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Absence of lithium-induced taste aversion after area postrema lesion
Brain Research, 201 (1980) 501-506 © Elsevier/North-Holland Blomedlcal Press
501
Absence of lithium-induced taste aversion after area postrema lesion
SUE RITTER, JOHN J. McGLONE* and KEITH W. KELLEY** Department of Veterinary and Comparative Anatomy, Pharmacology and Phystology, and (J. J. McG. and K. W. K.) Animal Scwnce Department, Washington State University, Pullman, Wash. 99164 (U.S.A.)
(Accepted July 17th, 1980) Key words: area postrema - - conditioned taste aversion - - lithium chloride - - scopolamine methyl
nitrate
-
-
D-amphetamine
Anatomical and physiological evidence indicates that the area postrema (AP) lacks a blood-brain barrier6, la and is thus permeable to blood-born substances which do not penetrate most other areas of the brain. The classical experiments of Borison (refs. 5, 7) demonstrated that the AP region contains chemoreceptors which stimulate vomiting in some species in response to certain drugs. This finding suggests that one function of the AP is to detect ingested toxins and trigger their expulsion from the gastrointestinal tract. In addition to producing vomiting, some toxic substances, which are encountered by animals in association with novel foods, may result in formation of learned responses known as conditioned taste aversions (CTAs)3A 1. These learned responses decrease the probability that animals will subsequently ingest particular foods which were previously associated with toxic effects. Berger et al. 4 were the first to demonstrate that the AP plays a critical role in the formation of CTA by some chemical substances. Taste aversions formed by scopolamine methyl nitrate (SMN), a neuroactive substance which does not cross the blood-brain barrier, were shown to be mediated by the AP. On the other hand, the CTA formed by D-amphetamine, a drug which readily penetrates the blood-brain barrier, does not require an intact AP. On the basis of these data, it appears that more than one mechanism may exist for the formation of CTAs. Moreover, these results provide evidence of an important role for the AP region in behavioral, as well as in gastrointestinal, functions. Lithium chloride (LiCI) is a compound which is widely used in C T A studles2,~2, t3. However, the mechanism by which LiCI induces CTAs ts not known. The * Present address: Animal Science Department, Mumford Hall, University of Illinois, Urbana, I11. 61801, U.S.A. ** To whom reprint requests should be addressed.
502 effectiveness of this drug as a conditioning agent may be due to its well-known ability to produce nausea and vomiting TM. If so, then L1CI may produce these effects by its action on the AP. On the other hand, action of LIC1 on the AP may not be critical for its effectiveness as a conditioning agent. Lithium has widespread effects on peripheral tissues and, in addition, is known to penetrate the blood-brain barrierg, 16. The present experiment was undertaken to determine whether the ability of LiC1 to produce CTA is mediated specifically by an action on the AP or whether the generahzed toxicity of this substancO 7,18 is sufficient to mediate the formation of a CTA m the absence of the AP. In our experiments, we lesioned the AP in adult male and female Sprague-Dawley rats. The AP region was exposed by slight enlargement of the foramen magnum and the AP was destroyed by briefly touching this structure with a triangular thermal probe (0.75 m m per side) z°. In some rats, the AP region was exposed, but no lesion was made. These animals served as sham-operated controls (shams) Both male and female lesioned rats lost more weight than shams immediately after surgery and maintained lower body weights than shams throughout the entire experiment. All rats were gaining weight at approximately the same rate, however, at the time experimental treatments were initiated. After recovery from surgery, lesioned and sham-operated rats were trained to drink from a 40 ml calibrated drinking tube. To facilitate training, a palatable solution consisting of Borden's sweetened condensed milk diluted 1.3 with water was presented m the calibrated tubes for 30 min on 4 occasions over an 8 day period. Milk consumption was recorded in each of the 4 training sessions. It is interesting to note that APlesioned rats consistently drank more of the sweetened solutions than shams. For example, the average intake of sweetened condensed milk across the 4 traimng sessions was 21.2 ~z 1.1 ml for AP-lesioned male rats but only 10.8 ~: 0.7 ml for sham-operated males (P < 0.001, bl-directional t-test). Likewise, AP-lesioned females drank an average of 14.3 ~ 1.3 ml during training, whereas shams drank only 7.3 ~_ 1.0 ml (P < 0.01). Enhanced intakes of the palatable novel solutions by lesioned rats during the CTA experiments were also observed (e.g. compare day 1 intakes of shams and lesioned rats in Table 1). In our first experiment we attempted to replicate the findings of Berger et al. that AP lesions abolish the conditioning of taste aversions by SMN but do not impair the conditioning of taste aversions by amphetamine 4. Six AP-lesloned and 8 sham-operated male rats were used in this experiment. Following training, the effects of D-amphetamine sulfate and SMN on taste aversion learning were evaluated m two CTA tests. On the conditioning day of each test (day 1), the ammals were presented with a novel flavored solution of Carnation Instant Breakfast (35.2 g strawberry or chocolate instant Breakfast in 232 nd water) for 30 mln. lmmedmtely after the 30 rain drinking period, all rats that drank more than 3.0 ml of the novel solution were given an l.p. injection of D-amphetamine sulfate(2 mg/kg) or SMN (l mg/kg). Seventy-two hours later (day 3), these same rats were tested for CTA in a 30 min drinking test during which they received a solution of the same flavor as they received on day 1. The conditioning-testing sequence was repeated so that all rats were tested with both drugs. At least one week was allowed to elapse between tests.
