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Effects of thyrotropin-releasing hormone, oxytocin and prolactin on thiopenthal-induced narcosis in rats
Brain ResearchBulletin,Vol. 28, pp. 78l-783, 1992 Copyright
Printed in the USA. All rights reserved.
0361-9230/92$5.00 + .OO Pergamon Press Ltd.
0 1992
Effects of Thyrotropin-Releasing Hormone, Oxytocin, and Prolactin on Thiopenthal-Induced Narcosis in Rats F. DRAGO,*’
F. MAUCERI,*
M. FIDILIO,t
S. CAVALIERE,*
L. PULVIRENTI*
AND
F. FOTIt
*Institute of Pharmacology and flnstitute of Anesthesiology, University of Catania Medical School, Catania, Italy Received
16 September
1986
DRAGO, F., F. MAUCERI, M. FIDILIO, S. CAVALIERE, L. PULVIRENTI AND F. FOTI. E&fs ofthyrotropin-releasing hormone, oxytocin, andprolactin on thiopenthal-induced narcosis in rats. BRAIN RES BULL 28(5) 78 l-783, 1992.-Neuropeptides that may induce behavioral activation-thyrotropin-releasing hormone (TRH), oxytocin (OXY), and prolactin (PRL)-were tested on thiopenthal-induced narcosis after IV administration in male rats. TRH caused a significant shortening of sleeping time at the doses of 3 and 5 mg/kg, but did not change this parameter at lower doses. Oxytocin was effective at all doses tested (200, 300, and 400 fig/kg). Prolactin also shortened sleeping time at the doses of 0.2 and 1 mg/kg administered IV, slightly increasing it at the dose of 5 mg/kg. These results indicate that various neuropeptides are capable of reducing the duration of thiopenthalinduced sleep in rats.
Thyrotropin-releasing hormone
Oxytocin
Thiopenthal
Prolactin
Narcosis
of 20°C with water and food available ad lib and a 12 L: 12 D cycle (lights on between 8:00 a.m. and 8:00 p.m.). All experiments were performed in the morning. Animals were used only once in the experimental procedure. Sodium thiopenthal (Farmitalia, Italy) was administered IP at the dose of 35 mg/kg. TRH, OXY, and PRL (ovine), purchased from Sigma (USA), were dissolved in physiologic saline with a drop per tube of HCl 0.1 N. Neuropeptides were administered IV 10 min after thiopenthal at the following doses: 1, 3, and 5 mg/kg for TRH; 200, 300, and 400 &kg for OXY; 0.2, 1, and 5 mg/kg for PRL. These doses were selected on the basis of their efficacy in inducing behavioral changes as described elsewhere (2,7,9). After thiopenthal administration, sleeping time was measured as time elapsing from the loss of the righting reflex to the retrieval of it until a maximum of 120 min. Data were expressed in median and analyzed using the twoway analysis of variance (ANOVA) with replication and the posthoc Mann-Whitney U-test for non-parametric data. A p value of 0.05 or less was considered indicative of a significant difference.
THYROTROPIN-releasing hormone (TRH) is a neuropeptide with peculiar effects on the CNS. Among other effects, TRH induces a state of behavioral “arousal” that has been compared to that of amphetamine ( 18). It has heen shown in various animal species that TRH antagonizes sedation, sleep, and hypothermia induced by various barbiturates (2,20). Similar interaction is known to be present with ethanol and other CNS depressants (2,3). This effect seems unrelated to classical endocrine actions of TRH since it is present in hypophysectomized and thyroidectomized animals and with TRH analogs devoid of any endocrine action (20). Interestingly, with labeled pentobarbital it has been shown that TRH does not alter barbiturate metabolism (3). TRH is active in antagonizing barbiturate-induced narcosis after both peripheral and central administration. Reduction of sleeping is also observed after injection in various brain areas. The maximum efficacy has been shown after administration of the peptide in the septal area, thus suggesting an involvement of the septohippocampal system in TRH antagonism of barbiturate-induced sleep (14). Oxytocin (OXY) and prolactin (PRL) are hormones that also exert behavioral effects, some of which are consistent with the induction of a state of “arousal” similar to that induced by TRH (4,5,8,9,11,12,17). These findings prompted us to perform a series of experiments to examine the possible influence of OXY and PRL on barbiturate-induced sleep compared to that of TRH.
