Psychopharmacology49, 249-252 (1976)

Psycho phhrmacology
9 by Springer-Verlag1976

Oral Taurine Effects on Inhibitory Behavior" Response Transients to Step-Like Schedule Changes
M I C H A E L A. P E R S I N G E R , G Y S L A I N E F. LAFRENIt~RE, and H E R M A N F A L T E R PsychochemistryLaboratory, Departments of Psychologyand Chemistry, Laurentian University, Sudbury, Ontario, Canada

Abstract. Rats habituated to D R L 6-s schedules that required response inhibition in order to obtain reward did not alter their total responses or efficiency ratios (response/reinforcement) when placed ad libitum (orally) on 0.9 % taurine (1.1 ___ 0.4 g/kg/24-h) relative to controls. In three separate experiments, taurineadministered rats did show significantly poorer adjustment profiles (higher response/reinforcement ratios) during the 15 min immediately following steplike increases in inhibition time demand to D R L 12 s. The effect was transient and was not significant in subsequent sessions. Taurine rats had been habituated to a D R L schedule intended to induce 'frustration' before the step-change did not differ from the taurine group maintained on the normal D R L schedule. No significant differences were noted between taurine and control groups, either before or after taurine administration or before or after the step-change in inhibition demand, with respect to defecation in the test chamber, daily fluid consumption, body weight or total responses. We concluded that oral taurine may inhibit learning during labile periods of adjustment following sudden changes of input demand but does not influence a well learned or established response pattern. These results imply taurine's role in the brain as a 'stabilizer' against short-term input fluctuations. Key words." Response inhibition - Taurine - D R L schedule - Rat - Response transients - Defecation - Frustration - Temporal discrimination - Sudden reinforcement schedule changes.

Taurine has been suggested by several authors (e.g., Davidson and Kaczamarek, 1971) as an inhibitory transmitter or modulator candidate i n the central

nervous system. In general, taurine administration has been reported to inhibit behavioral (Baskin et al., 1974; Persinger et al., 1976) and neuroelectrical (Van Gelder, 1972; Mut~ni et al., 1974) processes. We decided to evaluate the effect of oral taurine (at a concentration that did not alter normal fluid intake) upon a complex behavior requiring response inhibition and learning. Although very high doses (21 mmole/kg) injected intraperitoneally (i.p.) have been associated with decreases in fixed-ratio responding (Thut et al., 1976), such behavioral changes may only reflect reactions to acute chemical concentrations since similar response patterns were produced by high concentrations of other substances. If taurine is an inhibitor substance, then one might expect, simplistically, a facilitation of response inhibition. However, we suspected that the reported efficacy of taurine as an inhibitor of behavioral or neuroelectrical processes may be based on its propensity to retard labile CNS changes in the process of acquisition or consolidation. F r o m this point of view, taurine would be a CNS 'stabilizer' against shortterm input fluctuations. Newly acquired behaviors or recent deviations from neuroelectrical homeostasis would be significantly affected by taurine administration, older behaviors would not be influenced as much. The implication of this statement is most provocative with respect to taurine's therapeutic use: whereas recent CNS changes may be inhibited, undesirable and well established behaviors or congenital abnormalities may not be correspondingly inhibited by taurine treatments. To test this hypothesis, we exposed rats to a behavioral situation that required well learned inhibitory response sequences as well as adjustment to new patterns of inhibition. The task selected was a D R L (differential reinforcement of low rate of responding) schedule, wherein a subject must postpone responding for a required interval of time in order to receive

