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Endorphins and extinction: Differential actions on appetitive and adversive tasks
Life Sciences, Vol . 24, pp . Printed in the U.S .A .
1631-1(,36
Pergamon Press
ENDORPHINS AND ERTINCTION : DIFFERENTIAL ACTIONS ON APPETITIVE AND ADVERSIVE TASKS Michel Le Moal, George F . Roob and Floyd E. Bloom Laboratoire de Psychophysiologie, Faculté des Sciences Université de Bordeaux 33 Talencè, France and A. O . Davis Center for Behavioral Neurobiology The Salk Institute San Diego, California 92112 (Received in final form March 6,
1979)
Summary Alpha and gamma endorphin both inhibited the extinction of a rum~ay task for water reward is water-deprived rata after subcutaneous injections of microgram dosages . At similar doses, these same peptides produced opposing actions on the extinction of a pole-jumping avoidance task : alpha endorphin inhibited and gamma endorphin facilitated extinction . The effects of these peptides on motivated behavior may thus be situationdependent . Recent studies by De Wied and associates have demonstrated that minute quantities peptides derived from the molecular structure of ß-lipotropin (ß-LPH) can influence animal behavior when injected peripherally, particularly extinction beh~vior in aversively motivated tasks . In such tasks, the effects of Met -enkephalin (ß-LPH 61-65), alpha endorphin (ß-LPH 61-76) and Beta endorphin (ß-LPH 61-91) produce effects opposite to those of gamma endorphin (ß-LPH 61-77) (1,2) . These effects do not appear to be related to interactions with typical opiate receptors (1,3) . Actions similar to those of enkephalin and of alpha and beta endorphin were reported earlier by this group for peptide fragmente of the ß-LPH molecule (ß-LPH 47-53, also referred to as ACTH 4-10) (4,5) . While moat of these peptides were reported to inhibit the extinction of pole-jump avoidance tasks, gamma-endorphin uniquely facilitated extinction (2) . More recently, De Wied and associates have speculated that the effects of gamma-endorphin and especially the synthetic peptide des-Tyr-gamma endorphin (6) have some pharmacological properties similar to neuroleptic drugs . In order to investigate the sites and mechanisms by which these peripherally injected peptides can influence behavior, it is important to determine whether their effects can be generalized across different types of behavioral tasks . If the actions of these peptides were similar for extinction of both aversive and appetitive tasks, for example, a primary learning or memory substrate might be sought as the mechanism of action . Alternatively, if the effects of the peptides were test dependent, leas general mechanisms of action might be sought which may be more related . to specific motivational variables . 0024-3205/79/181631-06502 .00/0 Copyright (c) 1979 Pergamon Press, Inc .
1632
Endorphins and Extinction
Vol . 24, No . 18, 1979
We now report that at comparable doses (1-10 ug/rat) the effects of alpha and gamma endorphin on rat behavioral paradigms are, in fact, dependent upon the test situation . Specifically, in a pole-jump avoidance task alpha endorphin inhibited extinction while gamma endorphin facilitates extinction, as reported by the De Wied group (2) . However, in an appetitively motivated drinking test, both endorphins inhibited extinction . These results suggest that the actions of the peptides on behavior depend upon the nature of the reinforcera maintaining the behavior . Methods For the pole jumping task the procedures of De Wied and coworkers w..re followed (1) . Eighteen male Wister albino rats weighing between 100 and 120 g were used . The rats were trained to jump onto a pole within 5 sec after presentation of a conditioned stimulus which consisted of illuminating six 28 V lights on one wall . Rats which failed to jump within 5 sec received 1 .2 to 1 .7 mA, D .C . of scrambled foot shock (shock was provided by a BRS/LVE constant power shock generator, model SGS-003) . The rats received 10 trials/ day with intertrial intervals of 40, 60, and 80 seconds presented in a random order . Ten rats were trained for 3 days in experiment 1 and eight rata were trained for 4 days in experiment 2 . Following acquisition all rats were given a ten trial extinction session. Following this first extinction trial each rat was injected with peptide or vehicle . The rata in experiment 1 (30 trials acquisition) received 1 ug of alpha endorphin and the rats in