RESULTS
The results concerning the effect of TRH (1, 3, and 5 mg/ kg) on thiopenthal-induced sleep are shown in Fig. 1. A marked reduction of the sleeping time was found in rats treated with 3 and 5 mg/kg of the peptide, while the lower dose was ineffective in this respect. A shortening of the duration of thiopenthal-induced narcosis was also observed with OXY at all three doses
METHOD
Male, albino Wistar rats weighing 120- 150 g (Charles River, Italy) were housed five to a cage at a constant room temperature
’ Requests for reprints should be addressed to Filippo Drago, M.D., Ph.D., Institute of Pharmacology, Viale A. Doria, 6, 95 125 Catania, Italy. 781
782
DRAG0
ET AL.
MIN
MIN
100. 100
n,-n-
80-
80 60.
40-
9 CONTROLS
*
*
11
6
7
1
3
5
TRH
l
20.
o-
16 CONTROLS
used (Fig. 2). Administration of PRL at doses of 0.2 and 1 mg/ kg also reduced the duration of thiopenthal-induced sleep (Fig. 3). However, the greater dose of the peptide (5 mg/kg) enhanced it but not to a statistically significant extent. DISCUSSION
Evidence has been presented that TRH reduces sleep induced by ethanol and barbiturates with a mechanism unrelated to the release of thyroid hormones. Analeptic properties are suggested by a series of central effects of the hormone. It enhances DOPAinduced stimulation ( 19), antagonizes sedation and hypothermia induced by reserpine, chlorpromazine, and diazepam (3) and possesses antidepressant properties in animals (10) and humans (20). Moreover, IV injection of TRH in cats produces electroencephalographic (EEG) activation, restlessness, increased respiration, and other behavioral changes (6). Possible neuroanatomical substrates mediating some effects of TRH in pentobarbital-treated rats have been recently examined. The septohippocampal system seems to be the most important area that mediates TRH-induced reduction in pentobarbital-induced sleep. Furthermore, effects on temperature were evoked by TRH microinjections in a series of sites such as the anterior preoptic hypothalamic area, the medial thalamus, the periventticular gray, the interpeduncular nucleus, and the locus coeruleus (13). A number of studies have demonstrated that also OXY exerts various effects on animal behavior, some of which are consistent with a state of arousal. After intracerebroventricular injection of this peptide, pronounced hyperactivity, extensive foraging, squeaking and occasional barrel-rolling have been demonstrated in rodents (5), while other authors have shown excessive grooming, increased locomotor activity, and rearing (4,9,17). Moreover, electrophysiological studies revealed that after peripheral administration of the peptide a desynchronization of EEG is evident (12). Prolactin induces behavioral changes similar to those of OXY and TRH in terms of arousal. Both endogenous hyperprolactinaemia, induced by pituitary homografts under the kidney capsule, and intracerebroventricular administration of the hormone elicit excessive grooming (8). Moreover, endogenous
9
13
200
300
400
OXYTOCIN
(mg/kg)
FIG. I. Effects of IV injection of TRH on thiopenthal-induced narcosis in rats. TRH was injected 10 min after IP administration of thiopenthal (35 mg/kg). Values are expressed in median. Figures inside columns indicate the number of animals per group. *Significantly different as compared to controls (p < 0.01, Mann-Whitney U-test).