250 a reward. A l t h o u g h s t e a d y - s t a t e r e s p o n s e p a t t e r n s t y p i c a l l y are a c q u i r e d over time for this schedule, t r a n s i e n t r e s p o n s e p h e n o m e n a can be e v o k e d w h e n s u d d e n c h a n g e s in the i n h i b i t i o n t i m e are instituted. Such s h o r t - t e r m r e s p o n s e p a t t e r n s can differentiate subject p o p u l a t i o n s t h a t m o r e static schedule p r o c e dures c a n n o t ( H a l a s z et al., 1970; Persinger et al., 1974). W e suspected t h a t t a u r i n e a d m i n i s t r a t i o n w o u l d n o t influence well l e a r n e d responses to static schedules, b u t w o u l d exhibit s h o r t - t e r m effects d u r i n g t r a n s i e n t p e r i o d s o f a d j u s t m e n t to n e w i n h i b i t o r y demands. H o w e v e r , if rats receiving t a u r i n e were to d i s p l a y less i n h i b i t o r y r e s p o n d i n g o n l y d u r i n g the s h o r t p e r i o d following a schedule change, then a r g u m e n t s c o u l d be p o s i t e d t h a t t a u r i n e facilitates ' f r u s t r a t i o n ' or e m o t i o n a l r e s p o n d i n g to these extinction-like p r o c e d u r e s . Such a p o s s i b i l i t y is n o t i m p r o b a b l e in view o f the e x t r a o r d i n a r i l y high c o n c e n t r a t i o n s o f t a u r i n e n e u r o hypophysis and possibly ventral hypothalamus (Guid o t t i et al., 1972; C r a b a i et al., 1974). O n the o t h e r h a n d , if t a u r i n e a n i m a l s were e x p o s e d to a schedule t h a t was similar to the schedule a s s o c i a t e d with the s u d d e n change, t h e y s h o u l d show less failures o f inh i b i t i o n due to ~ factors d u r i n g this period. This stimulus o p e r a t i o n , in a d d i t i o n to the u s u a l m e a s u r e m e n t o f e m o t i o n a l b e h a v i o r , i.e., defecation, was i n c l u d e d in the p r e s e n t e x p e r i m e n t a l design. O r a l a d m i n i s t r a t i o n o f t a u r i n e was used since, u n l i k e o t h e r m o d e s , e.g., i.p. injections, less stress a n d h a n d l i n g artifacts c o n f o u n d the design. P a s s a g e o f t a u r i n e into the a d u l t m a m m a l i a n b r a i n has been d e s c r i b e d for this r o u t e ( U r q u h a r t et al., 1974), a n d m o s t i m p o r t a n t , it w o u l d be the m o s t likely r o u t e o f a d m i n i s t r a t i o n for h u m a n t r e a t m e n t . In a d d i t i o n , unpublished data from our laboratory (Falter and Persinger, 1975) indicate significantly elevated foreb r a i n a n d c e r e b e l l u m t a u r i n e levels ( + 11 G a n d + 18 ~ , respectively) in rats m a i n t a i n e d for 30 d a y s on 0.9 ~ t a u r i n e solutions d u r i n g D R L training.

Psychopharmacology 49 (1976) the subject had to postpone lever responding at least 6 s in order to receive a 35 mg Noyes food pellet reward. If the time elapsed since the last reward was less than 6 s when the next lever press occurred, then the next reward availability was postponed another 6 s. This schedule was maintained by automatic programming equipment for the 2 test chambers used. However one of the chambers was so constructed that 1 out of every 3 pellets (an empirical average) did not fall into the delivery through but fell out of the subject's reach beneath the grid floor. This was called the 'frustration' DRL schedule. Four of the subjects for each experiment were tested in this chamber. In all 3 experiments, subjects were maintained on the DRL 6-s schedule for 24 to 26 consecutive daily 30-min sessions until stable baselines were attained for daily total ratios of response (R)/total reinforcement (S+), i.e., R/S + ratios. A stable baseline was defined as not more than 10 ~ variation over a 5-day period for R/S ratios between 2 and 3. Four of the animals in each experiment (2 for each test chamber) were then given 0.9 ~ (0.07 M) taurine solutions in their graduated (ml) drinking cylinders. Pilot data indicated that this concentration did not significantly alter fluid consumption, a potentially important confounding variable in food reward operant studies. With this concentration of taurine, the average rat was expected to consume about lg/kg/24 h of taurine. The other subjects received the vehicle (tap water). The amount of either taurine solution or water consumed every day was measured just before the daily test session. Taurine and water were changed daily. After 7 days of taurine or water treatment, on what was called the 'step day', the schedule was suddenly changed half-way through the normal session from a DRL 6-s to a DRL 12-s schedule for the remaining 15 min, for each rat. The number of responses and reinforcements displayed before and after the 'step-change' in required inhibition time was recorded. During the later 10 to 14 daily sessions, the schedule remained at DRL 12 s. Subjects were always tested in the same chambers, in the same order and between 09: 00 and 13:00. Post-sessional measurements of defecation in the chamber were taken for each rat. All analyses were completed by an IBM 360-40 computer and checked by hand calculations.

RESULTS F o r analysis p u r p o s e s , the subjects were d i v i d e d into 4 g r o u p s (6 r a t s / g r o u p ) ' t a u r i n e - n o r m a l D R L schedule (TN), t a u r i n e - ' f r u s t r a t i o n a l ' D R L schedule (TF), c o n t r o l - n o r m a l D R L schedule (CN), a n d c o n t r o l ' f r u s t r a t i o n a l ' D R L schedule (CF). T h e m e a n R / S + ratios a n d their s t a n d a r d d e v i a t i o n s for the T N , T F , C N , a n d C F g r o u p s for the 5 d a y s b e f o r e a n d 5 days after t a u r i n e (or water) a d m i n i s t r a t i o n are s h o w n in F i g u r e 1. A 2-way analysis o f v a r i a n c e ( A N O V A ) i n d i c a t e d no statistically significant differences between schedules o r t r e a t m e n t s ( F < 1, d f = 1/20). T h e m e a n changes in ratios a n d their s t a n d a r d deviations, c a l c u l a t e d by d i v i d i n g the m e a n R / S + r a t i o s for each subject after the t a u r i n e or w a t e r t r e a t m e n t b y the m e a n R / S + ratios before the t r e a t m e n t for the T N , T F , C N , a n d C F g r o u p s , were 0.90 _+ 0.09, 0.97 + 0.16, 0.81 _ 0.25, 0.98 + 0.12, respectively. H o w e v e r a 2-way analysis o f v a r i a n c e ( A N O V A ) i n d i c a t e d no statistically significant differences between t r e a t m e n t s ( F < 1) n o r schedules ( F = 3.02;