503 TABLE I
Change in consumptton of novel solutions by areapostrema-lesioned ( APX) and sham-operated (SHAM) rats followmg drug administration (D-amphetamine or scopolamme methyl mtrate) after the day 1 drinking bout Day 1 (ml ± S.E.M.) D-Amphetamine APX SHAM Scopolamine APX SHAM
23.7 (n 11 6 (n
± = ~ =
1.2 6) 1.8 7)
20.6 ~ 1.7 (n = 6) 7.8 zk 1.0 (n = 8)
Day 3 (ml)
% Day 1
A Intake (ml)
7 7 zk 2.2*
32~
--16.0 ± 2.4
3.1 ± 1 3*
27~
--8.5 ± 2.2
107~
+3.0 ± 1.1
OH
--7.7 ± 1.0
22.1 i 2 8 O*
* P < 0.001, day 3 vs day 1, bi-d~rectlonal t-test.
Results of experiment 1, shown in Table 1, comfirm the findings of Berger et al. 4. Injections of SMN following day 1 exposure to the novel flavored solution abolished day 3 consumption in shams but did not diminish day 3 consumption in AP-lesioned rats. In contrast, amphetamine produced CTAs in both AP-lesioned and sham-operated rats. In our second experiment, we extended these fndings by testing the effects of AP lesion on CTAs induced by LiCI. Eight AP-lesioned and 9 sham-operated female rats were used in this experiment. After recovery from surgery, all rats were tested for CTA, as described, after i.p. injections of LiCI (125 mg/kg, 1.5 mEq/ml), SMN(I mg/kg) and saline (0.15 M). The sequence of drug administration was counterbalanced across the 3 tests. The order of flavor presentation was chocolate, strawberry, and eggnog. The presence of a CTA was determined by subtracting the day 1 from the day 3 consumption. Analysis of variance was performed on the change in consumption. The effects of flavor, body weight and day 1 consumption were removed by analysis of covariance. Thus, there was a 2 x 3 factorial arrangement of treatments with two surgical procedures (AP lesion and sham) and 3 drug treatments (LiCI, SMN, and saline). The results of experiment 2 (shown in Fig. 1) reveal that lesion of the AP prevented formation of the CTAs otherwise produced by SMN and LiC1. This was reflected by a significant surgical procedure by drug interaction (P < 0.05). There were no significant differences among any of the 3 drug treatments in the AP-lesioned group. On the other hand, both of these drugs caused significant depression of drinking on the test day in shams. At the conclusion of experimentation, male and female rats were anesthetized with Chloropent and perfused with 10 ~ formalin. Brains were embedded in paraffin and 7/~m sections were treated with Kluver-Barrera stain. The AP and surrounding
504
~,= +Io 1
z~ +8] --Oz i-o --
-~ ...I ~oO zoo
+6
8~
-a.
_>
-4-
~ o,~ ,o >-
T
-I-4
0.