7
ipg/
kg )
FIG. 2. Effects of IV injection of OXY on thiopenthal-induced narcosis in rats. Oxytocin was injected 10 min after IP administration of thiopenthal (35 mg/kg). Values are expressed in median. Figures inside columns indicate the number of animals per group. *Significantly different as compared to controls (p < 0.05, Mann-Whitney U-test).
hyperprolactinaemia enhances amphetamine- and apomorphineinduced stereotypies (1 I). This finding suggests a mediation of dopaminergic neurotransmission in the state of activation induced by the hormone. The present experiments show that PRL inhibits thiopenthal-induced narcosis only at the lower doses, while the dose of 5 mg/kg increases it. Interestingly, a similar dose-response curve was found for PRL-induced grooming (7) and, hence, this is not an unusual phenomenon for behavioral effects elicited by this hormone. All three neuropeptides were effective in reducing barbiturateinduced narcosis after intravenous administration. Most of the MIN
15
- 7
-
5
CONTROLS v
PRL
(mg/kg)
FIG. 3. Effects of IV injection of PRL on thiopenthal-induced narcosis in rats. Prolactin was injected 10 min after IP administration of thiopenthal (35 mg/kg). Values are expressed in median. Figures inside columns indicate the number of animals per group. *Significantly different as compared to controls (p < 0.05. Mann-Whitney U-test).
PEPTIDES AND THIOPENTHAL
783
SLEEP
behavioral changes elicited by TRH have been observed after peripheral administration of the hormone (20). Also, high plasma PRL levels are followed by behavioral changes (8,11) and the peripheral injection of OXY induces excessive grooming (9). These findings suggests that TRH, OXY, and PRL, or behaviorally active fragments of these hormones, may cross the bloodbrain barrier and reach the neural systems responsible for barbiturate-induced narcosis. The mechanism underlying the effects of TRH, OXY, and PRL on barbiturate-induced sleep is not yet clear although these hormones are known to interact with neurotransmitters in the brain. TRH seems to increase not-adrenaline (NE) turnover as it enhances the reduction of this monoamine induced by o(methyl-ptyrosine and increases 3-methoxy,4-hydroxyphenilglycol production (15). However, since the cu,-adrenergic receptor blocker phentolamine does not block TRH-induced reduction of pentobarbital sleep, it is unlikely that TRH effects on barbiturate-induced sleep involve noradrenergic transmission. A possible interaction with the choline@ system has been suggested too since atropine was found to antagonize the ability of TRH to reduce pentobarbital-induced narcosis in mice but not in rats (3). This is further supported by the fact that TRH reverses the suppression of cholinetgic activity seen in the hippocampus after
pentobarbital treatment (21). The arousal properties of TRH may also involve amino acid neurotransmitters since the hormone stimulates potassium-induced release of glutamic acid and aspartic acid from incubated slices of rat cerebral cortex (1). A number of reports in the last few years have dealt with the interaction of OXY with brain monoamines. A decrease in NE concentration in the hypothalamus and striatum was shown after OXY administration (23). Dopamine levels were uneffected, whereas contradictory results were found after measurement of serotonin concentration in hypothalamus and septum (22,24). As mentioned above, the behavioral activation induced by PRL seems to be mediated by the dopaminergic system. This is further supported by neurochemical data showing increased dopamine utilization in the nucleus caudatus and increased dopamine synthesis in the nucleus accumbens in rats with endogenous hyperprolactinaemia (16). The fact that both OXY and PRL inhibit thiopenthal-induced narcosis is in line with the observations of the behavioral “arousal” induced by these neuropeptides in animals (4,5,7,8,9,11,12,17). It is possible that, independently of the mechanism of action, the antagonism of barbiturate-induced sleep represents an aspect of the arousal state elicited by TRH, OXY, and PRL.
REFERENCES
4.
5.
6.
7. 8. 9. 10. 11. 12. 13.
