basket cells in the BA express CB1R, we next asked whether the targeted BA INs were CB1R-positive (Katona et al., 2001; McDonald and Mascagni, 2001a; Vereczki et al., 2016; Veres et al., 2017).”

“…of CCK-positive basket cells, thereby inhibiting the release of GABA specifically on the active pyramidal neurons: a form of short-term plasticity known as depolarization-induced suppression of inhibition (Katona et al. 1999; Katona et al. 2001; Ohno-Shosaku et al. 2001; Wilson et al. 2001).”

“…combinations of peptides such as cholecystokinin (CCK), somatostatin (SOM), vasoactive intestinal polypeptide (VIP), and calcium-binding proteins (Kemppainen and Pitk€anen, 2000; Katona et al., 2001; McDonald and Betette, 2001; Mascagni and McDonald, 2003; reviewed in Spampanato et al., 2011).”

“…into: (a) parvalbumin (PV), (b) somatostatin (SST), (c) cholecystokinin (CCK), (d) neuropeptide Y, (e) vaso-intestinal peptide (VIP), and (f) neurokinin 1subtypes (Kemppainen and Pitkanen, 2000; McDonald and Mascagni, 2002; Mascagni and McDonald, 2003; Sreepathi and Ferraguti, 2012) (Figure 1).”

“neurons (Katona et al. 2001; Yoshida et al. 2011) and at lower levels in glutamatergic pyramidal cells (Yoshida”

“CB1 cannabinoid receptors are highly abundant in brain areas, such as the nucleus accumbens, prefrontal cortex, amygdala, striatum, and hippocampus (Katona et al. 2001; De Vries and Schoffelmeer 2005), where they contribute to the regulation of a number of physiological functions, including motivation, memory, and emo…”

“Sometimes, the problem can be addressed by switching the order in which immunoperoxidase and immunogold labeling are performed (Katona et al., 2001) or using a sequential method of incubation in primary antibodies rather than the parallel method recommended here.”

“…(CeA), BNST, NAc and PFC] (Dong et al., 2001; Sah et al., 2003), are activated by CRF (Bittencourt and Sawchenko, 2000; Ugolini et al., 2008; Giesbrecht et al., 2010) and indirectly regulated by local CB1 receptor transmission (Katona et al., 2001; Azad et al., 2004; Zhu and Lovinger, 2005).”

“Thus, it is possible that AM251 odulates excitatory and inhibitory transmission in one or ore of these regions (Auclair et al., 2000; Chiu et al., 010; Katona et al., 2001; Domenici et al., 2006) to funcionally block the effects of CRF and CRF-dependent coaine withdrawal on anxiety-like behavior.”

“Moreover, activation of CB1 receptor either by exogenous or by endogenous cannabinoids inhibits the release of GABA mainly from CCK-positive interneurons and strongly suppresses GABAA receptor-mediated IPSCs in pyramidal neurons (Katona et al., 2001; Bodor et al., 2005).”

“[51,98,99].”

“The amygdala is a forebrain structure that has a high density of CB1 receptors; that is, the cannabinoid receptor subtype is predominantly found in the central nervous system (Katona et al., 2001).”

“GABAergic transmission, disinhibiting principle neurons innervating the central nucleus of the amygdala (CeA) thereby modulating its output (Katona et al., 2001; Azad et al., 2004).”

“Cannabinoid CB1 receptors are present at higher densities in pre-synaptic terminals such as the amygdala, hippocampus, anterior cingulate cortex and prefrontal cortex (Hajos & Freund, 2002; Herkenham et al., 1990; Katona et al., 2001; Pistis et al., 2004).”

“, 1998)—key regions implicated in fear learning—but are absent in the central and medial nuclei of the amygdala (Katona et al., 2001), regions involved in fear expression.”

“…CB1 receptor was measured after the administration of alprazolam in different brain regions closely involved in the modulation of anxiety such as the AMY and fields of the hippocampus (File et al., 2000; Hoffman and Lupica, 2000; Katona et al., 2001; Roohbakhsh et al., 2007; Tsou et al., 1999).”

