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Acute effects of taurine and a taurine antagonist on ethanol-induced central nervous system depression
European Journal of Pharmacology, 113 (1985) 275-278 Elsevier
275
Short communication ACUTE E F F E C T S OF T A U R I N E AND A T A U R I N E A N T A G O N I S T O N E T H A N O L - I N D U C E D CENTRAL NERVOUS SYSTEM DEPRESSION LINDA MATTUCCI-SCHIAVONE and ANDREW P. FERKO *
Department of Pharmacology, Hahnemann University, Philadelphia, PA, U.S.A. Received 9 May 1985, accepted 15 May 1985
L. M A T T U C C I - S C H I A V O N E and A.P. F E R K O , Acute effects of taurine and a taurine antagonist on ethanol-induced central nervous system depression, European J. Pharmacol. 113 ( 1 9 8 5 ) 2 7 5 - 2 7 8 .
Sprague-Dawley rats received taurine intracerebroventricularly (i.c.v.) 30 min prior to ethanol (4 g/kg, i.p.). The duration of ethanol-induced sleep time was increased with taurine at doses of 7.5, 14.0 and 25.0/~mol/kg. In another experiment, TAG (a taurine antagonist, i.c.v.) was given 5 min prior to taurine (i.c.v.) and ethanol was administered 30 rain later. TAG antagonized the effect of taurine to enhance ethanol-induced sleep time. These results suggest an interaction between taurine and the depressant effect of ethanol in the brain. Taurine antagonist (TAG)
Sleep time
Taurine
1. Introduction Reports in the literature indicate that taurine decreases the hypnotic effect of ethanol (lida and Hikichi, 1976; Boggan et al., 1978). This reduction in the effect of ethanol occurs with simultaneous injection (i.p.) of ethanol and taurine, or with taurine administration (i.v.) at 5 and 30 min prior to ethanol (Iida and Hikichi, 1976). Boggan et al. (1978) also showed that taurine significantly reduced ethanol-induced sleep time (hypnosis) in animals after simultaneous administration (i.p.) of ethanol and taurine. These reports show that taurine does not produce any observable pharmacological effect by itself or alter blood ethanol levels. In addition, taurine does not antagonize the effect of ethanol on seizure susceptibility, body temperature or brain 5-hydroxyindole acetic acid concentration (Boggan et al., 1978). Another study (Messiha, 1979) however, indicates that taurine fails to attenuate the hypnotic
* To whom all correspondence should be addressed: Department of Pharmacology, Hahnemann University, Broad and Vine Streets, Philadelphia, PA 19102, U.S.A. 0014-2999/85/$03.30 © 1985 Elsevier Science Publishers B.V.
Ethanol
effect of ethanol when taurine is administered (i.p.) in a dose similar to that used in earlier work. The variation in the results obtained for the interaction of taurine and ethanol on sleep time may be related to differences in experimental design, animal species or other factors. One factor may be that taurine does not readily pass the blood-brain barrier in significant amounts after acute administration (McGeer et al., 1978). This study examined the effect of taurine on ethanol-induced sleep time. As passage of taurine into the brain is questionable taurine was administered by i.c.v, injection. A taurine antagonist, T A G (6-aminoethyl-3-methyl-4H-1,2,4-benzothiadiazine-l,l-dioxide hydrochloride) (Yarbrough et al., 1981) was also used in these experiments.