Biggins, A. S.; Dodd, P. R.; Edwardson, J. A.; Hardy, J. A.; McDermott, J. R.; Smith, A. I. Studies on the release, degradation and presynaptic actions of thyrotropin-releasing hormone. In: GriWhs, E. C.; Bennet, G. W., eds. Thyrotropin-releasing hormone. New York: Raven Press; 1983:241-251. Breese, G. R.; Cott, J. M.; Cooper, B. R.; Prange, A. J.; Lipton, M. A. Antagonism of ethanol narcosis by thyrotropin-releasing hormone. Life Sci. 14:1053-1069; 1974. Breese, G. R.; Cott, J. M.; Cooper, B. R.; Prange, A. J.; Lipton, M. A.; Plotnikoff, N. P. Effects of thyrotropin-releasing hormone (TRH) on the action of pentobarbital and other centrally acting drugs. J. Pharmacol. Exp. Ther. 193:l l-22; 1974. Crine. A. F.: Boulanaer, iniection _. B.: Niaet. __ G. Effect of da&_ pretrial _ of oxytocin on rat behavior in the open field situation. Reg. Peptides 5:145-152; 1983. Delanoy, R.; Dunn, A. J.; Tintner, R. Behavioral responses to intracerebroventricularly administered neurohypophyseal peptides in mice. Hormone Behav. 11:348-362; 1978. Doi, T.; Saji, Y.; Nagawa, Y. Arousal effect of thyrotropin-releasing hormone (TRH) in hypothalamic lesioned cats. Basic Phannacol. Ther. 6:3229-3237; 1978. Drago, F.; Bohus, B.; Gispen, D. W.; Scapagnini, U.; De Wied, D. Prolactin-enhanced aroomina behavior: Interaction with ACTH. Brain Res. 263:277-282; 1983. Drago, F.; Canonico, P. L.; Bitetti, R.; Scapagnini, U. Systemic and intraventricular prolactin induces excessive grooming. Eur. J. Pharmacol. 65:457-458; 1980. Drago, F.; Pedersen, C. A.; Caldwell, J. D.; Prange, A. J. Oxytocin potently enhances novelty-induced grooming behavior in the rat. Brain Res. 368~287-295; 1986. Drago, F.; Pulvirenti, L.; Spadaro, F.; Pennisi, S. Effects of TRH and prolactin in the behavioral despair (swim) model of depression in rats. Psychoneuroendocrinology 15:l-8; 199 1. Drago, F.; Van Ree, J. M.; Bohus, B.; De Wied, D. Endogenous hyperprolactinemia enhances amphetamine- and apomorphine-induced stereotypy. Eur. J. Pharmacol. 72:249-253; 198 1. Fame, J.; Liseau, P.; Friconneau, C. In8uence de I’oxytocine sur I’eleo troencephalogmmme du Iapin. Rev. Neurol. 101:302-308; 1951. Kalivas, P. W.; Horita, A. Thyrotropin-releasing hormone: Neurogenesis of action in the pentobarbital narcotized rat. J. Pharmacol. Exp. Ther. 2 12:203-2 10; 1980.
14. Kalivas, P. W.; Ho&a, A. Involvement of the septohippocampal system in TRH antagonism of pentobarbital narcosis. In: GrifBhs, E. C., Bennet, G. W., eds. Thyrotropin-releasing hormone. New York: Raven Press; 1983:283-290. IS. Keller, H. H.; Bartolini, G.; Pletscher, A. Enhancement of cerebral noradrenaline turnover by thyrotropin-releasing hormone. Nature 248:528-529; 1974. 16. Kovacs, G.; Drago, F.; Acsai, L.; Tihanyi, A.; Scapagnini, U.; Telegdy, G. Catecholamine utilization in specific rat brain nuclei after shortterm hyperprolactinemia. Brain Res. 32429-34; 1984. 17. Meisemberg, G. Short-term behavioral effects of neurohypophyseal hormones: Pharmacological characteristics. Neuropharmacology 2 1: 309-3 16; 1982. 18. Metcalf, G.; Dettmar, P. W. Is thyrotropin-releasing hormone an endogenous ergotropic substance in the brain. Lancet 3:586-589; 1981. 19. Plotnikoff, N. P.; Prange, A. J.; Breese, G. R.; Andersen, M. S.; Wilson, I. C. Thyrotropin-releasing hormone: Enhancement of dopa activity by a hypothalamic hormone. Science 178:117-l 18; 1972. 20. Prange, A. J.; Nemeroff, C. B.; Lipton, M. A. Behavioral effects of peptides: Basic and clinical studies. In: Lipton, M. A.; Di Mascio, A.; Kiham, K. F., eds. Psychopharmacology: A generation of progress. New York: Raven Press; 1978:441-458. 21. Richter, J. A.; Walker, M. B. Effects of pentobarbital on the regulation of acetylcholine in different brain regions. Acta Physiol. Stand. 99: 336-344; 1977. 22. Schwanberg, H.; Kovacs, G. L.; Szabo, G.; Telegdy, G. Intraventricular administration of vasopressin and oxytocin atfects the steady state level of serotonin, dopamine and norepinephrine in rat brain. Endocrinol. Exp. 15:75-80; 1981. _ 23. Teleadv. G.: Kovaca. G. Role of monoamines in mediatina the action of ACTH, vasopressin and oxytocin. In: Collu, R.; B&beau, A.; Ducharme, J. R.; Rcchefort, J. D., eds. Central nervous system effects of hypothalamic hormones and other peptides. New York: Raven Press, 1979:189-205. 24. Telegdy, G.; Kovacs, G. Role of monoamines in mediating the action of the hormones on learning and memory. In: Brazier, M. A. B., ed. Brain mechanism of memory and learning: From small neuron to man, IBRO Monograph Series. New York Raven Press; 1979: 248-268. I_.
