- Email: [email protected]
Effect of hydrocortisone on single unit activity in midbrain raphé
242
SHORT COMMUNICATIONS
Effect of hydrocortisone on single unit activity in midbrain raph6 Injections of corticosterone produce an increased turnover of brain serotonin by activating tryptophan hydroxylase4, 5. This result contrasts with the effect of LSD-25 which decreases the turnover of brain serotonin 9. Small doses of LSD-25 (10--20 #g/kg) injected intravenously also produce a reversible inhibition of the spontaneous firing rate of single serotonergic neurons 3. Although direct evidence is lacking, it has been suggested that these two effects of LSD could be related as follows 1: LSD-25 mimicks the effects of the natural amine. The nervous system detects an 'excess' of serotonin and initiates inhibitory feedback processes which decrease the rate at which serotonin neurons fire and results in a decrease in serotonin turnover. It should be noted, however, that pretreatment of decerebrate cats with LSD antagonized the stimulatory effect of iontophoretically applied 5-HT on brain stem neurons 6. In a further attempt to study the interrelations between the metabolism of serotonin and neuronal activity, we have investigated the effects of intravenous administration of hydrocortisone (Solu-cortef) upon the firing rates of raph6 cells. Charles River male albino rats, weighing between 250-300 g, were anesthetized with chloral hydrate and placed in a stereotaxic device. A small burr hole was placed in the midline 0.35 mm anterior to frontal zero and a tungsten microelectrode lowered into the area of the dorsal and/or midline raph6 nuclei. These midbrain nuclei have been shown to contain serotonin by histochemical fluorescence7. The activity of a single cell was monitored on an oscilloscope, fed into an integrator and displayed on a chart recorder. Solu-cortef in doses of 10-15 mg/kg was introduced into the tail vein after the spontaneous activity of a cell had been monitored for approximately 10 min. The spontaneous activity of 11 cells located in the raph6 showed a significant partial or total inhibition; most demonstrated a gradual return to the basal rate (Fig. 1). None of the raph6 cells observed were unaffected by the Solu-cortef. Unlike LSD-25 which produces inhibition within 30-60 sec after injection, the effects of Solu-cortef were apparent only 5-8 rain after administration. Cells that were inhibited by Solu-cortef were also sensitive to LSD-25 (Fig. 1). The prior treatment with Solu-cortef probably does not affect the response time or the duration of the LSD-25 effect since these cells show the same kinetics of changed firing rates as do raph6 cells in animals that have not been pre-treated with Solucortef.
Fig. 1. Effects of hydrocortisone and LSD on the firing characteristics of a dorsal raph6 neuron. Brain Research, 41 (1972) 242-244
SHORT COMMUNICATIONS
243
Fig. 2. Effects of hydrocortisone and LSD on the firing characteristics of a neuron in the dorsal central gray. Solu-cortef was also tested on 12 neurons located outside the midbrain raphd where it produced one o f several effects: (a) 5 cells were excited; (b) 4 cells underwent a transient reduction in firing rate; (c) 3 cells were not affected. O f these 12 cells, 6 were inhibited by LSD-25 which was administered at varying times after the Solu-cortef injection (Fig. 2). Whether or not the corticosteroid sensitized these cells to LSD is not known. However, LSD inhibition of non-raphd neurons has not been observed in previous work. The mechanism by which Solu-cortefproduces an inhibition ofserotonin neurons is not known. However, the delay between injection and inhibition (5-8 min) may reflect enzymatic induction of tryptophan hydroxylase with a consequent increase in serotonin synthesis. I f an increase in serotonin level occurs, the nervous system may respond as it does to the 'serotonin excess' it senses upon injection of LSD, and a reduction in neuronal firing rate thus occurs. Other investigatorsS, 10 have reported inhibitory and excitatory effects of hydrocortisone in diencephalic neurons. I f corticosteroids produce all of their effects in the CNS by stimulating tryptophan hydroxylase activity, it is possible that the diencephalic responses also measure this effect since serotonin-like endings are found here 2. However, in the absence of a full understanding o f corticosteroid effects on brain metabolism and the detailed circuitry of the brain, experiments of the type reported here and those cited above cannot in themselves distinguish between direct and indirect hormonal or drug effects. This work was supported by N I M H Grants MH18424 and MH17929. Harvard Medical School, Massachusetts General Hospital, Boston, Mass. Abraham Ribicoff Research Center, Norwich Hospital, Norwich, Conn. (U.S.A.)