T
T
-6. -8-
]
-I0-
I
N:7[ [N:S, APX
SHAM
SALINE
N=7 APX
SHAM
SCOPOLAMINE
APX
SHAM
LITHIUM
Fig 1. Change m consumption of novel solutions by area postrema-lesJoned (APX) and sham-operated (SHAM) rats following drug administration (saline, LiCl, scopolamine methyl mtrate) after the day 1 drinking period. Animals that did not drink at least 3 ml on day 1 were ehmmated from that particular test. The N md~cated for each CTA test reflects the number of ammals that were tested w~th each drug. Lines above bars indicate standard error of means.
region were examined for damage. Histological analysis revealed that the AP was completely ablated in all lesioned rats. Surrounding tissue was also damaged in a few animals. Our results demonstrate that AP lesion abolishes the conditioning of taste averslons by LiCI and SMN, but does not influence the conditioning of amphetamine-induced taste aversions. This result has several important implications. Firstly, the presence of a CTA in AP-lesioned rats after amphetamine indicates that the lesioned rats are capable of learning a taste aversion and rules out the likelihood that taste aversion deficits after SMN and LIC1 in these rats are due to generalized behavioral or sensory disruption. Secondly, the fact that AP lesions abolish aversions to LiC1 and SMN, but not to amphetamine, supports previous findings which suggest that stimuli for conditioned aversions are received by more than one neural system 1,4. One interpretation of the results reported by Berger et al. 4 is that those substances, for example SMN, which produce CTA by activation of AP receptors are substances which do not cross the blood-brain barrier and that substances like amphetamine, which readily penetrate the brain, may act on systems which are independent of the AP. The observation that LiCI induces CTA by action on the AP is interesting with respect to this hypothesis since L1C1, unlike SMN, is known to cross the blood-brain barrier. This finding indicates that the AP and its neural connections may mediate the formation of CTA to some substances irrespective of their penetration into the brain. However, since LiC1 is known to clear rapidly from plasma and equilibrate slowly across the blood-brain barrlerg, 16, it is possible that the high blood level of lithium rapidly achieved after administration of this drug may be the effective stimulus for AP involvement in lithmm-induced CTA. Further experimentation wdl be required to determine whether hthlum-lnduced CTA is mediated by AP receptors on the blood side or on the brain side of the blood-brain barrier.
505 During the course of this study, two important observations were made regarding the effect of the AP on food intake and body weight. Firstly, AP-lesioned rats rapidly lost weight subsequent to surgery. Although lesioned rats soon began to gain weight at a rate that was similar to the rate of weight gain in the sham-operated controls, the absolute body weight of AP-lesioned rats remained below that of the controls throughout the experiment. Chronically decreased body weight following AP lesions was also observed by Carlisle and Reynolds 8 and by Edwards and Ritter 10. It might be argued that the failure of AP-lesioned rats to develop CTA after L~C1 and SMN administration might be due to chronically reduced body weight and increased hunger. However, the fact that AP-lesioned rats form aversions after a low dose of amphetamine makes this argument untenable. The second observation is that APlesioned rats consistently consumed more of the neutral training solution than did sham-operated rats. Increased consumption of highly palatable liquid food has been noted previously 1° and this finding suggests the interesting possibility that AP-lesioned rats may have a satiety deficit 8. These results and the findings of other investigators 4,7 suggest that the AP is a chemoreceptor for substances of widely disparate chemical structures. In addition, these results suggest that the AP may subserve a number of important behavioral roles. Specifically, AP lesions abolish the conditioning of taste aversion by LiCI and SMN and, in addition, may alter body weight maintenance and the ingestive response to palatable liquid foods. Companion studies in this laboratory also demonstrate that AP lesions abolish the anti-aggressive effect of LiC1 in both male and female rats14, aS. Thus, it appears that this brain region, previously studied primarily as a chemoreceptor area, is ripe for more detailed analysis with respect to behavioral functions. This research forms Scientific Paper 5429, College of Agriculture Research Center, Washington State University, Projects 0344, 0656 and 2344. Portions of this work were funded by PHS Grant NS 14450-02 to S. R. and PHS Grant MH 32812-01 to K. W. K. This investigation was also supported in part by funds provided for medical and biological research by the State of Washington Initiative Measure 171 to K. W. K. The authors wish to thank Nancy L. Pelzer for preparation of the histology, William J. Carmint for technical advice on the development of our lesioning procedure, and Dr. Barry D. Berger for helpful comments.
