Anxiolytic‐like effects of the selective metabotropic glutamate receptor 5 antagonist MPEP after its intra‐amygdaloid microinjection in three different non‐conditioned rat models of anxiety

Abstract

The intercalated islands, clusters of dopamine D1-rich GABAergic neurons, are interposed between the basolateral and central nuclei of the amygdala, and control the traffic of nerve impulses between these two structures. Metabotropic glutamate receptor 5- (mGluR5)-like immunoreactivity was studied by immunohistochemistry in this part of the amygdala and was found to be mainly restricted to the central and basolateral nuclei and to a lesser extent to the medial paracapsular intercalated islands. The role of the metabotropic glutamate receptor 5 in the modulation of anxiety has been studied in this region by microinjection of small volumes of the mGluR5 antagonist 2-methyl-6(phenylethenyl) pyridine (MPEP), with restricted diffusion from its injection site, into the rostral amygdala near the basolateral and central amygdaloid nuclei and the intercalated islands, and the behavior of the animals was evaluated using three non-conditioned models of anxiety. Anxiolytic-like effects were observed after MPEP administration in all tests used. In the White and Black Box test, MPEP (2 nmol per side) significantly increased the time spent in the white compartment of the box. In line with these results, MPEP (8 nmol per side) increased the exploration of the open arms of the Elevated Plus-Maze. Burying behavior latency was increased and burying behavior itself was decreased in the Shock-Probe Burying test. It is suggested that anxiolytic effects of MPEP may be mediated by blockade of mGluR5 in the basolateral and/or central amygdaloid nuclei, reducing glutamate transmission in the basolateral amygdaloid nuclei and glutamate output from the central amygdala.

Activation of Group II Metabotropic Glutamate Receptors Inhibits the Discriminative Stimulus Effects of Alcohol via Selective Activity Within the Amygdala

“…The coordinates for the nucleus accumbens and amygdala were AP + 1.7, ML + 1.5 mm, DV À5.5 mm, and AP À1.9, ML + 4.2, À6.5 DV (from skull), respectively (Paxinos and Waton, 1998). We made no attempt to functionally distinguish specific sub-nuclei of the accumbens (eg, core vs shell) or amygdala (eg, CeA, BLA, or LaDL) based on evidence that suggests that the distance of drug diffusion after microinjection could possibly be larger than the distance between each sub-nuclei (Perez de la Mora et al, 2006). Rats were allowed 1 week for recovery before resuming alcohol discrimination training.…”

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

“…However, given that under the microinfusion conditions used in this work, we have shown that [ 3 H]2-methyl-6 (phenylethynyl) pyridine, a compound with a similar molecular weight to TPMPA, diffused to an extent of 1 mm 3 (Pérez de la Mora et al 2006) in the amygdala, it is conceivable that TPMPA had acted on the rostral amygdala near its site of injection, namely the central nucleus, the basolateral complex, and the medial intercalated paracapsular islands (Esmaeili et al 2009;Rosas-Arellano and Miledi, personal communication).…”

“…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).…”

“…The rats were placed on the central square facing the open arms at the beginning of the test and were allowed to explore the maze for 5 min. The number of entries (as percentage of the total number of arm entries) into and the time (as percentage of the time spent in the open and closed arms) spent in the open arms of the maze were taken as measures of anxiety, and the total number of arm entries was taken as a measure of locomotion (Pellow et al 1985;Pérez de la Mora et al 2006. An entry was counted when the four paws of the rat were placed on the respective arm.…”

Essential Role for TRPC5 in Amygdala Function and Fear-Related Behavior

“…mGluRs and cholecystokinin 2 (CCK 2 ) receptors) in the amygdala may lead to the opening of heteromultimeric TRP channels containing the TRPC5 subunit (Faber et al, 2006;Meis et al, 2007). Moreover, pharmacological block of Group I mGluRs (mGluR1 and mGluR5 subtypes) in the amygdala diminished both innate (Perez de la Mora et al, 2006;Pietraszek et al, 2005) and learned fear responses (Rodrigues et al, 2002). Additionally, blockade of CCK 2 receptors, which are activated by endogenously released CCK in response to anxiety (innate fear) provoking stimuli, is associated with distinctive anxiolytic effects (Frankland et al, 1997;.…”