2. Materials and methods Male Sprague-Dawley rats (140-160 g) were obtained from Charles Rivers Laboratories, Inc. (Wilmington, MA) and were housed 6 to a cage at 2 2 + I ° C for 1 week prior to experimentation, with lights on from 6:00 a.m. to 6:00 p.m. The animals had free access to Purina Laboratory Chow
276 (Ralston Purina Co., St. Louis, MO) and water. They were fasted 18 h prior to drug or saline (0.9% NaCI) administration but water was available ad libitum. Ethanol solution (20% w / v ) for injection was prepared from 95% ethanol). Taurine was purchased from Fiuka Chemical Corp. (Haupage, NY). TAG, 6-aminomethyl-3-methyl-4H-1,2,4benzothiadiazine-l,l-dioxide hydrochloride, was a gift from Merck Sharp & Dohme Research Laboratories (Rahway, N J). The rats were anesthetized with an i.p. injection of ketamine (10 mg/kg) containing acepromazine. A craniotomy hole was made above the right ventricle at a point located 1 mm posterior to the frontoparietal suture and 1 mm from the midline. A polyethylene cannula, PE 10, was implanted through the hole and lowered to 4 mm below the skull to reach the ventricle and cemented in place (Stewart et al., 1978). Saline (10 /~1) was injected into the cannula and the top of the cannula was sealed with silicone adhesive. The scalp incision was closed with wound clips and the animals were allowed to recover for 3 days before the acute experiments. The same procedure was followed with control animals. The correct position of the cannula was verified at autopsy by using trypan blue dye. All i.c.v, injections were made in the conscious rat except where noted. Taurine and TAG were dissolved in saline shortly before the experiment and adjusted to pH 7.0. The concentrations of taurine and TAG in solution were varied according to the dose administered in order to inject a constant volume (10 #1) into the ventricle. Each drug injection was followed by saline (10 #1). Control animals received a total volume of 20 ~1 of saline. In the experiments requiring i.c.v, injection of two drugs (TAG and taurine), the volume of drug solution and of saline was reduced to 6 ~1 each.
loss of the righting reflex after ethanol injection and the return of the fighting reflex. Return of the righting reflex required that the animal be able to re-right itself within one min after again being placed on its back. A blood sample (20 #1) was taken from the orbital sinus of each animal when they regained the righting reflex. Ethanol content was measured by the enzymatic method ol Lundquist (1959). Since the duration of action ot taurine is less than the mean sleep time following ethanol (4 g/kg) administration (Martin et ai., 1981), a second injection of taurine was given 120 min into the sleep time. Control animals were handled identically but saline was administered instead of taurine. The next experiment was designed to find if T A G administration could alter ethanol-induced sleep time. TAG was injected in a dose of 0.075 or 0.15 #moi/kg, i.c.v., 5 min prior to ethanol (4 g/kg, i.p.). Due to the short duration of action of TAG (Wessberg et al., 1983), a second injection was made at 120 rain or at the end of the sleep time if this was less than 120 min. The final experiment involved TAG and the potentiation of ethanol-induced sleep time by i.c.v. injection of taurine. TAG (0.15 /tmol/kg, i.c.v.) was given 5 rain prior to taurine (14 /~mol/kg, i.c.v.), and ethanol was administered (4 g/kg, i.p.) 30 min later. The same procedure for injection of TAG and taurine was repeated at 120 min into the sleep time.
2.1. Ethanol-induced hypnosis (sleep time)
3. Results
Taurine was administered in a dose of 2.5, 7.5, 14 or 25 #mol/kg, i.c.v., 30 min prior to ethanol (4 g/kg, i.p.). Sleep time was used as an index of ethanol-induced central nervous system depression and was measured as the time interval between the
When various doses of exogenous taurine were administered by i.c.v, injection, the duration of ethanol-induced sleep time was increased significantly (table 1). The highest dose of taurine (25 # m o l / k g , i.c.v.) increased sleep time by 141%. No
2.2. Statistical analysis Significant differences were determined by analysis of variance (ANOVA). All multiple comparisons with a control were done by ANOVA followed by Scheffe's test. All data were analyzed using an Apple lie Computer.
277 TABLE 1 Effect of taurine on ethanol-induced sleep time. Taurine was administered (,umol/kg, i.c.v.) 30 min prior to ethanol (ETOH, 4 g/kg, i.p.). Values are means _+S.E.M. Treatment
N
Saline+ETOH(controls) 10 Taurine (2.5) + ETOH 5 Taurine (7.5)+ ETOH 6 Taurine (14.0)+ ETOH 5 Taurine(25.0)+ETOH 6
Sleep time (min)
Blood ETOH (mg/ml)
145.2+15.7 156.8 + 34.9 239.5 ± 20.5 * 244.8±14.6" 350.5_+ 12.5 **
3.16___0.07 3.22 + 0.18 2.90±0.09 2.69_+0.14" 2.30+0.10 **
Significantly different from controls: * P < 0.05, ** P < 0.01.
