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Classical and physiologic adaptive conditioned responses to anticholinergic drugs in conscious dogs
ht. f. Neurophmmnrol.. 1966, 5, 31 l-315
Pcrgamon Press
Printed in Gt. Britain.
CLASSICAL AND PHYSiOLOGlC ADAPTIVE RESPONSES TO ANTICHOLINERGIC CONSCIOUS DOGS”
CONDITIONED DRUGS IN
W. J. LANG, M. L. BROWN, S. GERSH~N and B. Ko~or, ~epartjllellt of Psychiatry at Missouri Institute of Psychiatry, University of Missouri Sell001 of Medicine, St. Louis, Missouri
Summary-In conscious, unrestrained dogs, equivalent doses of atropinc sulfate and Ditran produced a conditioned paradoxic salivary response and a classicaf conditioned respome of mydriasis when the animals were placed into the experimental chamber. The onset and extinction rates for these responses were almost identical for both drug groups and onset appeared after as few as six treatment sessions. Although these drugs arc parasympatholytic agents, a possible explanation of the responses implicates a sympatbctic nervous system activation. INTRODUCTION Tr IS wcli understood
that in classical Pavlovian conditioning the cond~tiol~ed stilnu~us evokes a conditioned response which is qualitativeIy similar to the response produced by the unconditioned stimulus alone. Soviet investigators have reported on many exampIes of this type of response employing several different drugs as the unconditioned stimulus (BYKOV, 1957). Their studies indicated that cardiovascular changes could be conditioned by these classical techniques employing such agents as nitroglycerin, morphine, strophanthin, acctylcholine and epinephrine. It has been reported that not all drug effects can be conditioned. GANTT ct uf. (1937) reported an inability to condition the hyperglycemic effects of epinephrine; FINCH (193X) was unable to produce conditioned salivation with pilocarpine; and KATZENELBOGENcf nl. (1939) could not condition secretion of gastric juice with histamine. In fact, responses opposite to the unconditioned response have been reported in a few instances (GAN.~I et al., 1937; BROWEN and GANTT, 1942); however, these findings were not consistent except when atropine was the drug used as the unconditioned stimulus (FINCH, 193X; Dorrvc, 1914; MULINOS and LIEB, 1929; WIKLER, 1948). Ditran (N-ethyl-3-piperidylcyclopentenylphenyl gIycoIate) is an anticholinergic atropinelike agent and produces similar behavioral responses in dog and man (WHITE et c/l., 1961; BELL et NI., 1964). Although these changes are qualitatively of a similar nature, quantitative differences have been claimed. Peripherally, atropine is reported to show greater anticholinergic activity than Ditran (cf. files; Lakeside Laboratories, inc.); whereas, centrally, HOROVITZ and CHOW(1962) noted that Ditran appeared to have a ten-fold greater potency than atropine. In view of these considerations, we were interested in comparing the effects of these two anticholinergics in the conditioning of salivary and mydriatic responses in dogs. * This work was silppor~cd in part by USPHS Grant MH I 1379. 311
W. J. LANC;,M. L. BROWN,S. GERSHONand B. KOROL
312
METHODS
Twelve mongrel dogs (weights between 8 and 13 kg) were used in 4 groups, each containing 3 dogs. The dogs were kept in fixed groups during the experimental procedures in order to keep conditions constant within the different treatments. Each group contained one dog given Ditran (0.5 mg/kg), one atropine sulfate (0.5 mg/kg) and one normal saline solution, the anticholinergics and normal saline solution each being injected intravenously
NUMBER
OF
TREATMENTS
FIG. I. Occurrence of salivation over time in the preinjection period for dogs on atropinc, Ditran or normal saline solution (N.S.) regimens. The average scores for salivation indicate the increased output per dog on a 0 to t-3 scale.
in volumes of O-2 cmz/kg. The treatment procedure consisted of bringing each group into the experimental room for a 30 min observation period before the injection. Prior to injection, the degree of salivation and the pupil size were evaluated. The values ascribed to these measures were: O-normal, -t 1=slight increase and +2=moderate increase and +3=marked increase in each parameter. Thus, t-3 represented maximally dilated pupils, or profuse salivation with saliva flowing out of the animal’s
NUMBER
FIG. 2.
OF
TREATMENTS
Degree of dilatation of the pupil in the preinjection period for dogs on atropine, Ditran or normal saline solution (N.S.) regimens. The average scores of pupil size indicate the degree of dilatation of the pupil per dog on a 0 to -I- 3 scale.
