Profound hypothermia in golden hamsters (Mesocricetus auratus) induced by serotonergic potentiating and noradrenergic inhibiting drugs

Profound hypothermia (6 degrees C) was induced in cold exposed golden hamsters (Mesocricetus auratus) by a combination of drugs that potentiate brain serotonergic activity (fluoxetine and pargyline) and inhibit noradrenergic activity (alpha-methyl-p-tyrosine). Individual drugs and combinations of 2 were ineffective.     

Profound hypothermia in golden hamsters (Mesocricetus auratus) induced by serotonergic potentiating and noradrenergic inhibiting drugs

Summary Profound hypothermia (6°C) was induced in cold exposed golden hamsters (Mesocricetus auratus) by a combination of drugs that potentiate brain serotonergic activity (fluoxetine and pargyline) and inhibit noradrenergic activity (alpha-methyl-p-tyrosine). Individual drugs and combinations of 2 were ineffective.Acknowledgements. We acknowledge the support of a research grant PCM74-05158 A01 to A.H.M. from the National Science Foundation (USA) and thank Lilly Research Laboratories, Indianapolis, Indiana, for the gift of fluoxetine (Lilly 110140).     

Effects of 6-hydroxydopamine on rat carotid body chief cells

Summary Administration of 6-hydroxydopamine (6-OHDA) in concentrations high enough to cause degeneration of perivascular adrenergic nerve terminals has no morphological effect on the catecholamine-storing cells of the rat carotid body. Uptake of 6-OHDA by carotid body chief cells may be more selective than that exhibited by small-intenselyfluorescent cells and other catecholamine-storing cells which are affected by 6-OHDA. Alternatively, the sustentacular cells which envelope the chief cells may provide an effective barrier against the uptake of 6-OHDA.Supported by a Grant-in-Aid from the American Heart Association (77 630) and with funds contributed in part by the Texas Affiliate.     

Extraneuronal serotonin accumulation in peripheral arteries of the rat

Accumulations of serotonin (5-HT) and norepinephrine (NE) were compared in control and 6-hydroxydopamine (6-OHDA) pretreated rat aorta, mesenteric and tail arteries. The distribution of these amines was corrected by subtracting tissue uptake of tritiated sorbitol in the extracellular space. 5-HT greatly accumulated both in control and 6-OHDA pretreated arteries. In contrast, NE accumulation in mesenteric and tail arteries was substantially decreased after 6-OHDA treatment. In the aorta 6-OHDA pretreatment did not affect the accumulation of both amines. These findings suggest that 5-HT accumulation in these arteries is mainly extraneuronal, and NE mainly neuronal. Since the accumulation of 5-HT in the aorta was not influenced by pretreatment with 10 microM NE, the extraneuronal uptake mechanisms for 5-HT and NE appear to be different.     

Catecholamine metabolism in the vas deferens and the adrenal gland with special reference to the central catecholamine-depleted state.

Experiments were carried out to elucidate the role of central catecholamines in regulating catecholamine metabolism in the vas deferens and adrenal gland of the rat. Rats were injected intracerebroventricularly (i.c.v.) with either vehicle or 6-hydroxydopamine (6-OHDA). Groups of animals pretreated with vehicle or 6-OHDA (i.c.v.) were injected intraperitoneally (i.p.) with alpha-methyl-para-tyrosine (AMT), a tyrosine hydroxylase inhibitor. Catecholamine turnover rates were estimated by determining norepinephrine or epinephrine content after administering AMT. Central norepinephrine and dopamine contents decreased significantly (p less than 0.05) after treatment with 6-OHDA and AMT. The norepinephrine content of the vas deferens of rats pretreated with 6-OHDA was markedly reduced (p less than 0.001) after administration of AMT, whereas that of the vehicle-treated rats remained unchanged. Administration of 6-OHDA had no effect on the norepinephrine or epinephrine content of the adrenal gland. The present results indicate that central monoaminergic neurons have an inhibitory effect on the adrenergic neurons of the vas deferens. In contrast, this inhibitory regulation does not appear to be exerted on the adrenal glands.     