WARREN E. FOOTE JEFFREY P. LIEB RICHARD L. MARTZ MALCOLM W. GORDON Brain Research, 41 (1972) 242-244
244
SHORT COMMUNICATIONS
1 ANDEN, N.-E., CORRODI, H., FUXE, K., AND HOKFELT, T., Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide, Brit. J. PharmacoL, 34 (1968) 1-7. 2 ANDI~N,N.-E., DAHLSTR()M, A., FUXE, K., LARSSON,K., OLSON, L., AND UNGERSTEDT, U., Ascending monoamine neurons to the telencephalon and diencephalon, Acta physiol, scand., 67 (1966) 313-326. 3 AGHAJANIAN,G. K., FOOTE, W. E., AND SHEARD, M. H., Lysergic acid diethylamide: sensitive neuronal units in the midbrain raph6, Science, 161 (1968) 706-708. 4 AZMITIA,E. C., ALGERI, S., AND COSTA, E., In vivo conversion of aH-L-tryptophan into aH-serotonin in brain areas in adrenalectomized rats, Science, 169 (1970) 201-203. 5 AZMITIA, E. C., AND MCEWEN, B. S., Corticosterone regulation of tryptophan hydroxylase in midbrain of the rat, Science, 166 (1969) 1274-1276. 6 BOAKES,R. J., BRADLEY, P. B., BRIGGS, I., AND DRAY, A., Antagonism of 5-hydroxytryptamine by LSD-25 in the central nervous system: a possible neuronal basis for the actions of LSD-25, Brit. J. Pharmacol., 40 (1970) 202-218. 7 DAHLSTR~M,A., AND FUXE, K., Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brainstem neurons, Acta physiol, scand., Suppl. 232 (1964) 1-55. 8 FELDMAN,S., AND DAENY, N., Effect of hydrocortisone on single cell activity in anterior hypothalamus, Israel J. Med. Sci., 2 (1966) 621-623. 9 ROSECRAN$,J. A., LOVELL, R. A., AND FREEDMAN,D. X., Effects of lysergic acid diethylamide on the metabolism of brain 5-hydroxytryptamine, Biochem. Pharmacol., 16 (1967) 2011-2021. 10 SLUSHER, M. A., HYDE, J. E., AND LAUFER, M., Effect of intracerebral hydrocortisone on unit activity in diencephalon in cats, J. Neurophysiol., 29 (1966) 157-169. (Accepted February 23rd, 1972)
Brain Research, 41 (1972) 242-244
SHORT COMMUNICATIONS
Effect of hydrocortisone on single unit activity in midbrain raph6 Injections of corticosterone produce an increased turnover of brain serotonin by activating tryptophan hydroxylase4, 5. This result contrasts with the effect of LSD-25 which decreases the turnover of brain serotonin 9. Small doses of LSD-25 (10--20 #g/kg) injected intravenously also produce a reversible inhibition of the spontaneous firing rate of single serotonergic neurons 3. Although direct evidence is lacking, it has been suggested that these two effects of LSD could be related as follows 1: LSD-25 mimicks the effects of the natural amine. The nervous system detects an 'excess' of serotonin and initiates inhibitory feedback processes which decrease the rate at which serotonin neurons fire and results in a decrease in serotonin turnover. It should be noted, however, that pretreatment of decerebrate cats with LSD antagonized the stimulatory effect of iontophoretically applied 5-HT on brain stem neurons 6. In a further attempt to study the interrelations between the metabolism of serotonin and neuronal activity, we have investigated the effects of intravenous administration of hydrocortisone (Solu-cortef) upon the firing rates of raph6 cells. Charles River male albino rats, weighing between 250-300 g, were anesthetized with chloral hydrate and placed in a stereotaxic device. A small burr hole was placed in the midline 0.35 mm anterior to frontal zero and a tungsten microelectrode lowered into the area of the dorsal and/or midline raph6 nuclei. These midbrain nuclei have been shown to contain serotonin by histochemical fluorescence7. The activity of a single cell was monitored on an oscilloscope, fed into an integrator and displayed on a chart recorder. Solu-cortef in doses of 10-15 mg/kg was introduced into the tail vein after the spontaneous activity of a cell had been monitored for approximately 10 min. The spontaneous activity of 11 cells located in the raph6 showed a significant partial or total inhibition; most demonstrated a gradual return to the basal rate (Fig. 1). None of the raph6 cells observed were unaffected by the Solu-cortef. Unlike LSD-25 which produces inhibition within 30-60 sec after injection, the effects of Solu-cortef were apparent only 5-8 rain after administration. Cells that were inhibited by Solu-cortef were also sensitive to LSD-25 (Fig. 1). The prior treatment with Solu-cortef probably does not affect the response time or the duration of the LSD-25 effect since these cells show the same kinetics of changed firing rates as do raph6 cells in animals that have not been pre-treated with Solucortef.