Classical and physiologic responses to anticholinergic
drugs in conscious dogs
313
mouth. The values were determined by two independent observers, and an average of the two evaluations was recorded. After 8 treatment trials 2 of the 4 control animals were started on Ditran and the remaining 2 on atropine sulphate as described above. In this way, totals of 6 dogs were observed with both the anticholinergics. At the same time, extinction trials were carried out on the original atropine and Ditran treated dogs by substituting normal saline solution for the test compounds. Since one of the Ditran treated dogs did not respond maximally after the eighth treatment, Ditran was continued until a maximal response was observed. The values for the extinction trials with Ditran were, therefore, calculated only on three dogs, whereas with atropine, four dogs were used. The values are plotted in Fig. 1 and 2, using the mean values per dog in each treatment category.
RESULTS EfSects oj‘the drugs alone Ditran and atropine produced the typical behavioral and physiologic effects that have been reported previously (BELL et al., 1964). Pupillary dilatation and marked dryness of the mouth resulted in every case after the administration of these compounds. Saline solution did not produce any obvious effects. Salivation Hyper-salivation became manifest in the period between the collection of the animals, their placement in the treatment room and the injection of the test drug. Salivation was blocked after the administration of either Ditran or atropine. None of these effects were observed with saline solution injections. In the majority of dogs the salivary response in the preparatory phase occurred after 4 exposures to atropine and peak effect was attained at the seventh trial. With Ditran, the salivary response first occurred after two exposures and peak effect was attained at the seventh treatment episode (see Fig. 1). Thus, although maximum sialogogic effects were equivalent in the 2 drug groups, the onset of the salivary response appeared earlier in the Ditran group (Fig. 1). It is quite apparent that these drug-associated responses remained consistently different from the reaction of the animals given saline solution alone. After the eighth treatment episode, saline solution was substituted for the atropine and Ditran injections. It was observed (Fig. 1) that prior to injection a discernible salivary response continued, in the course of the first trial it gradually diminished and after 3 sessions it returned to the control level in the majority of animals. Pupillary dilatation Both compounds produced a marked mydriasis in all animals after injection, A consistent dilatation of the pupil in the me-injection period also occurred after 4 or 5 treatments with Ditran or atropine and reached peak effect on the seventh experimental day. The animals given saline solution did not show any measurable change in pupil size (Fig. 2). When saline solution was substituted for the anticholinergic agents after the eighth treatment episode, the mydriasis apparent in the pre-treatment period diminished and reached control levels after the fourth or fifth saline solution treatment.
314
W. J. LANG,
M. L. BROU.N,S. GERSHON and B. KOROL DISCUSSION
A classical conditioned response to a drug was reported by BYK~V (1957) using an auditory stimulus (conditioned stimulus) coupled with nitroglycerin (unconditioned stimulus). After one hundred pairings the conditioned stimulus produced changes typical of those elicited by the unconditioned stimulus, nitroglycerin (increased heart rate and changes in EKG). Our experiments were not designed to investigate this type of classical conditioned response, but rather to study the responses evoked in the period prior to drug administration. In 1914, Doeve reported a paradoxic secretion of saliva from dogs receiving repeated treatments with atropine. MULIN~S and LIEB (1929) reported that the daily administration of atropine to dogs and cats resulted in a conditioned salivation. They observed that sativation was obtained in response to conditions previously innocous after repeated administration of atropine and concluded that the salivary conditioning was due to a central stimulating action of the drug. However, CRISLER (I 930) was unable to induce a conditioned salivation in two dogs who were given daily atropine injections for thirty days. The failure to condition salivation in this study might be due to the experimental design, which placed the animals in the observation apparatus ten to fifteen minutes qfier they had received the atropine treatment. Thus, any conditioned salivation would have been negated by the antisialogogic effects of atropine. FINCH (I 938) in parotid fistula prepared dogs and WIKLEK (1948) in dogs and cats reported that daily treatment with atropine did evince a conditionalsalivary response. WIKLER concluded that the appearance of conditioned salivation during daily injection of atropine was due to a conditioning of an adaptive response to dryness 01 the mouth produced by the direct eflects on the salivary glands. These latter findings and conclusions on the sialogogic effect of repeated atropine administration are in general accordance with our results. However, this proposed explanation is inadequate for interpreting the mydriasis observed. The observed salivary response was thus contrary to the response expected if classical Pavlovian conditioning mechanisms were operational. That is, if the experimental room served as the conditioned stimulus and the action of the drugs atropine or Ditran as the unconditioned stimulus, then one would predict that both the conditioned and unconditioned responses would be dryness of the mouth and mydriasis. It may bc spcculatccl that the observed deviant findings reflect a conditioned normal physiologic homcostatic response. When consideration of homeostasis is included in the interpretation of the rcsutI5. then it is quite conceivable that to the animal, the experimental room acts as a signal associalctl with dryness ofthe mouth and mydriasis. The animal then should respond with a conditioned hnmeostatic response of salivation and miosis. However, it was observed that whcrc:~\ cxccss salivation was apparent, mydriasis still persisted. The autonomic nervous system is frequently viewed purely as an d‘fector system, dcxpilc reports of the existence of fibers which arc apparently affcrent in function. LAU:Y :jnd I...NxY (1958) suggested that autonomic responses can function as stimuli through “feedbach via visceral afferents”. If autonomic responses have concomitant sensory elements, it i\ possible that these elements may provide the conditions necessary for the establishment 01‘ operant learning, dependent on response-associated CLICS. If such cues do exist, it would seem possible that autonomic responses could function as conditionable operants. If thi\ be so, one must consider why the mydriatic response occurring at the same time as the excessive salivation did not appear as a conditioned physiologic adaptativc rcsponsc of rniosis.
