Alterations in noradrenergic physiological characteristics with DOCA-hypertension: interaction between norepinephrine and GABA in rat lateral hypothalamus

Abstract

The lateral hypothalamus (LH) is involved in the central integration of fluid and electrolyte balance. Several studies have suggested a role for norepinephrine (NE) in these functions. In previous studies we presented evidence in support of a modulatory role for NE within the LH circuitry. Specifically, NE facilitated responses of LH cells to synaptic inputs and putative transmitters. In the present studies, we examined the influence of NE on the response of LH neurons to the inhibitory amino acid transmitter GABA. Neuronal responses were studied in normal, DOCA hypertensive, and 1% NaCl diet (HSD)-treated rats. Male rats were uninephrectomized and received a DOCA implant (200 mg/kg). They were given 1% NaCl and 0.1% KCl in their drinking water (4–6 weeks). HSD rats received the same treatment, except that no DOCA was given. Extracellularly recorded responses from single LH neurons to iontophoretic pulses (5–50 nA; 10 s duration) of GABA were examined before, during and after NE microiontophoresis (5–50 nA) in anesthetized rats. The results indicated a shift of NE modulatory action from potentiating to antagonizing GABA-induced inhibition. In control rats, NE routinely potentiated GABA depressant responses (19 of 26, 73%), whereas in HSD rats the ability of NE to enhance GABA responses was reduced to 33% of the cases tested (10 of 30). Likewise, NE did not augment, but rather antagonized GABA inhibition in the majority of cells recorded (21 of 35, 60%) from DOCA hypertensive rats. The β agonist isoproterenol was still capable of potentiating GABA inhibition of LH cells in HSD and DOCA treated animals, suggesting that the change in the capacity of NE to enhance GABA action is not a result of alterations in β receptor function, but could arise from a modification of the ratio between α- and β-adrenoceptors. NE modulating capability was also altered-in LH neurons responsive to experimentally induced changes in blood pressure. In summary, these findings suggest that chronic HSD and DOCA treatments can alter the modulatory capacities of NE within the LH. These alterations in noradrenergic action within hypothalamic cardiovascular centers might affect the way neurons respond to afferent barroceptor information, as well as the way they control sympathetic and parasympathetic effector mechanisms. A decrease in the inhibitory capacities of GABA transmission in these areas, due to alterations of NE, may play a role in the genesis of hypertension.