METHOD In three separate experiments, 24 male Wistar strain rats (Rattus norvegicus), 100, 150, or 230 days of age when selected were used as subjects (8 rats/experiment). Experiments I, II, and III began in June, September, and December, 1974, respectively. Before testing, subjects had been maintained in single cages and gradually reduced to 80 ~ free-feed body weight over a 21-day period. Subjects in Experiments I and III were maintained at this weight for the remainder of the study; weights of subjects in Experiment It were adjusted for growth. Following three days of continuous reinforcement training in single-lever Lafayette operant chambers (housed in ventilated masking noise .boxes), the reinforcement schedule was changed to a DRL 6-s program. In this situation,

M. A, Persinger et al. : Operant Response Inhibition and Oral Taurine in Rats

251

18 16 14 12 I0 + 8 6 4 2

A
9 Taurine ~ n= 6 O Control n=6

18 16 14 12 I0 8 6

B
9 Taurine O Control n=6 n=6

4
2

BASELINE

JSESSIONS

POSTSTEP

Fig. 1. Mean total response/total reinforcement ratios (R/S +) from the separate experiments for rats that were maintained on taurine or water orally during: pre-step DRL 6 s baseline sessions, the sudden mid-session step (.s-) from DR/_, 6 s to DRL :12 s, and post-step (DRL 12 s) sessions. Animals in A (TN, CN) had been exposed to normal DRL 6-s schedules while those in B (TF, CF) had been exposed to DRL 6-s schedules intended to induce 'frustration'. Vertical bars indicate standard deviations

d f = 1/20; P < 0.10). A 3-way ANOVA with one

measure repeated for total responses emitted before and after treatment application showed no significant differences on any factor. Defecation in the chamber before and after (+ 5 days) taurine or water administration also was found by 3-way ANOVA not to be significant at any level of analysis. Ratios of daily water consumption for the 5 days before and after treatment for the TN, TF, CN, and CF groups were 1.09 __ 0.17, 1.13 0.15, 1.12 _+ 0.27, and 1.01 0.05. These differences were not significant. Since the rats drank 2 5 - 5 0 ml of fluid/day, calculations demonstrated the taurine subjects were consuming 1.1 0.4 g of taurine/kg of body weight/24 h. The means and S.D.s for the R/S + ratios for different groups before and during the 15 rain after the

sudden schedule change ( 5 ) on the single step session and for post-step sessions are shown also in Figure 1. A 2-way ANOVA indicated only a significant treatment effect (F = 7.23 ; df = 1/20, P < 0.01 ; however, the homogeneity of variance test was significant (P < 0.01). Group variance tests indicated significant differences between the TN and TF groups (F = 12.48, df = 6/6, P < 0,01), and between the CN and CF groups (F = 176.80, df = 6/6, P < 0.001), but not between the TN and CN or TF and CF groups. The 12 frustration condition rats had significantly greater (F = 35.48, df= 12/12, P < 0.001) group variance than the 12 normal condition rats. When comparisons were made only between the control and taurine groups (with homogeneity of variance) tested in the normal D R L schedule, more significant differences were noted (t = 11.05; df= 1/10, P < 0.01). Nonparametric analysis also showed that the 12 taurine drinking rats were significantly different from the 12 control rats 0~2 = 9.86, df = J, P < 0.01) on this measure. A 3-way ANOVA for experiments (3), conditions (2), and chambres (2) also indicated that only the taurine and control differences were statistically significant ( F = 5.98, df= 1/12; P < 0.05). The mean post-step R/S + ratios between groups were not significant (F < l). Means and S.D.s for the number of fecal boluses left in the chambers on the step day for the above groups were 1.7 2.8, 0.0, 0.3 + 0.5, and 1.0 _+ 1.6, respectively (F < 1). Although there was a significant increase in defecation during the 5 days after the step relative to the 5-day baseline (F = 30.35; df= 1/20; P < 0.001), there were neither treatment or schedule differences (F < 1). There was a decrease in fluid consumption for all groups after the step change; the ratios of fluid consumed after with respect to before the step for the TN, TF, CN, and CF groups were 0.98 ___ 0.11, 0.96 _+ 0.22, 0.88 + 0.25, and 0.97 _+ 0.16 (F < 1). Pre/post-step ( 5 days) body weight losses for the 4 groups were 0.97, 0.96, 0.98, and 0.96 of the 80% body weight.

