Role of the amygdaloid cholecystokinin (CCK)/gastrin‐2 receptors and terminal networks in the modulation of anxiety in the rat. Effects of CCK‐4 and CCK‐8S on anxiety‐like behaviour and [³H]GABA release

Abstract

The amygdala plays a key role in fear and anxiety. The intercalated islands are clusters of glutamate-responsive GABAergic neurons rich in cholecystokinin (CCK)-2 receptors which control the trafficking of nerve impulses from the cerebral cortex to the central nucleus of amygdala. In this study, the nature of the CCK-glutamate-GABA interactions within the rat rostral amygdala, and their relevance for anxiety, were studied. CCK/gastrin-like immunoreactive nerve terminals were found to be mainly restricted to the paracapsular intercalated islands and the rostrolateral part of the main intercalated island. Behaviourally, the bilateral microinjection of CCK-4 (0.043-4.3 pmol/side) or CCK-8S (4.3 pmol/side) into the rostrolateral amygdala reduced the open-arm exploration in the elevated plus-maze without affecting locomotion. In contrast, neither CCK-4 nor CCK-8S (0.043-4.3 pmol/side) had any effects in the shock-probe burying test as compared with their saline-treated controls. Biochemically, CCK-4 (0.3 and 1.5 microm), unlike CCK-8S, enhanced significantly the K(+)-stimulated release of [(3)H]GABA from amygdala slices. These effects were fully prevented by prior superfusion of the slices with either the selective CCK-2 receptor antagonist CR2945 (3 microm), or 6,7-dinitroquinoxaline-2,3(1H,4H)-dione (DNQX), 10 microm, a glutamatergic (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate receptor antagonist. It is suggested that CCK modulates glutamate-GABA mechanisms by acting on CCK-2 receptors via volume transmission occurring at the level of the basolateral amygdaloid nucleus and/or by synaptic or perisynaptic volume transmission in the region of the rostrolateral main and paracapsular intercalated islands, resulting in subsequent disinhibition of the central amygdaloid nucleus and anxiety or panic-like behaviour.

Wiring and Volume Transmission in Rat Amygdala. Implications for Fear and Anxiety

“…In line with the anxiogenic role of the amygdaloid CCK-2 receptors found in our work [90][91][92][93][94][95][96][97][98][99][100][101][102] and the pharmacological experiments carried out in other laboratories [97][98][99][100][101]103], rats selected for having low exploratory activity in the open arms of the Elevated PlusMaze have upregulated the CCK-2 receptor gene in the amygdala and the periaqueductal grey region as compared with rats having a high exploratory activity and with home cage controls [108]. These results suggest that their anxious phenotype is associated with a high CCKergic tone operating via CCK-2 receptors.…”

“…Interestingly neither CCK-4 nor CCK-8S were able to modify the behavior of rats in the Shock-Probe Burying test [90] underling the suggestion that anxiety models may reflect activity in distinct neuronal systems [95] or mimic different features of anxiety [96]. Since in our experiments the transmission mediated through mGluR5 and dopamine D1 receptors was blocked by MPEP and SCH23390 and an anxiolytic-like behavior was observed in all the anxiety models used it is conceivable that mGluR5 and D1 receptor activities are having a tonic anxiogenic effect in the amygdala.…”

“…The resulting behavior was evaluated in the Elevated Plus-Maze which exploits the natural aversion of rodents for the open spaces [89]. The number of entries into and the time that the animals remained in the open arms of the maze decreased in comparison to saline microinjected rats indicating that both CCK peptides were producing anxiogenic effects [90]. Such effects seem to be mediated by the activation of CCK-2 receptors since, as indicated above, CCK-4 has only affinity for the type 2 CCK receptor.…”

Cannabinoid CB1 and Cholecystokinin CCK2 Receptors Modulate, in an Opposing Way, Electrically Evoked [3H]GABA Efflux from Rat Cerebral Cortex Cell Cultures: Possible Relevance for Cortical GABA Transmission and Anxiety

“…That either CB 1 -or CCK receptorrelated drugs influenced the electrically evoked, but not spontaneous, [ 3 H]GABA efflux is not surprising, because this type of efflux is calcium-independent and tetrodotoxin-insensitive and may thus rather reflect a membrane transport process instead of a vesicular release (Tomasini and Antonelli, 1998). This is also in line with a study performed by using a different in vitro preparation (Pérez de la Mora et al, 2007).…”

GABAA ρ receptor mechanisms in the rat amygdala and its role in the modulation of fear and anxiety

“…The elevated plus-maze used in this work was based essentially on the design of Pellow et al (1985) and was constructed as previously described (Pérez de la Mora et al 2006Mora et al , 2007, namely, the maze was made of wood and consisted of two open arms (50×10 cm) and two enclosed arms (50×10×40 cm) having an open roof. The arms were intersected at the central square (10×10 cm).…”