hypnosis was produced in control animals that received the maximum dose of taurine (25 # m o l / k g , i.c.v.). Analysis of blood ethanol concentrations at the end of the sleep time showed a corresponding decrease for each group as the length of sleep time increased. The next experiment investigated the effect of T A G (i.c.v.) on ethanol-induced sleep time. When two doses of TAG (0.075 or 0.15/~mol/kg, i.c.v.) were administered 5 min prior to ethanol (4 g/kg, i.p.), the duration of sleep time was reduced, but was not significantly different from that of the controls (data not shown). In control animals, TAG (0.15 # m o l / k g , i.c.v.) caused no visible alteration in behavior when it was given 5 min prior to saline (0.02 ml/g, i.p.). The results of the final experiment in this study (table 2) showed that TAG reduced the effect of taurine to prolong ethanol-induced sleep time. When TAG and taurine were both given prior to TABLE 2 Effect of TAG on the potentiation of ethanol-induced sleep time by taurine. TAG (0.15 ~tmol/kg, i.c.v.) was administered 5 rain prior to taurine (14 /~mol/kg, i.c.v.). Ethanol (ETOH, 4 g/kg, i.p.) was given 30 min after taurine. Values are means + S.E.M. Treatment
N
Saline + ETOH (controls) 10 Taurine + ETOH 5 TAG+taurine+ETOH 5
Sleep time (min)
Blood ETOH (mg/ml)
145.7 ± 14.6 244.8 ± 14.6 * 171.6:1:12.6"*
3.26 ± 0.11 2.68 ± 0.14 * 3.11+0.08"*
Significantly different from controls: * P < 0.05. Significantly different from group treated with taurine and ethanol: ** P < 0.05.
ethanol, the sleep time and blood ethanol concentrations were similar to values obtained from control animals.
4. Discussion
Taurine, a sulfur-containing amino acid, is found in brain tissue in high concentrations and is widely but unevenly distributed. This amino acid has a depressant effect in the central nervous system, suppressing neuronal activity in the spinal cord and brain (Curtis et al., 1968). The present results indicate that taurine (i.c.v.) can enhance the central depressant effect of ethanol. In addition, TAG attenuated the potentiating effect of taurine on ethanol-induced sleep time. Yarbrough et al. (1981) have reported that TAG was a selective taurine antagonist in their neuropharmacoiogical studies. Martin et al. (1981) have demonstrated that TAG blocks contraversive turning caused by taurine. Their other results show a lack of effect with TAG in a number of radioligand binding assays and that only [3H]taurine binding was affected by TAG. More recent work also supports the hypothesis that TAG is a selective antagonist of taurine in the rat brain (Wessberg et al., 1983). It has been suggested that taurine may subserve a neurotransmitter-type function in the central nervous system (Yarbrough et al., 1981). Taurine has been implicated in the effects of other drugs, particularly the narcotic analgesic agents. Taurine can induce a hyperalgesic state and antagonize the analgesic action of morphine in mice (Contreras and Tamayo, 1984; Yamamoto et al., 1981). Taurine partially reduces the development of tolerance to morphine and decreases the incidence of some abstinence signs (Contreras and Tamayo, 1984). It has been suggested that the hyperalgesic state which is produced by taurine may be due to antagonism of endogenous opioid peptides. The proposed mechanism for the blockade of morphine analgesia by taurine appears to be related to intracellular calcium events (Yamamoto et al., 1981; Contreras and Tomayo, 1984). At the'present time there seems to be no clear relationship between the mechanisms suggested for the combined effects of taurine and morphine and the results obtained in this work with taurine and
278 ethanol. Further experiments are requirued to und e r s t a n d m o r e fully t h e n e u r o a c t i v e r o l e o f t a u r i n e in central nervous system depression. This work may be facilitated by the use of TAG or other future specific taurine antagonists.
Acknowledgements We thank Linda Bush and Colleen Graham for typing the manuscript. This work was partly supported by a National Science Foundation Graduate Fellowship for Linda MattucciSchiavone.