Fig. 1. Effects of hydrocortisone and LSD on the firing characteristics of a dorsal raph6 neuron. Brain Research, 41 (1972) 242-244
SHORT COMMUNICATIONS
243
Fig. 2. Effects of hydrocortisone and LSD on the firing characteristics of a neuron in the dorsal central gray. Solu-cortef was also tested on 12 neurons located outside the midbrain raphd where it produced one o f several effects: (a) 5 cells were excited; (b) 4 cells underwent a transient reduction in firing rate; (c) 3 cells were not affected. O f these 12 cells, 6 were inhibited by LSD-25 which was administered at varying times after the Solu-cortef injection (Fig. 2). Whether or not the corticosteroid sensitized these cells to LSD is not known. However, LSD inhibition of non-raphd neurons has not been observed in previous work. The mechanism by which Solu-cortefproduces an inhibition ofserotonin neurons is not known. However, the delay between injection and inhibition (5-8 min) may reflect enzymatic induction of tryptophan hydroxylase with a consequent increase in serotonin synthesis. I f an increase in serotonin level occurs, the nervous system may respond as it does to the 'serotonin excess' it senses upon injection of LSD, and a reduction in neuronal firing rate thus occurs. Other investigatorsS, 10 have reported inhibitory and excitatory effects of hydrocortisone in diencephalic neurons. I f corticosteroids produce all of their effects in the CNS by stimulating tryptophan hydroxylase activity, it is possible that the diencephalic responses also measure this effect since serotonin-like endings are found here 2. However, in the absence of a full understanding o f corticosteroid effects on brain metabolism and the detailed circuitry of the brain, experiments of the type reported here and those cited above cannot in themselves distinguish between direct and indirect hormonal or drug effects. This work was supported by N I M H Grants MH18424 and MH17929. Harvard Medical School, Massachusetts General Hospital, Boston, Mass. Abraham Ribicoff Research Center, Norwich Hospital, Norwich, Conn. (U.S.A.)
WARREN E. FOOTE JEFFREY P. LIEB RICHARD L. MARTZ MALCOLM W. GORDON Brain Research, 41 (1972) 242-244
244
SHORT COMMUNICATIONS
1 ANDEN, N.-E., CORRODI, H., FUXE, K., AND HOKFELT, T., Evidence for a central 5-hydroxytryptamine receptor stimulation by lysergic acid diethylamide, Brit. J. PharmacoL, 34 (1968) 1-7. 2 ANDI~N,N.-E., DAHLSTR()M, A., FUXE, K., LARSSON,K., OLSON, L., AND UNGERSTEDT, U., Ascending monoamine neurons to the telencephalon and diencephalon, Acta physiol, scand., 67 (1966) 313-326. 3 AGHAJANIAN,G. K., FOOTE, W. E., AND SHEARD, M. H., Lysergic acid diethylamide: sensitive neuronal units in the midbrain raph6, Science, 161 (1968) 706-708. 4 AZMITIA,E. C., ALGERI, S., AND COSTA, E., In vivo conversion of aH-L-tryptophan into aH-serotonin in brain areas in adrenalectomized rats, Science, 169 (1970) 201-203. 5 AZMITIA, E. C., AND MCEWEN, B. S., Corticosterone regulation of tryptophan hydroxylase in midbrain of the rat, Science, 166 (1969) 1274-1276. 6 BOAKES,R. J., BRADLEY, P. B., BRIGGS, I., AND DRAY, A., Antagonism of 5-hydroxytryptamine by LSD-25 in the central nervous system: a possible neuronal basis for the actions of LSD-25, Brit. J. Pharmacol., 40 (1970) 202-218. 7 DAHLSTR~M,A., AND FUXE, K., Evidence for the existence of monoamine containing neurons in the central nervous system. I. Demonstration of monoamines in the cell bodies of brainstem neurons, Acta physiol, scand., Suppl. 232 (1964) 1-55. 8 FELDMAN,S., AND DAENY, N., Effect of hydrocortisone on single cell activity in anterior hypothalamus, Israel J. Med. Sci., 2 (1966) 621-623. 9 ROSECRAN$,J. A., LOVELL, R. A., AND FREEDMAN,D. X., Effects of lysergic acid diethylamide on the metabolism of brain 5-hydroxytryptamine, Biochem. Pharmacol., 16 (1967) 2011-2021. 10 SLUSHER, M. A., HYDE, J. E., AND LAUFER, M., Effect of intracerebral hydrocortisone on unit activity in diencephalon in cats, J. Neurophysiol., 29 (1966) 157-169. (Accepted February 23rd, 1972)
Brain Research, 41 (1972) 242-244