Excitatory Amino Acid Receptor Antagonists Block the Cardiovascular and Anxiety Responses Elicited by g-Aminobutyric AcidA Receptor Blockade in the Basolateral Amygdala of Rats

Blockade of g-aminobutyric acid (GABAA) receptors in the anterior basolateral amygdala (BLA) with bicuculline methiodide results in an increase in heart rate, blood pressure and “anxiety” in rats. Glutamate receptors in the BLA are also reported to be involved in eliciting anxiety responses. The purpose of this study was to investigate the interaction between GABAergic inhibition and glutamatergic excitation in the BLA. Male Wistar rats were implanted with femoral arterial catheters and bilateral chronic microinjection cannulae into the BLA. Each animal was injected with either artificial cerebrospinal fluid (100 nl), bicuculline methiodide (20 pmol/100 nl) or bicuculline methiodide 1 one dose of an antagonist of either the N-methyl-D-aspartate receptor [AP5 (20 and 100 pmol) and dizocilpine (25 and 125 pmol)] or the non-N-methyl-D-aspartate ionotropic receptor [CNQX (10 and 50 pmol) and GYKI 52466 (50 and 250 pmol)]. Increases in heart rate, blood pressure and “anxiety” (as measured in the social interaction test) observed in rats after bicuculline methiodide injections into the BLA were blocked in a dose dependent manner with the concurrent injections of either N-methyl-D-aspartate or non-N-methyl-D-aspartate antagonists, suggesting that activation of both subtypes of glutamate ionotropic receptors may be necessary for the responses elicited by GABAA receptor blockade in the anterior basolateral amygdala. Anxiety and stress are mental states that are characterized by emotional responses of fear and apprehension, along with physiological responses such as increases inHR, BP, respiration and gastrointestinal motility. Both animal studies (Hilton and Zbrozyna, 1963; Kapp et al., 1982) and human studies (Feindel and Penfield, 1954) have shown that stimulation of the amygdala results in behavioral and physiological responses associated with anxiety. In contrast, lesions of this area are associated with a decrease in fear and anxiety (Weiskrantz, 1956; Narabayashi et al., 1963). The basolateral nucleus in particular has been implicated in regulating “anxiety” in rats. Inhibiting the activity of the BLA with glutamate antagonists or lesions will block both the acquisition and expression of conditioned fear in rats (Miserendino et al., 1990; Kim and McGaugh, 1992; Campeau and Davis, 1995). Thus, it has been suggested that the BLA acts as an integration center for sensory and memory information in the anxiety response and that glutamate neurotransmission is critical in regulating these responses (LeDoux et al., 1990; Campeau and Davis, 1995). Blockade of GABAA receptors in the anterior portion of the BLA leads to increases HR, BP as well as experimental “anxiety” as assessed in the SI and conflict tests (Sanders and Shekhar 1991; 1995a, b). In addition, this area of the amygdala contains the highest concentration of benzodiazepine receptors (Niehoff and Kuhar, 1983). The anxiolytic effects produced by systemic benzodiazepines can be reversed by direct injections of the benzodiazepine receptor antagonist flumazenil into the BLA (Sanders and Shekhar, 1995a). It appears that the GABA-benzodiazepine receptor complex in the BLA also plays a critical role in regulating anxiety re-