References Boggan, W.O., C. Medberry and D.H. Hopkins, 1978, Effects of taurine on some pharmacological properties of ethanol, Pharmacol. Biochem. Behav. 9, 469. Contreras, E. and L. Tamayo, 1984, Effects of taurine on tolerance to and dependence on morphine in mice, Arch. Int. Pharmacodyn. 267, 224. Curtis, D.R., L. Hosli and G.A.R. Johnston, 1968, A pharmacological study of the depression of spinal neurons by glycine and related amino acids, Exp. Brain Res. 6, 1.
lida, S. and M. Hikichi, 1976, Effect of taurine on ethanol-induced sleeping time in mice, J. Study Alcohol, 37, 19. Lundquist, F., 1959, The determination of ethyl alcohol in blood and tissue, Methods Biochem. Anal. 1,217. Martin, G.E., R.J. Benedsky and M. Williams, 1981, Further evidence for selective antagonism of taurine by 6aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine- 1,1 -dioxide, Brain Res. 299, 530. McGeer, P.L., J.C. Eccles and E.G. McGeer, 1978, Molecular Neurobiology of the Mammalian Brain, Plenum Press, New York. Messiha, F.S., 1979, Taurine, analogues and ethanol elicited responses, Brain Res. Bull. 4, 603. Stewart, J.J., N.W. Weisbrodt and T. Burks, 1978, Central and peripheral actions of morphine on intestinal transit, J. Pharmacol. Exp. Ther. 205, 547. Wessberg, P., T. Hedner,.J. Hedner and J. Jonason, 1983, Effect of taurine antagonist on some respiratory and cardiovascular parameters, Life Sci. 33, 1649. Yamamoto, H., H.W. McCain, K. Izumi, S. Misawa and E.L. Way, 1981, Effects of amino acids, especially taurine and T-aminobutyric acid (GABA), on analgesic and calcium depletion induced by morphine in mice, European J. Pharmacol. 71, 177. Yarbrough, G.G., D.K. Singh and D.A. Taylor, 1981, Neuropharmacological characterization of a taurine antagonist, J. Pharmacol. Exp. Ther. 219, 604.
275
Short communication ACUTE E F F E C T S OF T A U R I N E AND A T A U R I N E A N T A G O N I S T O N E T H A N O L - I N D U C E D CENTRAL NERVOUS SYSTEM DEPRESSION LINDA MATTUCCI-SCHIAVONE and ANDREW P. FERKO *
Department of Pharmacology, Hahnemann University, Philadelphia, PA, U.S.A. Received 9 May 1985, accepted 15 May 1985
L. M A T T U C C I - S C H I A V O N E and A.P. F E R K O , Acute effects of taurine and a taurine antagonist on ethanol-induced central nervous system depression, European J. Pharmacol. 113 ( 1 9 8 5 ) 2 7 5 - 2 7 8 .
Sprague-Dawley rats received taurine intracerebroventricularly (i.c.v.) 30 min prior to ethanol (4 g/kg, i.p.). The duration of ethanol-induced sleep time was increased with taurine at doses of 7.5, 14.0 and 25.0/~mol/kg. In another experiment, TAG (a taurine antagonist, i.c.v.) was given 5 min prior to taurine (i.c.v.) and ethanol was administered 30 rain later. TAG antagonized the effect of taurine to enhance ethanol-induced sleep time. These results suggest an interaction between taurine and the depressant effect of ethanol in the brain. Taurine antagonist (TAG)
Sleep time
Taurine
1. Introduction Reports in the literature indicate that taurine decreases the hypnotic effect of ethanol (lida and Hikichi, 1976; Boggan et al., 1978). This reduction in the effect of ethanol occurs with simultaneous injection (i.p.) of ethanol and taurine, or with taurine administration (i.v.) at 5 and 30 min prior to ethanol (Iida and Hikichi, 1976). Boggan et al. (1978) also showed that taurine significantly reduced ethanol-induced sleep time (hypnosis) in animals after simultaneous administration (i.p.) of ethanol and taurine. These reports show that taurine does not produce any observable pharmacological effect by itself or alter blood ethanol levels. In addition, taurine does not antagonize the effect of ethanol on seizure susceptibility, body temperature or brain 5-hydroxyindole acetic acid concentration (Boggan et al., 1978). Another study (Messiha, 1979) however, indicates that taurine fails to attenuate the hypnotic
* To whom all correspondence should be addressed: Department of Pharmacology, Hahnemann University, Broad and Vine Streets, Philadelphia, PA 19102, U.S.A. 0014-2999/85/$03.30 © 1985 Elsevier Science Publishers B.V.