1 Amit, Z., Levitan, D. E., Brown, Z. W. and Rogan, F., Possible involvement of central factors in the medmtion of conditioned taste aversion, Neuropharmacology, 16 (1977) 121-124. 2 Arthur, J. B., Taste aversion is impaired by interpolated amygdaloid stimulation but not by posttraining amygdaloid stimulation, Behav. Biol., 13 (1975) 369-376. 3 Berger, B. D., Conditioning of food aversions by rejection of psychoactive drugs, J. comp.physiol. PsychoL, 81 (1972) 21-26 4 Berger, B. D., Wise, C. D. and Stein, L, Area postrema damage and bait shyness, J. comp physiol. Psychol, 83 (1973) 475-479. 5 Bonson, FI. L, Area postrema: chemoreceptor trigger zone for vomiting - is that all?, Life Sci, 14 (1974) 1807-1817.
506 6 Borison, H. L. and Bnzzee, K. R., Morphology of emetic chemoreceptor trigger zone m cat medulla oblongata, Proc. Soc. exp Biol. (N. Y ), 77 (1951) 38-42. 7 Borison, H. L. and Wang, S. C., Physiology and pharmacology of vomiting, Pharmacol Rev, 5 (1953) 193-230. 8 Carlisle, H. J. and Reynolds, R. W., Effect of amphetamine on food intake m rats with brain stem lesions, Amer. J. Physiol., 201 (1961) 965-967. 9 Davenport, V D , Distribution of parenterally administered lithium in plasma, brain, and muscle of rats, Amer J. Physiol., 163 (1950) 633-641. 10 Edwards, G. and Rltter, R. C., Area postrema lesions cause increased retake of highly palatable food, Neurosci Abstr, 698 (1979) 215. 11 Garcia, J. and Koelhng, R. A., A comparison of aversions induced by X-rays, toxins and drugs m the rat, Radiation Res SuppL, 7 (1967) 439-450. 12 Ionescu, E. and Buresova, D., Failure to elicit conditioned taste aversion by severe poisoning, Pharmacol. Biochern Behav , 6 (1977) 251-254. 13 Kemble, E. D and Nagel, J. A., Failure to form a learned taste aversion in rats with amygdaloid lesions, Bull Psychon Soc., 2 (1973) 155-156. 14 McGlone, J. J., Rltter, S. and Kelley, K. W., Area postrema lesions ehmmate the antlaggressive and aversive conditioning properties of hthmm, Neurosci. Abstr., 2234 (1979) 655 15 McGlone, J. J., Rltter, S and Kelley, K. W., The antiaggressive effect of hthmm as abohshed by area postrema lesion, Physiol. Behav., 24 (1980) 1095-1100. 16 Mornson, J. M., Pntchard, H. D., Brande, M. L. and Aguanns, W. D., Plasma and brain hthium levels after lithium carbonate and lithium chloride administration by different routes in rats, Proc Soc exp. Biol. (N.Y.), 137 (1971) 889-892. 17 Rush, J and Mendels, J., Effects of lithium chloride on munctdal behavior m rats, Phatmacol. Biochem. Behav., 3 (1975) 795-797. 18 Vacaflor, L , Lithium side effects and toxicity: the clinical picture. In F N Johnson (Ed.), Lithium Research and Therapy, Academac Press, New York, 1975, pp. 221-225. 19 Wilson, A. S and Ho, A. K. S., Studies on the area postrema in rats and mice, J Anat. (Lond.), 103 (1968) 208. 20 Ylitalo, P., Stu&es on the role of the central and autonomic nervous systems on the toxaclty of 5hydroxytryptamine in anaesthetized rats, Ann. Med. exp. Biol. Fenn., 50 (1972) 195-204.
501
Absence of lithium-induced taste aversion after area postrema lesion
SUE RITTER, JOHN J. McGLONE* and KEITH W. KELLEY** Department of Veterinary and Comparative Anatomy, Pharmacology and Phystology, and (J. J. McG. and K. W. K.) Animal Scwnce Department, Washington State University, Pullman, Wash. 99164 (U.S.A.)