“This is consistent with past reports in the hippocampus (Katona et al., 1999), PFC (Fitzgerald, Mackie, & Pickel, 2013), and the somatosensory cortex (Bodor et al.”

“…1999, 2001; Marsicano and Lutz, 1999; Matsuda et al., 1993; McDonald and Mascagni, 2001; Tsou et al., 1998), hippocampus (Herkenham et al., 1990; Katona et al., 1999, 2001; Marsicano and Lutz, 1999; Matsuda et al., 1993; McDonald and Mascagni, 2001; Tsou et al., 1998), or cerebral cortex (Bodor…”

“presynaptic neurons within the central nervous system (CNS), particularly among GABAergic interneurons, and peripheral neurons as well as on astrocytes and oligodendrocytes (Huang et al., 2001; Katona et al., 2001; Ohno-Shosaku et al., 2001; Szabo et al., 2005).”

“Type-1 cannabinoid receptors densely populate the amygdala (Katona et al. 2001; Mackie 2005), and their activation can inhibit excitatory input to this area of the brain (Azad et al. 2003).”

“Cannabinoid CB1 receptors are expressed in brain regions involved in memory processing, including the hippocampus, the amygdala and the prefrontal cortex (Katona et al., 2001; Wilson and Nicoll, 2002; Li et al., 2008), and treatment with the CB1 receptor antagonist rimonabant has been shown to impair the reconsolidati…”

“Further, the distribution of CB1 receptors in rat brain is also consistent with an involvement of this system in the regulation of emotional reactivity, with high levels of CB1 expression in structures such as the amygdala, anterior cingulate cortex and prefrontal cortex (Herkenham et al. 1990; Glass et al. 1997; Kato…”

“In the amygdala, presynaptical axon terminals with CB1 receptors are in close proximity to GABAergic receptors.(11) Due to the close anatomic relationship, a negative feedback mechanism to presynaptic CB1 receptors changes the arousal state.”

“However, in BLA, CB 1 receptors are highly expressed in axon terminals of GABAergic neurons modulating GABA release via a presynaptic mechanism [48].”

“Our speculation for the mechanism underlying the observed changes in BLA CB1 and FAAH mRNA is based on the presence of presynaptic, inhibitory, CB1 receptors on both GABAergic and glutamatergic neurons (Domenici et al., 2006; Katona et al., 2001, 2006; Marsicano and Lutz, 1999).”

“modifications of GABAergic, serotonergic, and monoaminergic neurotransmission by CBs, etc.) have also been demonstrated [ 26-28 ].”

“…and 2-arachidonoylglycerol (2-AG) are synthesized and released postsynaptically to act as retrograde messengers at presynaptic cannabinoid receptor 1 (CNR1, also known as CB1R or CB1A) located on both glutamatergic and gammaaminobutyric acid (GABA)-ergic axon terminals (Katona et al., 2001, 2006).”

“most likely on synaptic terminals (Katona et al., 2001).”

“Although there is little proof [76] as well as contradictory views [77,80,83] regarding the existence of CB1 receptors on glutamatergic cells, in situ hybridization investigations suggest that they exist, although in far lower amounts than GABAergic neurons [84].”

“dala), that are directly involved in mood regulation (31) and other regions in neural circuits known to be involved in the physiological regulation and dysregulation of mood and anxiety (32).”