experiment 2 (40 trials acquisition) received 1 ug of gamma endorphin (both equal Extinction trials were then repeated again at 2 and 4 to 10 ug/kg) . hours after injection . Twenty-one male hooded rate (200-240 g) of the Long Evana strain were used in the drinking test . The apparatus consisted of a runway with two arms at a 60° angle ; each arm was 61 cm in length 12 .5 cm in width and 15 cm in height . The runway was constructed of aluminum with a floor of brass rode 2 .0 cm apart and a removable clear plexiglass roof . At one end of the arm a metal drinking tube protruded 3 cm into the arm. Contact with this tube registered an audible click . The rats were water deprived for 24 hours and on day 2 training began . Each rat received one trial per day for 7 consecutive days . A trial began with the placing of the rat facing the back wall in the long arm of the maze . Latency to run to the end of the opposite arm and to lick the water tube was recorded to the nearest second . The rat was allowed to drink for a total duration of 30 sec . Following each daily session, the rats were allowed to drink for 30 min., and thus were 23 .5 hr . water deprived before each daily test . Extinction testing was studied on the eighth day . Here the drinking tube remained in place but did not contain water. During the first extinction trial the rats were allowed to lick the dry tube in two separate bouts ; they were removed 30 seconds after the second bout . The rats were then randomly separated into three experimental groups and injected with either 10 ug per rat of alpha endorphin, 10 ug per rat of gamma endorphin (both equal to 40 ug/kg) or vehicle . All drugs were dissolved in physiological saline and injected subcutaneously in a volume of 0 .5 ml . Three subsequent extinction trials were performed every two hours. Data were subjected to a Kruskal-Wallis analysis of variance and/or a Mann-Whitney U-test (7) .
1633
Endorphins and Extinction
Vol . 24, No . 18, 1979
Reaulta As already reported by De Wied et al (2), alpha and gamma endorphin produce apparently opposite effects on the extinction of the pole jump task (Table I) . According to the protocol of those reports (2) alpha endorphin (1 yg/rat ; subcutaneous injection) delayed extinction of rate trained three days, while gamma endorphin at the same does facilitated extinction of rata trained for 4 days . Ia the present study, rate receiving 3 days training (30 acquisition trials) continued to jump significantly more to the conditioned stimulus when tented at 2 hours after receiving alpha endorphin (Mann-Whitney U - 0, p < 0.01) but by 4 hours were not significantly different from controls injected with only the saline vehicle. Conversely, rate given 4 days training (40 acquisition trials) jumped significantly fewer times/session than saline injected rata when tested at both 2 and 4 hrs after reThese ceiving gamma endorphin (Mann-Whitney U ~ 0 .5, p < 0 .02) . results closely reproduce those reported by De Wied et al (2) and indicate that peripherally injected peptides can influence animal behavior over long periods encompassing several hours . However, the effects are dependent upon training exposure, and in these tests the differences between the actions of the peptides depends upon the duration of the acquisition phase of the training . Alpha endorphin has the effect of delaying extinction to a degree equalled by ten additional acquisition trials (1 additional acquisition day) while gamma endorphin has the effect of accelerating extinction to the degree exhibited by the less fully trained rate . In the De Wied experiments (2) gamma endorphin did not alter the 3-day extinction nor did alpha endorphin alter 4-day extinction . Table I Effects of Alpha Endorphin and Gamma Endorphin on Extinction of Active Avoidance Behavior Groupe
(n)
Training
No . of Positive Responses in 10 trials of Extinction 0 hra .
Saline 0.5 ml Alpha endorphin 1 ug/rat Saline 0 .5 ml Gamma endorphin 1 ug/rat
+2 hrst
+ 4 hra
(5)
3 days
8 .Ott (7-10)
2 .0 (1-5)
(0-2)
(5)
3 days
8 .0 (8-9)
9 .0 * (8-10)
7 .0 (0-8)
(4)
4 days
9 .0 (9-10)
8 .5 (7-10)
8.5 (7-10)
(4)
4 days
9 .0 (8-10)
3 .0 (1-7)
1 .0* (0-5)
t Peptide or saline was injected immediately after this first
extinction session Two more extinction sessions followed 2 and 4 hours after injection tt tiedian and range in parenthesis * Aeterick indicates significant (p < 0 .05) difference from saline
1634
Endorphins and Extinction
Vol . 24, No .
