Lateral hypothalamic area neurotransmission and neuromodulation of the specific cardiac effects of insular cortex stimulation

Microstimulation of the rat posterior insular cortex in phase with the ECG R wave elicits pure cardiac effects unaccompanied by changes in blood pressure or respiration. This technique has successfully demonstrated cardiac chronotropic organisation and arrhythmogenesis within the insula. Pathways exist linking the insular cortex with the lateral hypothalamic area (LHA). Similarly, the LHA has previously been shown to mediate the sympathetic and blood pressure effects of insular cortex stimulation. Therefore it was anticipated that the tachycardia elicited by insular phasic microstimulation would be responsive to LHA manipulations. Insular tachycardia sites in 28 chloralose-anesthetised male Wistar rats were phasically stimulated once with each cardiac cycle using 500 microA for 1 min before and after microinfusions (390 nl) into the LHA. The insular tachycardia response was abolished by LHA microinfusions of the synaptic blocker cobaltous chloride (4 mM). LHA microinjection of kynurenic acid (250 mM) attenuated insular tachycardia by 95%. Microinjection of naloxone (30 mM) similarly attenuated the tachycardia by 95%. Met-enkephalin (3.5 mM) was without effect on this response whereas Leu-enkephalin (3.5 mM) and neuropeptide Y (0.01 mM) (NPY) doubled the magnitude of the tachycardia. Dynorphin (0.12 mM), a specific kappa opioid receptor agonist, augmented the response to stimulation of insular tachycardia sites 8-fold. Consequently, it is suggested that the LHA contains an obligatory synapse mediating insular tachycardia and that glutamate is the likely neurotransmitter at this site. Neuromodulation of insular tachycardia may be effected by opiate kappa and NPY receptors, a finding of considerable clinical relevance.