(Accepted July 17th, 1980) Key words: area postrema - - conditioned taste aversion - - lithium chloride - - scopolamine methyl
nitrate
-
-
D-amphetamine
Anatomical and physiological evidence indicates that the area postrema (AP) lacks a blood-brain barrier6, la and is thus permeable to blood-born substances which do not penetrate most other areas of the brain. The classical experiments of Borison (refs. 5, 7) demonstrated that the AP region contains chemoreceptors which stimulate vomiting in some species in response to certain drugs. This finding suggests that one function of the AP is to detect ingested toxins and trigger their expulsion from the gastrointestinal tract. In addition to producing vomiting, some toxic substances, which are encountered by animals in association with novel foods, may result in formation of learned responses known as conditioned taste aversions (CTAs)3A 1. These learned responses decrease the probability that animals will subsequently ingest particular foods which were previously associated with toxic effects. Berger et al. 4 were the first to demonstrate that the AP plays a critical role in the formation of CTA by some chemical substances. Taste aversions formed by scopolamine methyl nitrate (SMN), a neuroactive substance which does not cross the blood-brain barrier, were shown to be mediated by the AP. On the other hand, the CTA formed by D-amphetamine, a drug which readily penetrates the blood-brain barrier, does not require an intact AP. On the basis of these data, it appears that more than one mechanism may exist for the formation of CTAs. Moreover, these results provide evidence of an important role for the AP region in behavioral, as well as in gastrointestinal, functions. Lithium chloride (LiCI) is a compound which is widely used in C T A studles2,~2, t3. However, the mechanism by which LiCI induces CTAs ts not known. The * Present address: Animal Science Department, Mumford Hall, University of Illinois, Urbana, I11. 61801, U.S.A. ** To whom reprint requests should be addressed.
502 effectiveness of this drug as a conditioning agent may be due to its well-known ability to produce nausea and vomiting TM. If so, then L1CI may produce these effects by its action on the AP. On the other hand, action of LIC1 on the AP may not be critical for its effectiveness as a conditioning agent. Lithium has widespread effects on peripheral tissues and, in addition, is known to penetrate the blood-brain barrierg, 16. The present experiment was undertaken to determine whether the ability of LiC1 to produce CTA is mediated specifically by an action on the AP or whether the generahzed toxicity of this substancO 7,18 is sufficient to mediate the formation of a CTA m the absence of the AP. In our experiments, we lesioned the AP in adult male and female Sprague-Dawley rats. The AP region was exposed by slight enlargement of the foramen magnum and the AP was destroyed by briefly touching this structure with a triangular thermal probe (0.75 m m per side) z°. In some rats, the AP region was exposed, but no lesion was made. These animals served as sham-operated controls (shams) Both male and female lesioned rats lost more weight than shams immediately after surgery and maintained lower body weights than shams throughout the entire experiment. All rats were gaining weight at approximately the same rate, however, at the time experimental treatments were initiated. After recovery from surgery, lesioned and sham-operated rats were trained to drink from a 40 ml calibrated drinking tube. To facilitate training, a palatable solution consisting of Borden's sweetened condensed milk diluted 1.3 with water was presented m the calibrated tubes for 30 min on 4 occasions over an 8 day period. Milk consumption was recorded in each of the 4 training sessions. It is interesting to note that APlesioned rats consistently drank more of the sweetened solutions than shams. For example, the average intake of sweetened condensed milk across the 4 traimng sessions was 21.2 ~z 1.1 ml for AP-lesioned male rats but only 10.8 ~: 0.7 ml for sham-operated males (P < 0.001, bl-directional t-test). Likewise, AP-lesioned females drank an average of 14.3 ~ 1.3 ml during training, whereas shams drank only 7.3 ~_ 1.0 ml (P < 0.01). Enhanced intakes of the palatable novel solutions by lesioned rats during the CTA experiments were also observed (e.g. compare day 1 intakes of shams and lesioned rats in Table 1). In our first experiment we attempted to replicate the findings of Berger et al. that AP lesions abolish the conditioning of taste aversions by SMN but do not impair the conditioning of taste aversions by amphetamine 4. Six AP-lesloned and 8 sham-operated male rats were used in this experiment. Following training, the effects of D-amphetamine sulfate and SMN on taste aversion learning were evaluated m two CTA tests. On the conditioning day of each test (day 1), the ammals were presented with a novel flavored solution of Carnation Instant Breakfast (35.2 g strawberry or chocolate instant Breakfast in 232 nd water) for 30 mln. lmmedmtely after the 30 rain drinking period, all rats that drank more than 3.0 ml of the novel solution were given an l.p. injection of D-amphetamine sulfate(2 mg/kg) or SMN (l mg/kg). Seventy-two hours later (day 3), these same rats were tested for CTA in a 30 min drinking test during which they received a solution of the same flavor as they received on day 1. The conditioning-testing sequence was repeated so that all rats were tested with both drugs. At least one week was allowed to elapse between tests.