18, 1979
Administration of alpha and gamma endorphin (10 ug/rat) also produced significant effects on extinction when water deprived rats were examined in a runway in which they had previously learned to find water . Rats given only saline injections (Fig . 1) showed a time-dependent steady increase in the latency to approach the dry tube over the three extinction sessions . This trend was significant : Xr= 15 .34, df-3 P < 0 .01 (Friedman analysis of variance) . In contrast, rats receiving either alpha or gamma endorphin continue to approach the dry tube as quickly as they had on acquisition trials, even though being permitted contact with the dry tube . In this teat, both peptides produced identical actions, equally enhancing the resistance to extinction, and these effects lasted for at least 6 hours . A KrusalWallis one-way analysis of variance showed a significant difference between the groups at extinction III and IV (p < 0 .02) with both alpha and gamma endorphin showing significantly shorter latencies than the saline group (Mann-Whitney U _< 5, p < 0 .01) . These same results with gamma endorphin were replicated using Wistar albino rats in the same test and apparatus .
InJ~eNon
D~ fnjMian
Figure 1 Median latency to touch a dry water tube during successive extinction sessions . Peptides were injected (40 ug/kg) immediately after the first extinction session . Asterick indicates significant difference from saline group ; ** p < O.Oh n~7 in each group .
Discussion The present results confirm the findings of De Wied and associates in demonstrating that the subcutaneous injection of small amounts of endorphin analogues can alter the behavior of rats during extinction (1,2) . Here alpha endorphin increased resistance to extinction of an active avoidance task (pole-jump), but gamma endorphin decreased resistance to extinction . These behavioral effects are particularly interesting because the doses required are very small (1-10 g) and the behavioral change is still manifest several hours after the injection . That peptide-like compounds in
Vol . 24, No . 18, 1979
Endorphins and Extinction
163 5
small doses can significantly alter behavior has been demonstrated previously for angiotenain in drinking (8) and lutenizing hormone releasing factor in sexual behavior (9) and suggests that new dimensions must be considered in the study of behavioral pharmacology . In addition the present study extends the results of De Wied and associates by examining the effects of alpha and gamma endorphin on extinction of an appetitive task . Here, both alpha and gamma endorphin increased resistance to extinction in a runway task for water . These results make any simple interpretations in terms of neuroleptic activity difficult to accept . For example, alpha endorphin facilitates extinction of avoidance tasks and thus according to De Wied carries behavioral information opposite to that of gamma endorphin . Using these reaulte De Wied and associates have speculated about the possibility of an endogenous neuroleptic with a chemical structure related to gamma endorphin (6) . The fact that both alpha and gamma endorphin delay extinction in an appetitive task suggest that these interpretations as regards an opposite mode of action for these two peptides must be re-evaluated . One possible interpretation of the results on extinction of an avoidance response is that alpha and gamma endorphin are acting on some emotional substrate that is specific to aversive situations . Alpha and gamma endorphin also have opposite effects on passive avoidance behavior with alpha endorphin facilitating and gamma endorphin attenuating the retention of the avoidance response (1,2) . These reaulte are consistent to the interpretation discussed by De Wied where alpha endorphin "temporarily increases the motivational value of environmental stimuli, e .g ., aversive stimulation" (1) . Gamma endorphin would then presumably produce the opposite effect, i .e ., decreasing "fear" motivation . This interpretation would explain the delay in extinction seen in the appetitive experiment with gamma endorphin since it is established that anxiolytic drugs will prolong extinction (11) . However, it is not clear how an increase in "fear" produced by alpha endorphin would also delay extinction in an appetitive task . One possibility would be that the endorphins are also interacting with a motivational state specific to water reinforcement . Some evidence exists that suggests that peripheral injection of morphine and ß-endorphins can stimulate vasopressin release (12,13) and this in turn could alter water balance and thirst itself . Whether the differential effects on extinction in appetitive and aversive tasks found in the present experiments will extend to the use of other reinforcers remains to be determined . Finally, it is still of great interest to determine the Although physiological site and mechanism of action of these peptides . De Wied and associates seem to have eliminated any peripheral endo crinological mediation, and their results with intraventricular injections suggest a central action, (1,2) no studies to date have shown whether these peptides are acting directly upon the brain. Although the long term behavioral effects can be explained by an action of the drug on a particular behavioral contingency during a specified and possibly short period of time, further studies are needed to define where and how these peptides are producing their behavioral effects .