Printed in the USA. All rights reserved.
0361-9230/92$5.00 + .OO Pergamon Press Ltd.
0 1992
Effects of Thyrotropin-Releasing Hormone, Oxytocin, and Prolactin on Thiopenthal-Induced Narcosis in Rats F. DRAGO,*’
F. MAUCERI,*
M. FIDILIO,t
S. CAVALIERE,*
L. PULVIRENTI*
AND
F. FOTIt
*Institute of Pharmacology and flnstitute of Anesthesiology, University of Catania Medical School, Catania, Italy Received
16 September
1986
DRAGO, F., F. MAUCERI, M. FIDILIO, S. CAVALIERE, L. PULVIRENTI AND F. FOTI. E&fs ofthyrotropin-releasing hormone, oxytocin, andprolactin on thiopenthal-induced narcosis in rats. BRAIN RES BULL 28(5) 78 l-783, 1992.-Neuropeptides that may induce behavioral activation-thyrotropin-releasing hormone (TRH), oxytocin (OXY), and prolactin (PRL)-were tested on thiopenthal-induced narcosis after IV administration in male rats. TRH caused a significant shortening of sleeping time at the doses of 3 and 5 mg/kg, but did not change this parameter at lower doses. Oxytocin was effective at all doses tested (200, 300, and 400 fig/kg). Prolactin also shortened sleeping time at the doses of 0.2 and 1 mg/kg administered IV, slightly increasing it at the dose of 5 mg/kg. These results indicate that various neuropeptides are capable of reducing the duration of thiopenthalinduced sleep in rats.
Thyrotropin-releasing hormone
Oxytocin
Thiopenthal
Prolactin
Narcosis
of 20°C with water and food available ad lib and a 12 L: 12 D cycle (lights on between 8:00 a.m. and 8:00 p.m.). All experiments were performed in the morning. Animals were used only once in the experimental procedure. Sodium thiopenthal (Farmitalia, Italy) was administered IP at the dose of 35 mg/kg. TRH, OXY, and PRL (ovine), purchased from Sigma (USA), were dissolved in physiologic saline with a drop per tube of HCl 0.1 N. Neuropeptides were administered IV 10 min after thiopenthal at the following doses: 1, 3, and 5 mg/kg for TRH; 200, 300, and 400 &kg for OXY; 0.2, 1, and 5 mg/kg for PRL. These doses were selected on the basis of their efficacy in inducing behavioral changes as described elsewhere (2,7,9). After thiopenthal administration, sleeping time was measured as time elapsing from the loss of the righting reflex to the retrieval of it until a maximum of 120 min. Data were expressed in median and analyzed using the twoway analysis of variance (ANOVA) with replication and the posthoc Mann-Whitney U-test for non-parametric data. A p value of 0.05 or less was considered indicative of a significant difference.