503 TABLE I
Change in consumptton of novel solutions by areapostrema-lesioned ( APX) and sham-operated (SHAM) rats followmg drug administration (D-amphetamine or scopolamme methyl mtrate) after the day 1 drinking bout Day 1 (ml ± S.E.M.) D-Amphetamine APX SHAM Scopolamine APX SHAM
23.7 (n 11 6 (n
± = ~ =
1.2 6) 1.8 7)
20.6 ~ 1.7 (n = 6) 7.8 zk 1.0 (n = 8)
Day 3 (ml)
% Day 1
A Intake (ml)
7 7 zk 2.2*
32~
--16.0 ± 2.4
3.1 ± 1 3*
27~
--8.5 ± 2.2
107~
+3.0 ± 1.1
OH
--7.7 ± 1.0
22.1 i 2 8 O*
* P < 0.001, day 3 vs day 1, bi-d~rectlonal t-test.
Results of experiment 1, shown in Table 1, comfirm the findings of Berger et al. 4. Injections of SMN following day 1 exposure to the novel flavored solution abolished day 3 consumption in shams but did not diminish day 3 consumption in AP-lesioned rats. In contrast, amphetamine produced CTAs in both AP-lesioned and sham-operated rats. In our second experiment, we extended these fndings by testing the effects of AP lesion on CTAs induced by LiCI. Eight AP-lesioned and 9 sham-operated female rats were used in this experiment. After recovery from surgery, all rats were tested for CTA, as described, after i.p. injections of LiCI (125 mg/kg, 1.5 mEq/ml), SMN(I mg/kg) and saline (0.15 M). The sequence of drug administration was counterbalanced across the 3 tests. The order of flavor presentation was chocolate, strawberry, and eggnog. The presence of a CTA was determined by subtracting the day 1 from the day 3 consumption. Analysis of variance was performed on the change in consumption. The effects of flavor, body weight and day 1 consumption were removed by analysis of covariance. Thus, there was a 2 x 3 factorial arrangement of treatments with two surgical procedures (AP lesion and sham) and 3 drug treatments (LiCI, SMN, and saline). The results of experiment 2 (shown in Fig. 1) reveal that lesion of the AP prevented formation of the CTAs otherwise produced by SMN and LiC1. This was reflected by a significant surgical procedure by drug interaction (P < 0.05). There were no significant differences among any of the 3 drug treatments in the AP-lesioned group. On the other hand, both of these drugs caused significant depression of drinking on the test day in shams. At the conclusion of experimentation, male and female rats were anesthetized with Chloropent and perfused with 10 ~ formalin. Brains were embedded in paraffin and 7/~m sections were treated with Kluver-Barrera stain. The AP and surrounding
504
~,= +Io 1
z~ +8] --Oz i-o --
-~ ...I ~oO zoo
+6
8~
-a.
_>
-4-
~ o,~ ,o >-
T
-I-4
0.
T
T
-6. -8-
]
-I0-
I
N:7[ [N:S, APX
SHAM
SALINE
N=7 APX
SHAM
SCOPOLAMINE
APX
SHAM
LITHIUM
Fig 1. Change m consumption of novel solutions by area postrema-lesJoned (APX) and sham-operated (SHAM) rats following drug administration (saline, LiCl, scopolamine methyl mtrate) after the day 1 drinking period. Animals that did not drink at least 3 ml on day 1 were ehmmated from that particular test. The N md~cated for each CTA test reflects the number of ammals that were tested w~th each drug. Lines above bars indicate standard error of means.