Catecholamine metabolism in the vas deferens and the adrenal gland with special reference to the central catecholamine-depleted state

Experiments were carried out to elucidate the role of central catecholamines in regulating catecholamine metabolism in the vas deferens and adrenal gland of the rat. Rats were injected intracerebroventricularly (i.c.v.) with either vehicle or 6-hydroxydopamine (6-OHDA). Groups of animals pretreated with vehicle or 6-OHDA (i.c.v.) were injected intraperitoneally (i.p.) with alpha-methyl-para-tyrosine (AMT), a tyrosine hydroxylase inhibitor. Catecholamine turnover rates were estimated by determining norepinephrine or epinephrine content after administrating AMT.Central norepinephrine and dopamine contents decreased significantly (p<0.05) after treatment with 6-OHDA and AMT. The norepinephrine content of the vas deferens of rats pretreated with 6-OHDA was markedly reduced (p<0.001) after administration of AMT, whereas that of the vehicle-treated rats remained unchanged. Administration of 6-OHDA had no effect on the norepinephrine or epinephrine content of the adrenal gland.The present results indicate that central monoaminergic neurons have an inhibitory effect on the adrenergic neurons of the vas deferens. In contrast, this inhibitory regulation does not appear to be exerted on the adrenal glands.     

Differential sensitivity of pinna reflex and esophageal temperature to clonidine in mice depleted of central noradrenaline by DSP-4

Mice injected with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a selective noradrenergic neurotoxin, had marked depletions of central noradrenaline and an attenuated post-decapitation reflex. DSP-4-treated mice exhibited an increased sensitivity to the alpha 2-adrenoceptor agonist clonidine as measured by inhibition of the pinna reflex, but normal sensitivity as measured by hypothermia. This differential sensitivity may reflect the presence of supersensitive postsynaptic alpha 2-adrenoceptors in some, but not all, CNS regions after DSP-4 treatment.     

Chemical sympathectomy reveals pre-and postsynaptic effects of neuropeptide Y (NPY) in the cardiovascular system

Summary Intravenous injection of neuropeptide Y (NPY) caused short-lasting dose-dependent pressor responses in anesthetized rats. NPY was equipotent with noradrenaline in producing proportional pressor effects. Chemical sympathectomy, following the administration of 100 mg/kg 6-hydroxydopamine (6-OHDA), significantly potentiated the systemic pressor effects elicited by NPY or noradrenaline. Pretreatment with 2 nmol NPY enhanced the noradrenaline-induced pressor response in control rats. NPY did not change the basal tension of isolated rat aortic strips but significantly potentiated the contractile activity induced by 16 nM noradrenaline. This effect of NPY was not observed in aortic strips from rats pretreated with 6-OHDA. The presence of pre-and postsynaptic sites of action for NPY in the cardiovascular system of the rat is discussed.     

Chemical sympathectomy reveals pre- and postsynaptic effects of neuropeptide Y (NPY) in the cardiovascular system

Intravenous injection of neuropeptide Y (NPY) caused short-lasting dose-dependent pressor responses in anesthetized rats. NPY was equipotent with noradrenaline in producing proportional pressor effects. Chemical sympathectomy, following the administration of 100 mg/kg 6-hydroxydopamine (6-OHDA), significantly potentiated the systemic pressor effects elicited by NPY or noradrenaline. Pretreatment with 2 nmol NPY enhanced the noradrenaline-induced pressor response in control rats. NPY did not change the basal tension of isolated rat aortic strips but significantly potentiated the contractile activity induced by 16 nM noradrenaline. This effect of NPY was not observed in aortic strips from rats pretreated with 6-OHDA. The presence of pre- and postsynaptic sites of action for NPY in the cardiovascular system of the rat is discussed.     

The bisphosphonates HEBP and AHPrBP but not AHBP inhibit mineral mobilization and lysosomal enzyme release from mouse calvarial bones in tissue culture

Summary Mice injected with DSP-4 [N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine], a selective noradrenergic neurotoxin, had marked depletions of central noradrenaline and an attenuated post-decapitation reflex. DSP-4-treated mice exhibited an increased sensitivity to the ₂-adrenoceptor agonist clonidine as measured by inhibition of the pinna reflex, but normal sensitivity as measured by hypothermia. This differential sensitivity may reflect the presence of supersensitive postsynaptic ₂-adrenoceptors in some, but not all, CNS regions after DSP-4 treatment.Acknowledgments. The authors gratefully acknowledge the excellent technical assistance of Mr P. E. Richards. DSP-4 hydrochloride and clonidine hydrochloride were synthesized by Beecham Pharmaceuticals Research Division.     

Effects of brain monoamine depletion on thermoregulation,active avoidance,and food and water intake in rats

Summary Intraventricular administration of 6-OHDA or 5,6-DHT suppressed food intake, whereas their effect on active avoidance produced a suppression with the former and an enhancement with the latter. The increased water intake was specifically associated with 5,6-DHT treatment in rats.This work supported by grants from the National Science Council (Republic of China), J. Aron Charitable Foundation (USA) and John B. Pierce Foundation (USA). The authors are grateful to Drs C.Y. Chai and H. H. Lu for their support and advice.     