THYROTROPIN-releasing hormone (TRH) is a neuropeptide with peculiar effects on the CNS. Among other effects, TRH induces a state of behavioral “arousal” that has been compared to that of amphetamine ( 18). It has heen shown in various animal species that TRH antagonizes sedation, sleep, and hypothermia induced by various barbiturates (2,20). Similar interaction is known to be present with ethanol and other CNS depressants (2,3). This effect seems unrelated to classical endocrine actions of TRH since it is present in hypophysectomized and thyroidectomized animals and with TRH analogs devoid of any endocrine action (20). Interestingly, with labeled pentobarbital it has been shown that TRH does not alter barbiturate metabolism (3). TRH is active in antagonizing barbiturate-induced narcosis after both peripheral and central administration. Reduction of sleeping is also observed after injection in various brain areas. The maximum efficacy has been shown after administration of the peptide in the septal area, thus suggesting an involvement of the septohippocampal system in TRH antagonism of barbiturate-induced sleep (14). Oxytocin (OXY) and prolactin (PRL) are hormones that also exert behavioral effects, some of which are consistent with the induction of a state of “arousal” similar to that induced by TRH (4,5,8,9,11,12,17). These findings prompted us to perform a series of experiments to examine the possible influence of OXY and PRL on barbiturate-induced sleep compared to that of TRH.
RESULTS
The results concerning the effect of TRH (1, 3, and 5 mg/ kg) on thiopenthal-induced sleep are shown in Fig. 1. A marked reduction of the sleeping time was found in rats treated with 3 and 5 mg/kg of the peptide, while the lower dose was ineffective in this respect. A shortening of the duration of thiopenthal-induced narcosis was also observed with OXY at all three doses
METHOD
Male, albino Wistar rats weighing 120- 150 g (Charles River, Italy) were housed five to a cage at a constant room temperature
’ Requests for reprints should be addressed to Filippo Drago, M.D., Ph.D., Institute of Pharmacology, Viale A. Doria, 6, 95 125 Catania, Italy. 781
782
DRAG0
ET AL.
MIN
MIN
100. 100
n,-n-
80-
80 60.
40-
9 CONTROLS
*
*
11
6
7
1
3
5
TRH
l
20.
o-
16 CONTROLS
used (Fig. 2). Administration of PRL at doses of 0.2 and 1 mg/ kg also reduced the duration of thiopenthal-induced sleep (Fig. 3). However, the greater dose of the peptide (5 mg/kg) enhanced it but not to a statistically significant extent. DISCUSSION
Evidence has been presented that TRH reduces sleep induced by ethanol and barbiturates with a mechanism unrelated to the release of thyroid hormones. Analeptic properties are suggested by a series of central effects of the hormone. It enhances DOPAinduced stimulation ( 19), antagonizes sedation and hypothermia induced by reserpine, chlorpromazine, and diazepam (3) and possesses antidepressant properties in animals (10) and humans (20). Moreover, IV injection of TRH in cats produces electroencephalographic (EEG) activation, restlessness, increased respiration, and other behavioral changes (6). Possible neuroanatomical substrates mediating some effects of TRH in pentobarbital-treated rats have been recently examined. The septohippocampal system seems to be the most important area that mediates TRH-induced reduction in pentobarbital-induced sleep. Furthermore, effects on temperature were evoked by TRH microinjections in a series of sites such as the anterior preoptic hypothalamic area, the medial thalamus, the periventticular gray, the interpeduncular nucleus, and the locus coeruleus (13). A number of studies have demonstrated that also OXY exerts various effects on animal behavior, some of which are consistent with a state of arousal. After intracerebroventricular injection of this peptide, pronounced hyperactivity, extensive foraging, squeaking and occasional barrel-rolling have been demonstrated in rodents (5), while other authors have shown excessive grooming, increased locomotor activity, and rearing (4,9,17). Moreover, electrophysiological studies revealed that after peripheral administration of the peptide a desynchronization of EEG is evident (12). Prolactin induces behavioral changes similar to those of OXY and TRH in terms of arousal. Both endogenous hyperprolactinaemia, induced by pituitary homografts under the kidney capsule, and intracerebroventricular administration of the hormone elicit excessive grooming (8). Moreover, endogenous
9
13
200
300
400
OXYTOCIN
(mg/kg)
FIG. I. Effects of IV injection of TRH on thiopenthal-induced narcosis in rats. TRH was injected 10 min after IP administration of thiopenthal (35 mg/kg). Values are expressed in median. Figures inside columns indicate the number of animals per group. *Significantly different as compared to controls (p < 0.01, Mann-Whitney U-test).