Classical and physiologic responses to anticholinergic
drugs in conscious dogs
315
It could be that these two autonomic responses are split and thus the mydriasis develops, in fact, as a classical conditioned response and the salivation as a result of a homeostatic conditioned response. Another explanation may be that the mydriasis is a result of an alarm reaction associated with the behavioral changes induced by the anticholinergics and this also may beclassicallyconditioned. Such an alarm reaction, activating centrally mediated sympathetic reflexes, could be the mechanism by which the observed sialogogic and mydriatic effects were produced. liowever, a firm explanation for this split in these responses is nor readily available.
REFERENCES 131LA., C.,
S., CAIUCOM, II. and I-IOLAN, G. (1964). Behavioral antagonism 10 :I nc!v psychotomimetic--J B 329. Arc/l. in/. Phntwmcodyn. 147: 8-25. MHOGDEN, W. J. and GANTT, W. H. (1942). Intraneural conditioning: cerebellar conditioned reflexes. ,4&. CIXSHON,
Nertrol. Psychint. Chicngo. 48: 437455. thrtov, K. M. (1957). The CerebrcrlCortexnnclthe
I~tternolOrgtrus. Editor W. H. GANTT,Chemical Publishing, New York. C‘HISLEH, G. (1930). Salivation is unnecessary for the establishment of the salivary conditioned reflex induced by morphine. Anl. J. Physiol. 94: 553-556. I)oI-vE, W. C. A. (1914). Die abnormen Kaubewegungen mit erhiihter Salivation nach Atropininstillatic,n211 ins Auge von Hund und Katze. 2. 7’ientled. 18: 77-91. FINCH, G. (1938). Salivary conditioning in atropinized dogs. Afro. J. Physiol. 124: 136-141. GANTT, W. H., KATZENELBOGEN, S. and LOUCKS,R. B. (1937). An attempt to condition adrenalin hyperglycemia. Bull. Johns Hopkirrs Hosp. 60: 4oo-411. Ho~ovr~z, A. P. and CHOW, M. I. (1962). Effects of centrally acting drugs on the correlation of electrocortical activity and wakefulness of cats. J. Phormac. exp. Ther. 137: 127-132. KATZENELBOGEN, S., LOUCKS,R. B. and GANTT, W. H. (1939). An attempt to condition gastric secretion to histamine. A/U. J. Physiol. 128: 10-18. I.ACI:Y, J. 1. and LACEY,B. C. (1958). The relationship of resting autonomic activity ot motor impulsivity. In The Btairz and HIIMWI Behavior. Williams and Wilkins, Baltimore, Proc. Assoc. Res. Nerv. Men/. Dis., Vol. XXXVI. Lakeside Laboratories, Inc. Preclinical and clinical information brochure. MlJLINOS, M. G. and LIEB,C. C. (1929). Pharmacology of learning. Am. J. fhysiol. 90: 456-457. WtirrE, R. I’., NASH, C. B., WLIST~KBEKE, E. J. and POSSANZA,G. J. (1961). Phylogenetic comparison of central actions produced by different doses of atropine and hyoscine. Arch. int. Phortmcodvn. 132: 349.-363.
WIKI~K, A. (1948). Recent progress in research Ps.vchiur. 105: 329-338.