Ethanol
effect of ethanol when taurine is administered (i.p.) in a dose similar to that used in earlier work. The variation in the results obtained for the interaction of taurine and ethanol on sleep time may be related to differences in experimental design, animal species or other factors. One factor may be that taurine does not readily pass the blood-brain barrier in significant amounts after acute administration (McGeer et al., 1978). This study examined the effect of taurine on ethanol-induced sleep time. As passage of taurine into the brain is questionable taurine was administered by i.c.v, injection. A taurine antagonist, T A G (6-aminoethyl-3-methyl-4H-1,2,4-benzothiadiazine-l,l-dioxide hydrochloride) (Yarbrough et al., 1981) was also used in these experiments.
2. Materials and methods Male Sprague-Dawley rats (140-160 g) were obtained from Charles Rivers Laboratories, Inc. (Wilmington, MA) and were housed 6 to a cage at 2 2 + I ° C for 1 week prior to experimentation, with lights on from 6:00 a.m. to 6:00 p.m. The animals had free access to Purina Laboratory Chow
276 (Ralston Purina Co., St. Louis, MO) and water. They were fasted 18 h prior to drug or saline (0.9% NaCI) administration but water was available ad libitum. Ethanol solution (20% w / v ) for injection was prepared from 95% ethanol). Taurine was purchased from Fiuka Chemical Corp. (Haupage, NY). TAG, 6-aminomethyl-3-methyl-4H-1,2,4benzothiadiazine-l,l-dioxide hydrochloride, was a gift from Merck Sharp & Dohme Research Laboratories (Rahway, N J). The rats were anesthetized with an i.p. injection of ketamine (10 mg/kg) containing acepromazine. A craniotomy hole was made above the right ventricle at a point located 1 mm posterior to the frontoparietal suture and 1 mm from the midline. A polyethylene cannula, PE 10, was implanted through the hole and lowered to 4 mm below the skull to reach the ventricle and cemented in place (Stewart et al., 1978). Saline (10 /~1) was injected into the cannula and the top of the cannula was sealed with silicone adhesive. The scalp incision was closed with wound clips and the animals were allowed to recover for 3 days before the acute experiments. The same procedure was followed with control animals. The correct position of the cannula was verified at autopsy by using trypan blue dye. All i.c.v, injections were made in the conscious rat except where noted. Taurine and TAG were dissolved in saline shortly before the experiment and adjusted to pH 7.0. The concentrations of taurine and TAG in solution were varied according to the dose administered in order to inject a constant volume (10 #1) into the ventricle. Each drug injection was followed by saline (10 #1). Control animals received a total volume of 20 ~1 of saline. In the experiments requiring i.c.v, injection of two drugs (TAG and taurine), the volume of drug solution and of saline was reduced to 6 ~1 each.
loss of the righting reflex after ethanol injection and the return of the fighting reflex. Return of the righting reflex required that the animal be able to re-right itself within one min after again being placed on its back. A blood sample (20 #1) was taken from the orbital sinus of each animal when they regained the righting reflex. Ethanol content was measured by the enzymatic method ol Lundquist (1959). Since the duration of action ot taurine is less than the mean sleep time following ethanol (4 g/kg) administration (Martin et ai., 1981), a second injection of taurine was given 120 min into the sleep time. Control animals were handled identically but saline was administered instead of taurine. The next experiment was designed to find if T A G administration could alter ethanol-induced sleep time. TAG was injected in a dose of 0.075 or 0.15 #moi/kg, i.c.v., 5 min prior to ethanol (4 g/kg, i.p.). Due to the short duration of action of TAG (Wessberg et al., 1983), a second injection was made at 120 rain or at the end of the sleep time if this was less than 120 min. The final experiment involved TAG and the potentiation of ethanol-induced sleep time by i.c.v. injection of taurine. TAG (0.15 /tmol/kg, i.c.v.) was given 5 rain prior to taurine (14 /~mol/kg, i.c.v.), and ethanol was administered (4 g/kg, i.p.) 30 min later. The same procedure for injection of TAG and taurine was repeated at 120 min into the sleep time.