7
ipg/
kg )
FIG. 2. Effects of IV injection of OXY on thiopenthal-induced narcosis in rats. Oxytocin was injected 10 min after IP administration of thiopenthal (35 mg/kg). Values are expressed in median. Figures inside columns indicate the number of animals per group. *Significantly different as compared to controls (p < 0.05, Mann-Whitney U-test).
hyperprolactinaemia enhances amphetamine- and apomorphineinduced stereotypies (1 I). This finding suggests a mediation of dopaminergic neurotransmission in the state of activation induced by the hormone. The present experiments show that PRL inhibits thiopenthal-induced narcosis only at the lower doses, while the dose of 5 mg/kg increases it. Interestingly, a similar dose-response curve was found for PRL-induced grooming (7) and, hence, this is not an unusual phenomenon for behavioral effects elicited by this hormone. All three neuropeptides were effective in reducing barbiturateinduced narcosis after intravenous administration. Most of the MIN
15
- 7
-
5
CONTROLS v
PRL
(mg/kg)
FIG. 3. Effects of IV injection of PRL on thiopenthal-induced narcosis in rats. Prolactin was injected 10 min after IP administration of thiopenthal (35 mg/kg). Values are expressed in median. Figures inside columns indicate the number of animals per group. *Significantly different as compared to controls (p < 0.05. Mann-Whitney U-test).
PEPTIDES AND THIOPENTHAL
783
SLEEP
behavioral changes elicited by TRH have been observed after peripheral administration of the hormone (20). Also, high plasma PRL levels are followed by behavioral changes (8,11) and the peripheral injection of OXY induces excessive grooming (9). These findings suggests that TRH, OXY, and PRL, or behaviorally active fragments of these hormones, may cross the bloodbrain barrier and reach the neural systems responsible for barbiturate-induced narcosis. The mechanism underlying the effects of TRH, OXY, and PRL on barbiturate-induced sleep is not yet clear although these hormones are known to interact with neurotransmitters in the brain. TRH seems to increase not-adrenaline (NE) turnover as it enhances the reduction of this monoamine induced by o(methyl-ptyrosine and increases 3-methoxy,4-hydroxyphenilglycol production (15). However, since the cu,-adrenergic receptor blocker phentolamine does not block TRH-induced reduction of pentobarbital sleep, it is unlikely that TRH effects on barbiturate-induced sleep involve noradrenergic transmission. A possible interaction with the choline@ system has been suggested too since atropine was found to antagonize the ability of TRH to reduce pentobarbital-induced narcosis in mice but not in rats (3). This is further supported by the fact that TRH reverses the suppression of cholinetgic activity seen in the hippocampus after
pentobarbital treatment (21). The arousal properties of TRH may also involve amino acid neurotransmitters since the hormone stimulates potassium-induced release of glutamic acid and aspartic acid from incubated slices of rat cerebral cortex (1). A number of reports in the last few years have dealt with the interaction of OXY with brain monoamines. A decrease in NE concentration in the hypothalamus and striatum was shown after OXY administration (23). Dopamine levels were uneffected, whereas contradictory results were found after measurement of serotonin concentration in hypothalamus and septum (22,24). As mentioned above, the behavioral activation induced by PRL seems to be mediated by the dopaminergic system. This is further supported by neurochemical data showing increased dopamine utilization in the nucleus caudatus and increased dopamine synthesis in the nucleus accumbens in rats with endogenous hyperprolactinaemia (16). The fact that both OXY and PRL inhibit thiopenthal-induced narcosis is in line with the observations of the behavioral “arousal” induced by these neuropeptides in animals (4,5,7,8,9,11,12,17). It is possible that, independently of the mechanism of action, the antagonism of barbiturate-induced sleep represents an aspect of the arousal state elicited by TRH, OXY, and PRL.
REFERENCES
4.
5.
6.
7. 8. 9. 10. 11. 12. 13.
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