DISCUSSION The results of three replications indicated that well established or habituated response modes ostensibly involving inhibitory processes were not readily influenced by ingestion of 0.9 ~o taurine for more than one week. The fact that improvement of inhibition was still possible was indicated by the decreasing response/reinforcement ratios for all groups during baseline sessions. Instead, the major taurine effect occurred immediately following the change in response demand,

252 when the rats were a t t e m p t i n g to a d j u s t to the new l e a r n i n g scheduIe. R a t s m a i n t a i n e d on a n o r m a l D R L 6 s schedule while receiving t a u r i n e d i s p l a y e d signific a n t l y poorer a d j u s t m e n t i m m e d i a t e l y following the step-like c h a n g e to D R L 1 2 s , relative to c o n t r o l s ; however, this effect was t r a n s i e n t a n d n o t e v i d e n t in p o s t - s t e p sessions. Such an effect s u p p o r t s the thesis o f t a u r i n e acting as a ' s t a b i l i z e r ' a g a i n s t s h o r t - t e r m (relative to the r e s p o n s e system) i n p u t fluctuations. This effect is interesting in light o f t a u r i n e ' s likely affinity for c a l c i u m ions, which have a p r o p e n s i t y to r e t a r d a c q u i s i t i o n (John, 1967): It is u n l i k e l y t h a t the results were artifacts o f w a t e r c o n s u m p t i o n , b o d y weight, o r t o t a l lever r e s p o n d i n g since the g r o u p s d i d n o t differ significantly on these measures. T h e c o n f o u n d i n g effects o f ' e m o t i o n a l ' o r ' f r u s t r a t i o n ' b e h a v i o r following s u d d e n decreases in r e i n f o r c e m e n t r a t i o s d o n o t seem likely since t a u r i n e subjects d i d n o t d i s p l a y greater c h a m b e r defecation, a l t h o u g h a n y w e a k effect m a y have been m a s k e d b y the highly significant p o s t - s t e p increases in this m e a s u r e for all groups. R e i n f o r c e m e n t histories int e n d e d to i n d u c e ' f r u s t r a t i o n ' were a s s o c i a t e d with such large increases in g r o u p response v a r i a b i l i t y t h a t the role o f this f a c t o r in the t a u r i n e effect is still n o t clear.

Psychopharmacology 49 (1976) Crabai, F., Sitzia, A., Pepeu, G.: Taurine concentration in the neurohypophysis of different animaI species. J. Neurochem. 23, 1091 - 1092 (1974) Davidson, A. N., Kaczamarek, L. K. : Taurme-a possible neurotransmitter? Nature (Lond.) 234, 107-108 (1971) Van Gelder, N. M.: Antagonism by ta~rine of cobalt induced epilepsy in cat and mouse. Brain Res. 47, 157-165 (1972) Guidotti, A., Badiani, G., Pepeu, G. : Taurine distribution in cat brain. J. Neurochem. 19, 431-435 (1972) Halasz, M. F., Hughes, K. R., Humpherys, D. R., Persinger, M. A. : Radiogenic cerebellar malformation : elicitation of behavioural transients to unmask compensated deficits of operant learning in rats. Amer. Zool. 10, 33 (1970) John, E. R. : Mechanisms of memory. New York: Academic Press 1967 Mutani, R., Bergamini, L., Fariello, R., Delsedime, M. : Effects of taurine on cortical acute epileptic foci. Brain Res. 70, 170173 (1974) Peck, E. J., Awapara, J. : Formation of taurme and isethionic acid in the rat brain. Biochim. biophys. Acta (Amst.) 141, 499- 506 (1967) Persinger, M.A., Lafreni~re, G.F., Ossenkopp, K.P.: Behavioural, physiological, and histological changes in rats exposed during various developmental stages to ELF magnetic fields. In : ELF and VLF electromagnetic field effects, M. A. Persinger, ed., pp, 177-226. New York: Plenum 1974 Persinger, M. A., Valliant, P. M., Falter, H. : Weak inhibitory behavioural effects of postnatal-preweaning taurine injections in rats. Develop. Psychobiot. 9, 131-136 (1976) Thut, P. D., Hruska, R. E., Huxtable, R., Bressler, R.: Effect of taurine on eating and drinking behaviour. In: Taurine, R. Huxtable and A. Barbeau, eds., pp. 357-364. New York: Ravin 1976 Urquhart, N., Perry, T. L., Hansen, S., Kennedy, J.: Passage of taurine into the adult mammalian brain J. Neurochem. 22, 871 - 872 (1974) Received September 2, 1975; Final Version May 21, 1976

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