“Limbic brain regions, such as the amygdala, hippocampus and cortex, contain high densities of these receptors (Katona et al. 2001; Hájos and Freund 2002; Tzavara et al. 2003; Pistis et al. 2004; Viveros et al. 2007) which regulate anxiety-related responses by modulating mainly GABAergic, serotoninergic and noradrenerg…”

“Several studies have shown that stress exposure reinstates drug-induced conditioned place preference (CPP) [5,6] through multiple mechanisms including an increased release of corticotrophin releasing factor (CRF) [7] that alters the GABAergic transmission [8,9], decreases oxytocin in lateral septum and amygdala [10,11…”

“…neurotransmission was shown in many regions of the central and peripheral nervous systems (Gifford and Ashby, 1996; Shen et al., 1996; Nakazi et al., 2000; Katona et al., 2001; Szabo et al., 2000, 2001; Hoffman et al., 2003; for reviews, see Schlicker and Kathmann, 2001; Freund et al., 2003).”

“Furthermore, CB1 receptor agonists reduced the GABA-A receptor-mediated evoked and spontaneous IPSPs in the region (Katona et al., 2001).”

“First, similarly to their distribution in vivo (Katona et al., 2001; Bodor et al., 2005; Thibault et al., 2013), CB1Rs display an axonally polarized distribution in cultured neurons (Coutts et al., 2001; Leterrier et al., 2006; McDonald et al., 2007; Simon et al., 2013).”

“CB1 receptors are highly expressed in the amygdala where they modulate synaptic transmission (Katona et al., 2001) and neuronal firing (Pistis et al.”

“The endocannabinoids [44] and their receptor CB1R [124] are implicated in synaptic plasticity in many areas of the brain [90,122] and are known to modulate behavioural memory [40,61,166], including spatial memory [194].”

“, 2003; Tasker and Herman, 2011), predominantly on GABAergic terminals within the BLA (Katona et al., 2001).”

“Although Katona et al. (2001) have observed no effect of cannabinoids on GABAergic transmission in this region, a recent study by Roberto et al. (2010) verified that CB1 receptor activation in the CeA decreased evoked GABAA receptor-mediated inhibitory postsynaptic potentials.”

“Conclusions: Our data indicate that chronic WIN55,212-2 administration results in sustained effects on locomotor activity, similar to those observed after acute administration, and modulates the dopaminergic and GABAergic systems in a region-, dose-, and neurotransmitter-selective manner Keywords:…”

“CB1R immunostaining was increased in the LA, BLA, BMA, and CeA (p 0.05), but not in the MeA, of non-recruited WARs, when compared to recruited.”

“homogenates, (3) labeled CB1 receptor-transfected but not control ATt20 cells (Ledent et al., 1999; Hajos et al., 2000; Katona et al., 2001).”

“Considering the direct connection between the PFC and the AMY and its role in controlling anxiety and fear responses, such data are suggesting a relevant role for CB1 actions in emotional processes [71].”

“This idea is further supported by the fact that the amygdala, known for its crucial role in associating emotionally charged stimuli (for a review Phelps & LeDoux, 2005), presents high CB1 receptors density (Katona et al., 2001; McDonald & Mascagni, 2001) and also exhibits increased levels of AEA and 2-AG after present…”

“1990), which are highly expressed in structures involved in the regulation of anxiety such as the amygdala, hippocampus, anterior cingulate and prefrontal cortex (Herkenham et al. 1991; Katona et al. 2001; Tzavara et al. 2003; Pistis et al. 2004).”

“In view of the fact that the activation of the amygdala CB1 receptors, which are highly expressed on the GABAergic neurons, has been suggested to reduce GABAergic synaptic transmission in this brain region [57-61], a possible explanation for the improving effect of ACPA on scopolamine-induced memory impairment may be…”

“17 Cortical GABAergic dysfunction after BFCN lesion Endocannabinoids act as retrograde synaptic messengers on presynaptic terminals and modulate the release of different neurotransmitters through the activation of CB1 receptors (Katona et al., 2001; Ohno-Shosaku et al., 2001).”

“With respect to the human amygdala, we observed a tendency of higher AEA amounts compared to the neocortex (Fig. 3). Since CB1 receptors are known to be expressed at high levels in certain amygdala nuclei ( Katona et al. 2001 ), one may assume an involvement of endocannabinoid signaling in, e.g., emotional behavior.”