2.1. Ethanol-induced hypnosis (sleep time)
3. Results
Taurine was administered in a dose of 2.5, 7.5, 14 or 25 #mol/kg, i.c.v., 30 min prior to ethanol (4 g/kg, i.p.). Sleep time was used as an index of ethanol-induced central nervous system depression and was measured as the time interval between the
When various doses of exogenous taurine were administered by i.c.v, injection, the duration of ethanol-induced sleep time was increased significantly (table 1). The highest dose of taurine (25 # m o l / k g , i.c.v.) increased sleep time by 141%. No
2.2. Statistical analysis Significant differences were determined by analysis of variance (ANOVA). All multiple comparisons with a control were done by ANOVA followed by Scheffe's test. All data were analyzed using an Apple lie Computer.
277 TABLE 1 Effect of taurine on ethanol-induced sleep time. Taurine was administered (,umol/kg, i.c.v.) 30 min prior to ethanol (ETOH, 4 g/kg, i.p.). Values are means _+S.E.M. Treatment
N
Saline+ETOH(controls) 10 Taurine (2.5) + ETOH 5 Taurine (7.5)+ ETOH 6 Taurine (14.0)+ ETOH 5 Taurine(25.0)+ETOH 6
Sleep time (min)
Blood ETOH (mg/ml)
145.2+15.7 156.8 + 34.9 239.5 ± 20.5 * 244.8±14.6" 350.5_+ 12.5 **
3.16___0.07 3.22 + 0.18 2.90±0.09 2.69_+0.14" 2.30+0.10 **
Significantly different from controls: * P < 0.05, ** P < 0.01.
hypnosis was produced in control animals that received the maximum dose of taurine (25 # m o l / k g , i.c.v.). Analysis of blood ethanol concentrations at the end of the sleep time showed a corresponding decrease for each group as the length of sleep time increased. The next experiment investigated the effect of T A G (i.c.v.) on ethanol-induced sleep time. When two doses of TAG (0.075 or 0.15/~mol/kg, i.c.v.) were administered 5 min prior to ethanol (4 g/kg, i.p.), the duration of sleep time was reduced, but was not significantly different from that of the controls (data not shown). In control animals, TAG (0.15 # m o l / k g , i.c.v.) caused no visible alteration in behavior when it was given 5 min prior to saline (0.02 ml/g, i.p.). The results of the final experiment in this study (table 2) showed that TAG reduced the effect of taurine to prolong ethanol-induced sleep time. When TAG and taurine were both given prior to TABLE 2 Effect of TAG on the potentiation of ethanol-induced sleep time by taurine. TAG (0.15 ~tmol/kg, i.c.v.) was administered 5 rain prior to taurine (14 /~mol/kg, i.c.v.). Ethanol (ETOH, 4 g/kg, i.p.) was given 30 min after taurine. Values are means + S.E.M. Treatment
N
Saline + ETOH (controls) 10 Taurine + ETOH 5 TAG+taurine+ETOH 5
Sleep time (min)
Blood ETOH (mg/ml)
145.7 ± 14.6 244.8 ± 14.6 * 171.6:1:12.6"*
3.26 ± 0.11 2.68 ± 0.14 * 3.11+0.08"*
Significantly different from controls: * P < 0.05. Significantly different from group treated with taurine and ethanol: ** P < 0.05.
ethanol, the sleep time and blood ethanol concentrations were similar to values obtained from control animals.