011 the
neurophysiologic
basis of morphine addiction,
A,,,. J.
Pcrgamon Press
Printed in Gt. Britain.
CLASSICAL AND PHYSiOLOGlC ADAPTIVE RESPONSES TO ANTICHOLINERGIC CONSCIOUS DOGS”
CONDITIONED DRUGS IN
W. J. LANG, M. L. BROWN, S. GERSH~N and B. Ko~or, ~epartjllellt of Psychiatry at Missouri Institute of Psychiatry, University of Missouri Sell001 of Medicine, St. Louis, Missouri
Summary-In conscious, unrestrained dogs, equivalent doses of atropinc sulfate and Ditran produced a conditioned paradoxic salivary response and a classicaf conditioned respome of mydriasis when the animals were placed into the experimental chamber. The onset and extinction rates for these responses were almost identical for both drug groups and onset appeared after as few as six treatment sessions. Although these drugs arc parasympatholytic agents, a possible explanation of the responses implicates a sympatbctic nervous system activation. INTRODUCTION Tr IS wcli understood
that in classical Pavlovian conditioning the cond~tiol~ed stilnu~us evokes a conditioned response which is qualitativeIy similar to the response produced by the unconditioned stimulus alone. Soviet investigators have reported on many exampIes of this type of response employing several different drugs as the unconditioned stimulus (BYKOV, 1957). Their studies indicated that cardiovascular changes could be conditioned by these classical techniques employing such agents as nitroglycerin, morphine, strophanthin, acctylcholine and epinephrine. It has been reported that not all drug effects can be conditioned. GANTT ct uf. (1937) reported an inability to condition the hyperglycemic effects of epinephrine; FINCH (193X) was unable to produce conditioned salivation with pilocarpine; and KATZENELBOGENcf nl. (1939) could not condition secretion of gastric juice with histamine. In fact, responses opposite to the unconditioned response have been reported in a few instances (GAN.~I et al., 1937; BROWEN and GANTT, 1942); however, these findings were not consistent except when atropine was the drug used as the unconditioned stimulus (FINCH, 193X; Dorrvc, 1914; MULINOS and LIEB, 1929; WIKLER, 1948). Ditran (N-ethyl-3-piperidylcyclopentenylphenyl gIycoIate) is an anticholinergic atropinelike agent and produces similar behavioral responses in dog and man (WHITE et c/l., 1961; BELL et NI., 1964). Although these changes are qualitatively of a similar nature, quantitative differences have been claimed. Peripherally, atropine is reported to show greater anticholinergic activity than Ditran (cf. files; Lakeside Laboratories, inc.); whereas, centrally, HOROVITZ and CHOW(1962) noted that Ditran appeared to have a ten-fold greater potency than atropine. In view of these considerations, we were interested in comparing the effects of these two anticholinergics in the conditioning of salivary and mydriatic responses in dogs. * This work was silppor~cd in part by USPHS Grant MH I 1379. 311
W. J. LANC;,M. L. BROWN,S. GERSHONand B. KOROL
312
METHODS
Twelve mongrel dogs (weights between 8 and 13 kg) were used in 4 groups, each containing 3 dogs. The dogs were kept in fixed groups during the experimental procedures in order to keep conditions constant within the different treatments. Each group contained one dog given Ditran (0.5 mg/kg), one atropine sulfate (0.5 mg/kg) and one normal saline solution, the anticholinergics and normal saline solution each being injected intravenously
NUMBER
OF
TREATMENTS
FIG. I. Occurrence of salivation over time in the preinjection period for dogs on atropinc, Ditran or normal saline solution (N.S.) regimens. The average scores for salivation indicate the increased output per dog on a 0 to t-3 scale.
in volumes of O-2 cmz/kg. The treatment procedure consisted of bringing each group into the experimental room for a 30 min observation period before the injection. Prior to injection, the degree of salivation and the pupil size were evaluated. The values ascribed to these measures were: O-normal, -t 1=slight increase and +2=moderate increase and +3=marked increase in each parameter. Thus, t-3 represented maximally dilated pupils, or profuse salivation with saliva flowing out of the animal’s
NUMBER
FIG. 2.
OF
TREATMENTS
Degree of dilatation of the pupil in the preinjection period for dogs on atropine, Ditran or normal saline solution (N.S.) regimens. The average scores of pupil size indicate the degree of dilatation of the pupil per dog on a 0 to -I- 3 scale.