Degeneration of adrenergic axons in the longitudinal muscle coat of the rat duodenum following treatment with 6-hydroxydopamine.

Following systemic treatment with 6-OHDA, electron microscopy of adult rat duodenum showed degenerating adrenergic axons in the longitudinal muscle coat making neuromuscular relationships with gaps of varied widths.     

Effects of brain monoamine depletion on thermoregulation, active avoidance, and food and water intake in rats

Intraventricular administration of 6-OHDA or 5,6-DHT suppressed food intake, whereas their effect on active avoidance produced a suppression with the former and an enhancement with the latter. The increased water intake was specifically associated with 5,6-DHT treatment in rats.     

In vivo continuous electrochemical determination of dopamine release in rat neostriatum]

Polarographic micro-electrodes (carbon fiber, o. d. 8 micron) implanted in the Rat caudate nucleus, allowed a practically continuous in vivo monitoring (one measurement every 5 sec.) of the extra-cellular concentration of dopamine released by striatal dopaminergic terminals. Administration of amphetamine produced a reproducible increase of the oxidation current. This effect was suppressed after the selective degeneration of the striatal dopaminergic terminals following the injection of 6-OHDA into the substantia nigra or after inhibition of the synthesis of the amine by alpha methyl-p-tyrosin. After 5 hrs. this drug produced a 70% decrease of the oxidation current.     

Extravesicular noradrenaline in developing peripheral adrenergic nerves

Summary Using a fluorescence technique numerous developing noradrenergic nerve terminals were observed in the muscle coat of the rat ductus deferens, between 2 and 6 days postpartum. In the electron microscope similar developing nerve terminals possessed an extensive system of tubular endoplasmic reticulum but did not contain the small dense cored vesicles characteristic of mature noradrenergic nerve terminals. Thus the tubular reticulum is proposed as an alternative storage site for noradrenaline in developing adrenergic nerves.     

Haloperidol produces hypothermic effects in rats

Intraperitoneal administration of either haloperidol or chlorpromazine produced hypothermia both in the cold (8 degrees C) and at room temperature (22 degrees C). The hypothermia was brought about both by a decrease in metabolic heat production and an increase in the cutaneous temperature of tail and foot skin. However, at a higher temperature (29 degrees C), there were no changes in rectal temperature and other thermoregulatory responses.     

Lesions in the substantia nigra of rats induce thermoregulatory deficit in the cold

Summary Rats with either electrolytic or chemical (6-hydroxydopamine) lesions in the substantia nigra displayed decreased metabolism and hypothermia when they were exposed to cold (8 °C T_a), although they showed no deficiency in thermoregulation at both moderate (22 °C) and hot (30 °C) environmental temperatures.This work was supported by grants from the Pjing-Ling Neurological Foundation (Veterans General Hospital, Taipei, Taiwan, China) and the National Science Council (Republic of China). The authors are grateful to Mr C.C. Wei for his generous support.     

The effects of brain monoamine depletion on p-chlorophenyl-alanine-induced hypothermia

Summary I.p. administration of p-chlorophenylalanine produced a fall in rectal temperature in rats. The hypothermia was attenuated after pretreatment of the animals with 5,6-dihydroxytryptamine, but was unaffected after pretreatment of the animals with 6-hydroxydopamine.This work was supported by grants from the National Science Council (Republic of China) and J. Aron Charitable Foundation (USA). The authors are grateful to Dr C.Y. Chai, Dr T.H. Yin, Dr H.H. Lu and Mr C.C. Wei for their advice and support.     

Effects of thyrotrophic-releasing hormone (TRH) on thermoregulation in the rat

At ambient temperatures (Ta) of both 8 and 22 degrees C, intraventricular administration of TRH (10-80 microgram) produced a dose-dependent hypothermia in rats. The hypothermia was due to both decreased metabolic heat production and cutaneous vasodilatation. In contrast, at 30 degrees C Ta, TRH increased metabolic heat production (due to behavioral excitation) and led to hyperthermia.     

Effects of DL-propranolol on the thermoregulatory responses of rats at different ambient temperatures

Summary Direct administration of propranolol (100–400 g) into the lateral cerebral ventricle of rats produced a dose-dependent hypothermia at ambient temperatures (T_a) of 8 and 22°C. The hypothermia was due to decreased metabolism and cutaneous vasodilation. The hypothermia induced by propranolol was antagonized by pretreatment with isoproterenol (50 g).This work was supported by the grants from the National Science Council (Republic of China) and the Pjing-Ling Neurological Foundation (Veterans General Hospital). The authors are grateful to Mr C.C. Wei for generous support.