4. Discussion
Taurine, a sulfur-containing amino acid, is found in brain tissue in high concentrations and is widely but unevenly distributed. This amino acid has a depressant effect in the central nervous system, suppressing neuronal activity in the spinal cord and brain (Curtis et al., 1968). The present results indicate that taurine (i.c.v.) can enhance the central depressant effect of ethanol. In addition, TAG attenuated the potentiating effect of taurine on ethanol-induced sleep time. Yarbrough et al. (1981) have reported that TAG was a selective taurine antagonist in their neuropharmacoiogical studies. Martin et al. (1981) have demonstrated that TAG blocks contraversive turning caused by taurine. Their other results show a lack of effect with TAG in a number of radioligand binding assays and that only [3H]taurine binding was affected by TAG. More recent work also supports the hypothesis that TAG is a selective antagonist of taurine in the rat brain (Wessberg et al., 1983). It has been suggested that taurine may subserve a neurotransmitter-type function in the central nervous system (Yarbrough et al., 1981). Taurine has been implicated in the effects of other drugs, particularly the narcotic analgesic agents. Taurine can induce a hyperalgesic state and antagonize the analgesic action of morphine in mice (Contreras and Tamayo, 1984; Yamamoto et al., 1981). Taurine partially reduces the development of tolerance to morphine and decreases the incidence of some abstinence signs (Contreras and Tamayo, 1984). It has been suggested that the hyperalgesic state which is produced by taurine may be due to antagonism of endogenous opioid peptides. The proposed mechanism for the blockade of morphine analgesia by taurine appears to be related to intracellular calcium events (Yamamoto et al., 1981; Contreras and Tomayo, 1984). At the'present time there seems to be no clear relationship between the mechanisms suggested for the combined effects of taurine and morphine and the results obtained in this work with taurine and
278 ethanol. Further experiments are requirued to und e r s t a n d m o r e fully t h e n e u r o a c t i v e r o l e o f t a u r i n e in central nervous system depression. This work may be facilitated by the use of TAG or other future specific taurine antagonists.
Acknowledgements We thank Linda Bush and Colleen Graham for typing the manuscript. This work was partly supported by a National Science Foundation Graduate Fellowship for Linda MattucciSchiavone.
References Boggan, W.O., C. Medberry and D.H. Hopkins, 1978, Effects of taurine on some pharmacological properties of ethanol, Pharmacol. Biochem. Behav. 9, 469. Contreras, E. and L. Tamayo, 1984, Effects of taurine on tolerance to and dependence on morphine in mice, Arch. Int. Pharmacodyn. 267, 224. Curtis, D.R., L. Hosli and G.A.R. Johnston, 1968, A pharmacological study of the depression of spinal neurons by glycine and related amino acids, Exp. Brain Res. 6, 1.
lida, S. and M. Hikichi, 1976, Effect of taurine on ethanol-induced sleeping time in mice, J. Study Alcohol, 37, 19. Lundquist, F., 1959, The determination of ethyl alcohol in blood and tissue, Methods Biochem. Anal. 1,217. Martin, G.E., R.J. Benedsky and M. Williams, 1981, Further evidence for selective antagonism of taurine by 6aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine- 1,1 -dioxide, Brain Res. 299, 530. McGeer, P.L., J.C. Eccles and E.G. McGeer, 1978, Molecular Neurobiology of the Mammalian Brain, Plenum Press, New York. Messiha, F.S., 1979, Taurine, analogues and ethanol elicited responses, Brain Res. Bull. 4, 603. Stewart, J.J., N.W. Weisbrodt and T. Burks, 1978, Central and peripheral actions of morphine on intestinal transit, J. Pharmacol. Exp. Ther. 205, 547. Wessberg, P., T. Hedner,.J. Hedner and J. Jonason, 1983, Effect of taurine antagonist on some respiratory and cardiovascular parameters, Life Sci. 33, 1649. Yamamoto, H., H.W. McCain, K. Izumi, S. Misawa and E.L. Way, 1981, Effects of amino acids, especially taurine and T-aminobutyric acid (GABA), on analgesic and calcium depletion induced by morphine in mice, European J. Pharmacol. 71, 177. Yarbrough, G.G., D.K. Singh and D.A. Taylor, 1981, Neuropharmacological characterization of a taurine antagonist, J. Pharmacol. Exp. Ther. 219, 604.