Jerry M. Cott

Thyrotropin releasing hormone: Antagonism of pentobarbital in rodents

Abstract Thyrotropin releasing hormone (TRH) antagonizes the behavioral and temperature reducing effects of pentobarbital in rodents. The hormone is effective whether given before or after the barbiturate. This antagonism by TRH of the effects of pentobarbital probably does not depend upon thyroid hormone release as L-triiodothyronine administration is ineffective.

Antagonism of ethanol narcosis by thyrotropin releasing hormone

Abstract Thyrotropin releasing hormone (TRH) reduced the narcosis and hypothermia produced by ethanol in mice. This action of TRH does not appear related to release of thyroid hormone or to the effects of a metabolite of TRH. The ability of TRH to reduce the actions of ethanol after intracisternal injection suggests that the mechanism of the ethanol antagonism is central in origin. The antagonism of ethanol by TRH does not appear to be related to an amphetamine-like stimulant action.

Effects of catecholamine-depleting drugs and amphetamine on self-stimulation of brain following various 6-hydroxydopamine treatments.

Changes in electrical self-stimulation responding were examined in rats with electrodes implanted in the lateral hypothalamus following 6-hydroxydopamine treatments which depleted brain dopamine, norepinephrine or both of these catecholamines. Acute depression of self-stimulation occurred after treatments which reduced brain dopamine, but did not occur in rats treated to deplete just brain norepinephrine. A chronic deficit in self-stimulation responding occurred in rats treated with 6-hydroxydopamine in combination with pargyline to reduce both brain amines, while responding of animals in which brain dopamine was reduced returned to levels observed prior to 6-hydroxydopamine treatment. A dose of α-methyl-tyrosine (25 mg/kg), which did not affect responding of control rats, caused a significant reduction in responding of rats depleted of brain dopamine. This treatment did not affect responding of rats depleted of brain norepinephrine. Administration of the dopamine-Β-hydroxylase inhibitor, U-14624, failed to affect self-stimulation in spite of an additional 70% reduction of brain norepinephrine content. The response to a dose of d-amphetamine (0.25 mg/kg), that increased self-stimulation of control rats, was significantly reduced in rats with brain dopamine selectively depleted. Rats in which norepinephrine was depleted responded to d-amphetamine like the control group. α-Methyltyrosine antagonized the increased self-stimulation responding following administration of d-amphetamine (1 mg/kg) to reserpinized rats, while U-14624 did not. Results support the hypothesis that central dopaminergic fibers have an important involvement in the maintenance of self-stimulation of brain.

Antagonism of the analeptic activity of thyrotropin-releasing hormone (TRH) by agents which enhance GABA transmission.

Administration of 10 mg/kg TRH to mice was found to reduce the sleep and hypothermia induced by 4.7 g/kg ethanol. However, TRH did not reduce the sleep of mice that were given γ-hydroxybutyric acid (GHBA), baclophen, or aminooxyacetic acid (AOAA) in combination with 3 g/kg ethanol. TRH also failed to reverse the hypothermia induced by the combination of ethanol and baclophen or GHBA, and the characteristic neurological effects of TRH e.g. tremor, increased muscle tone, and increased respiratory rate were reduced. In addition, TRH-induced locomotor stimulation was prevented by pretreatment with small doses of the GABA-ergic agents, and while 30 mg/kg TRH reduced the hypothermia produced by large doses of the GABA-ergic drugs, it did not antagonize the locomotor retardation produced by baclophen or GHBA. A hypothesis that the analeptic effects of TRH may be mediated via an inhibition of GABA systems is discussed.

Parameters of alteration of pentobarbital response by hypothalamic polypeptides.

Both thyrotropin-releasing hormone (TRH) and amphetamine antagonize pentobarbital. They are more effective in the day than at night. This is true for TRH even when the dose of pentobarbital is increased at night to prolong sedation. Under this condition the day-night difference is lost for amphetamine. Both substances are more effective in cold ambient temperatures (18 degrees C) and less effective in warm temperatures, but their activity at warmer temperatures (37 degrees C) is still substantial. In contrast, somatotropin release-inhibiting factor (SRIF) augments the effects of pentobarbital at room temperature. This action is unaffected by time of day. However, the increase in sleeping time is lost in both a warm environment and in a cold environment.