region were examined for damage. Histological analysis revealed that the AP was completely ablated in all lesioned rats. Surrounding tissue was also damaged in a few animals. Our results demonstrate that AP lesion abolishes the conditioning of taste averslons by LiCI and SMN, but does not influence the conditioning of amphetamine-induced taste aversions. This result has several important implications. Firstly, the presence of a CTA in AP-lesioned rats after amphetamine indicates that the lesioned rats are capable of learning a taste aversion and rules out the likelihood that taste aversion deficits after SMN and LIC1 in these rats are due to generalized behavioral or sensory disruption. Secondly, the fact that AP lesions abolish aversions to LiC1 and SMN, but not to amphetamine, supports previous findings which suggest that stimuli for conditioned aversions are received by more than one neural system 1,4. One interpretation of the results reported by Berger et al. 4 is that those substances, for example SMN, which produce CTA by activation of AP receptors are substances which do not cross the blood-brain barrier and that substances like amphetamine, which readily penetrate the brain, may act on systems which are independent of the AP. The observation that LiCI induces CTA by action on the AP is interesting with respect to this hypothesis since L1C1, unlike SMN, is known to cross the blood-brain barrier. This finding indicates that the AP and its neural connections may mediate the formation of CTA to some substances irrespective of their penetration into the brain. However, since LiC1 is known to clear rapidly from plasma and equilibrate slowly across the blood-brain barrlerg, 16, it is possible that the high blood level of lithium rapidly achieved after administration of this drug may be the effective stimulus for AP involvement in lithmm-induced CTA. Further experimentation wdl be required to determine whether hthlum-lnduced CTA is mediated by AP receptors on the blood side or on the brain side of the blood-brain barrier.
505 During the course of this study, two important observations were made regarding the effect of the AP on food intake and body weight. Firstly, AP-lesioned rats rapidly lost weight subsequent to surgery. Although lesioned rats soon began to gain weight at a rate that was similar to the rate of weight gain in the sham-operated controls, the absolute body weight of AP-lesioned rats remained below that of the controls throughout the experiment. Chronically decreased body weight following AP lesions was also observed by Carlisle and Reynolds 8 and by Edwards and Ritter 10. It might be argued that the failure of AP-lesioned rats to develop CTA after L~C1 and SMN administration might be due to chronically reduced body weight and increased hunger. However, the fact that AP-lesioned rats form aversions after a low dose of amphetamine makes this argument untenable. The second observation is that APlesioned rats consistently consumed more of the neutral training solution than did sham-operated rats. Increased consumption of highly palatable liquid food has been noted previously 1° and this finding suggests the interesting possibility that AP-lesioned rats may have a satiety deficit 8. These results and the findings of other investigators 4,7 suggest that the AP is a chemoreceptor for substances of widely disparate chemical structures. In addition, these results suggest that the AP may subserve a number of important behavioral roles. Specifically, AP lesions abolish the conditioning of taste aversion by LiCI and SMN and, in addition, may alter body weight maintenance and the ingestive response to palatable liquid foods. Companion studies in this laboratory also demonstrate that AP lesions abolish the anti-aggressive effect of LiC1 in both male and female rats14, aS. Thus, it appears that this brain region, previously studied primarily as a chemoreceptor area, is ripe for more detailed analysis with respect to behavioral functions. This research forms Scientific Paper 5429, College of Agriculture Research Center, Washington State University, Projects 0344, 0656 and 2344. Portions of this work were funded by PHS Grant NS 14450-02 to S. R. and PHS Grant MH 32812-01 to K. W. K. This investigation was also supported in part by funds provided for medical and biological research by the State of Washington Initiative Measure 171 to K. W. K. The authors wish to thank Nancy L. Pelzer for preparation of the histology, William J. Carmint for technical advice on the development of our lesioning procedure, and Dr. Barry D. Berger for helpful comments.
1 Amit, Z., Levitan, D. E., Brown, Z. W. and Rogan, F., Possible involvement of central factors in the medmtion of conditioned taste aversion, Neuropharmacology, 16 (1977) 121-124. 2 Arthur, J. B., Taste aversion is impaired by interpolated amygdaloid stimulation but not by posttraining amygdaloid stimulation, Behav. Biol., 13 (1975) 369-376. 3 Berger, B. D., Conditioning of food aversions by rejection of psychoactive drugs, J. comp.physiol. PsychoL, 81 (1972) 21-26 4 Berger, B. D., Wise, C. D. and Stein, L, Area postrema damage and bait shyness, J. comp physiol. Psychol, 83 (1973) 475-479. 5 Bonson, FI. L, Area postrema: chemoreceptor trigger zone for vomiting - is that all?, Life Sci, 14 (1974) 1807-1817.
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