Classical and physiologic responses to anticholinergic
drugs in conscious dogs
313
mouth. The values were determined by two independent observers, and an average of the two evaluations was recorded. After 8 treatment trials 2 of the 4 control animals were started on Ditran and the remaining 2 on atropine sulphate as described above. In this way, totals of 6 dogs were observed with both the anticholinergics. At the same time, extinction trials were carried out on the original atropine and Ditran treated dogs by substituting normal saline solution for the test compounds. Since one of the Ditran treated dogs did not respond maximally after the eighth treatment, Ditran was continued until a maximal response was observed. The values for the extinction trials with Ditran were, therefore, calculated only on three dogs, whereas with atropine, four dogs were used. The values are plotted in Fig. 1 and 2, using the mean values per dog in each treatment category.
RESULTS EfSects oj‘the drugs alone Ditran and atropine produced the typical behavioral and physiologic effects that have been reported previously (BELL et al., 1964). Pupillary dilatation and marked dryness of the mouth resulted in every case after the administration of these compounds. Saline solution did not produce any obvious effects. Salivation Hyper-salivation became manifest in the period between the collection of the animals, their placement in the treatment room and the injection of the test drug. Salivation was blocked after the administration of either Ditran or atropine. None of these effects were observed with saline solution injections. In the majority of dogs the salivary response in the preparatory phase occurred after 4 exposures to atropine and peak effect was attained at the seventh trial. With Ditran, the salivary response first occurred after two exposures and peak effect was attained at the seventh treatment episode (see Fig. 1). Thus, although maximum sialogogic effects were equivalent in the 2 drug groups, the onset of the salivary response appeared earlier in the Ditran group (Fig. 1). It is quite apparent that these drug-associated responses remained consistently different from the reaction of the animals given saline solution alone. After the eighth treatment episode, saline solution was substituted for the atropine and Ditran injections. It was observed (Fig. 1) that prior to injection a discernible salivary response continued, in the course of the first trial it gradually diminished and after 3 sessions it returned to the control level in the majority of animals. Pupillary dilatation Both compounds produced a marked mydriasis in all animals after injection, A consistent dilatation of the pupil in the me-injection period also occurred after 4 or 5 treatments with Ditran or atropine and reached peak effect on the seventh experimental day. The animals given saline solution did not show any measurable change in pupil size (Fig. 2). When saline solution was substituted for the anticholinergic agents after the eighth treatment episode, the mydriasis apparent in the pre-treatment period diminished and reached control levels after the fourth or fifth saline solution treatment.
314
W. J. LANG,
M. L. BROU.N,S. GERSHON and B. KOROL DISCUSSION
A classical conditioned response to a drug was reported by BYK~V (1957) using an auditory stimulus (conditioned stimulus) coupled with nitroglycerin (unconditioned stimulus). After one hundred pairings the conditioned stimulus produced changes typical of those elicited by the unconditioned stimulus, nitroglycerin (increased heart rate and changes in EKG). Our experiments were not designed to investigate this type of classical conditioned response, but rather to study the responses evoked in the period prior to drug administration. In 1914, Doeve reported a paradoxic secretion of saliva from dogs receiving repeated treatments with atropine. MULIN~S and LIEB (1929) reported that the daily administration of atropine to dogs and cats resulted in a conditioned salivation. They observed that sativation was obtained in response to conditions previously innocous after repeated administration of atropine and concluded that the salivary conditioning was due to a central stimulating action of the drug. However, CRISLER (I 930) was unable to induce a conditioned salivation in two dogs who were given daily atropine injections for thirty days. The failure to condition salivation in this study might be due to the experimental design, which placed the animals in the observation apparatus ten to fifteen minutes qfier they had received the atropine treatment. Thus, any conditioned salivation would have been negated by the antisialogogic effects of atropine. FINCH (I 938) in parotid fistula prepared dogs and WIKLEK (1948) in dogs and cats reported that daily treatment with atropine did evince a conditionalsalivary response. WIKLER concluded that the appearance of conditioned salivation during daily injection of atropine was due to a conditioning of an adaptive response to dryness 01 the mouth produced by the direct eflects on the salivary glands. These latter findings and conclusions on the sialogogic effect of repeated atropine administration are in general accordance with our results. However, this proposed explanation is inadequate for interpreting the mydriasis observed. The observed salivary response was thus contrary to the response expected if classical Pavlovian conditioning mechanisms were operational. That is, if the experimental room served as the conditioned stimulus and the action of the drugs atropine or Ditran as the unconditioned stimulus, then one would predict that both the conditioned and unconditioned responses would be dryness of the mouth and mydriasis. It may bc spcculatccl that the observed deviant findings reflect a conditioned normal physiologic homcostatic response. When consideration of homeostasis is included in the interpretation of the rcsutI5. then it is quite conceivable that to the animal, the experimental room acts as a signal associalctl with dryness ofthe mouth and mydriasis. The animal then should respond with a conditioned hnmeostatic response of salivation and miosis. However, it was observed that whcrc:~\ cxccss salivation was apparent, mydriasis still persisted. The autonomic nervous system is frequently viewed purely as an d‘fector system, dcxpilc reports of the existence of fibers which arc apparently affcrent in function. LAU:Y :jnd I...NxY (1958) suggested that autonomic responses can function as stimuli through “feedbach via visceral afferents”. If autonomic responses have concomitant sensory elements, it i\ possible that these elements may provide the conditions necessary for the establishment 01‘ operant learning, dependent on response-associated CLICS. If such cues do exist, it would seem possible that autonomic responses could function as conditionable operants. If thi\ be so, one must consider why the mydriatic response occurring at the same time as the excessive salivation did not appear as a conditioned physiologic adaptativc rcsponsc of rniosis.
