Gamma-Aminobutyric Acid and Dysregulation of TSH Secretion in Uremic Male Rats

Abstract

The role of gamma-aminobutyric acid (GABA) in the abnormal secretion of thyrotropic hormone (TSH) in uremia was studied in male Sprague-Dawley rats rendered renally insufficient by subtotal nephrectomy. Baseline TSH concentrations in normal control animals and in the uremic animals were similar. The peak TSH response to thyrotropin-releasing hormone (TRH; 5 μg i.v.) was significantly blunted in the uremic animals compared to the controls. Pretreatment of the uremic animals with the specific GABA antagonist, bicuculline (1.5 μmol i.v.) resulted in normalization of the peak TSH response to TRH. Bicuculline pretreatment, however, did not alter the basal secretion of TSH in either the normal or the uremic animals, and it also did not augment the TRH-stimulated TSH response in the normal animals. Sham-operated animals demonstrated basal and TRH-stimulated TSH responses comparable to the control group. In order to assess whether the weight loss associated with uremia could have accounted for the blunted TRH-stimulated TSH secretion in the uremic animals, a group of rats were starved so that their weights were comparable to those of the uremic animals. Basal and TRH-stimulated TSH responses in this group were not significantly different from the controls. Bicuculline pretreatment of the starved animals also failed to alter the basal and TRH-stimulated TSH responses. These data indicate that an increase in central gabaergic tone may be partly responsible for the blunted TSH response to TRH seen in uremia, but that GABA is not an important modulator of TSH secretion in the normal rat.

Dopamine and TSH Secretion in Uremic Male Rats

“…The data presented here, as well as our previous data based on GABA receptor blockade [9], indicate that increased activity of central dopaminergic as well as gabaergic neurons may be involved in the dysregulation ofTSH secretion in uremia. Earlier ex periments using intracerebroventricular in jection of GABA have shown that the de crease in basal TSH secretion following GABA administration can be reversed by pretreatment of the animals with pimozide [8], These findings suggested that the sup pressive effect of GABA, at least on basal TSH secretion, was mediated via dopamine.…”

“…We have previously described our findings on the effects of GABA receptor blockade with bicuculline on the basal and TRH-stimulated TSH release in normal and uremic rats [9], Our previous data suggested a possible role for elevated GABA levels as a cause of blunted TSH secretion in uremia.…”

“…In addition to abnormalities in peripheral thyroid hormone dynamics, patients with ESRD also exhibit central dysregulation of thyroid hormone secretion such as a blunted TSH response to TRH [4,5], The mecha nism for the abnormal TRH-stimulated TSH response in patients with ESRD is unknown but could, theoretically, be related to a down-regulation of TRH receptors on the pituitary thyrotroph or to an increase in the secretion or activity of neurotransmitters known to inhibit TSH secretion. The neuro transmitters, dopamine (DA) and gammaaminobutyric acid (GABA) have been shown to inhibit TSH secretion [6,7], In some experiments, the inhibitory effects of GABA have been demonstrated to be mediated through dopamine [8], We have previously reported our findings on the effects of the GABA antagonist, bicuculline, in uremic male rats [9], The present study is an attempt to explore the role of dopamine in the regu lation of TSH secretion in uremia.…”

Endogenous Opioids and TSH Secretion in Azotemic Male Rats

“…A decrease in TSH secretion can occur as a consequence of elevation of central inhibitory neurotransmitters such as dopamine or GABA [20,24] and/or an increase in the secre tion of hypothalamic inhibitory peptides such as somato statin [11,26]. We have previously described our findings on the effects of GABA receptor blockade with bicuculline on the basal and TRH-stimulated TSH release in normal and uremic rats [8], Our previous data suggested a possible role for elevated GABA levels as a cause of blunted TSH secretion in uremia. The present study investigated the role of endogenous opioids in the dysregulation of TSH secre tion in uremic rats.…”

“…In certain instances opioi dergic suppression of TSH secretion may be dopamine mediated, since dopamine blockade eliminates the inhib itory effect of morphine on cold-induced TSH secretion [22], In some experiments, the inhibitory effects of GABA have been demonstrated to be mediated through dopamine [25]. We have previously reported our findings on the ef fects of the GABA antagonist bicuculline in uremic male rats [8], Opioid agonists have been reported to decrease the stress-induced fall in TSH in experimental animals [10], an event that can be blocked by administration of the narcotic antagonist naloxone. The present study is an attempt to ex plore the role of endogenous opioids in the regulation of TSH secretion in uremia.…”