Classical and physiologic responses to anticholinergic
drugs in conscious dogs
315
It could be that these two autonomic responses are split and thus the mydriasis develops, in fact, as a classical conditioned response and the salivation as a result of a homeostatic conditioned response. Another explanation may be that the mydriasis is a result of an alarm reaction associated with the behavioral changes induced by the anticholinergics and this also may beclassicallyconditioned. Such an alarm reaction, activating centrally mediated sympathetic reflexes, could be the mechanism by which the observed sialogogic and mydriatic effects were produced. liowever, a firm explanation for this split in these responses is nor readily available.
REFERENCES 131LA., C.,
S., CAIUCOM, II. and I-IOLAN, G. (1964). Behavioral antagonism 10 :I nc!v psychotomimetic--J B 329. Arc/l. in/. Phntwmcodyn. 147: 8-25. MHOGDEN, W. J. and GANTT, W. H. (1942). Intraneural conditioning: cerebellar conditioned reflexes. ,4&. CIXSHON,
Nertrol. Psychint. Chicngo. 48: 437455. thrtov, K. M. (1957). The CerebrcrlCortexnnclthe
I~tternolOrgtrus. Editor W. H. GANTT,Chemical Publishing, New York. C‘HISLEH, G. (1930). Salivation is unnecessary for the establishment of the salivary conditioned reflex induced by morphine. Anl. J. Physiol. 94: 553-556. I)oI-vE, W. C. A. (1914). Die abnormen Kaubewegungen mit erhiihter Salivation nach Atropininstillatic,n211 ins Auge von Hund und Katze. 2. 7’ientled. 18: 77-91. FINCH, G. (1938). Salivary conditioning in atropinized dogs. Afro. J. Physiol. 124: 136-141. GANTT, W. H., KATZENELBOGEN, S. and LOUCKS,R. B. (1937). An attempt to condition adrenalin hyperglycemia. Bull. Johns Hopkirrs Hosp. 60: 4oo-411. Ho~ovr~z, A. P. and CHOW, M. I. (1962). Effects of centrally acting drugs on the correlation of electrocortical activity and wakefulness of cats. J. Phormac. exp. Ther. 137: 127-132. KATZENELBOGEN, S., LOUCKS,R. B. and GANTT, W. H. (1939). An attempt to condition gastric secretion to histamine. A/U. J. Physiol. 128: 10-18. I.ACI:Y, J. 1. and LACEY,B. C. (1958). The relationship of resting autonomic activity ot motor impulsivity. In The Btairz and HIIMWI Behavior. Williams and Wilkins, Baltimore, Proc. Assoc. Res. Nerv. Men/. Dis., Vol. XXXVI. Lakeside Laboratories, Inc. Preclinical and clinical information brochure. MlJLINOS, M. G. and LIEB,C. C. (1929). Pharmacology of learning. Am. J. fhysiol. 90: 456-457. WtirrE, R. I’., NASH, C. B., WLIST~KBEKE, E. J. and POSSANZA,G. J. (1961). Phylogenetic comparison of central actions produced by different doses of atropine and hyoscine. Arch. int. Phortmcodvn. 132: 349.-363.
WIKI~K, A. (1948). Recent progress in research Ps.vchiur. 105: 329-338.
011 the
neurophysiologic
basis of morphine addiction,
A,,,. J.