Endorphins and Extinction
1636
Vol . 24, No . 18, 1979
Acknowledgements The authors would like to thank Drs . Nicholas Ling and Roger Guillemin for the preparation of the synthetic endorphins . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 .
B . DE WIED, B . BONUS, J .M . VAN REE, and I . URBAN, J . Pharm . Exp . Ther . _204 570-580 (1978) . D . DE WIED, G . L . ROVACS, B . BONUS, M . M . VAN REE, and H .M . GREVEN, Eur . J . Pharm . 49 427-436 (1978) . H . RIGTER, Science 200 83-85 (1978) . D . DE WIED, Soc . Exp . Biol . Med . _122 28-32 (1966) . B . BONUS and D . DE WIED, Science _153 318-320 (1966) . D . DE WIED, B . BONUS, J . M . VAN REE, G . L . KOVACS, and H .M . GREVEN, Lancet _1 1046 (1978) . S . SIEGEL, Nonparametric statistics , McGraw-Hill, New York (1956) . J .T . FITZSIMONS and B .J . SIMONS, J . Physiol (London) _203 45-57 (1969) . R .L . MOSS and S .M . McCANN, Science _181 177-179 (1973) . D . DE WIED, _The Neurosciences , Third Study Program , Eds . F .O . Schmitt and F .G . Worden, pps . 653-666, MIT Press, Cambridge (1974) . J .A . GRAY, J . Comp . Physiol . Psychol . 6 9 55-64 (1969) . R .C . DE BODO, J . Pharm . Exp . Ther . _82 74-85 (1944) L-F . TSENG, H .H . LOH, C .H . LI . Int . J . Peptid e Res . _12 173-176 (1978) .
1631-1(,36
Pergamon Press
ENDORPHINS AND ERTINCTION : DIFFERENTIAL ACTIONS ON APPETITIVE AND ADVERSIVE TASKS Michel Le Moal, George F . Roob and Floyd E. Bloom Laboratoire de Psychophysiologie, Faculté des Sciences Université de Bordeaux 33 Talencè, France and A. O . Davis Center for Behavioral Neurobiology The Salk Institute San Diego, California 92112 (Received in final form March 6,
1979)
Summary Alpha and gamma endorphin both inhibited the extinction of a rum~ay task for water reward is water-deprived rata after subcutaneous injections of microgram dosages . At similar doses, these same peptides produced opposing actions on the extinction of a pole-jumping avoidance task : alpha endorphin inhibited and gamma endorphin facilitated extinction . The effects of these peptides on motivated behavior may thus be situationdependent . Recent studies by De Wied and associates have demonstrated that minute quantities peptides derived from the molecular structure of ß-lipotropin (ß-LPH) can influence animal behavior when injected peripherally, particularly extinction beh~vior in aversively motivated tasks . In such tasks, the effects of Met -enkephalin (ß-LPH 61-65), alpha endorphin (ß-LPH 61-76) and Beta endorphin (ß-LPH 61-91) produce effects opposite to those of gamma endorphin (ß-LPH 61-77) (1,2) . These effects do not appear to be related to interactions with typical opiate receptors (1,3) . Actions similar to those of enkephalin and of alpha and beta endorphin were reported earlier by this group for peptide fragmente of the ß-LPH molecule (ß-LPH 47-53, also referred to as ACTH 4-10) (4,5) . While moat of these peptides were reported to inhibit the extinction of pole-jump avoidance tasks, gamma-endorphin uniquely facilitated extinction (2) . More recently, De Wied and associates have speculated that the effects of gamma-endorphin and especially the synthetic peptide des-Tyr-gamma endorphin (6) have some pharmacological properties similar to neuroleptic drugs . In order to investigate the sites and mechanisms by which these peripherally injected peptides can influence behavior, it is important to determine whether their effects can be generalized across different types of behavioral tasks . If the actions of these peptides were similar for extinction of both aversive and appetitive tasks, for example, a primary learning or memory substrate might be sought as the mechanism of action . Alternatively, if the effects of the peptides were test dependent, leas general mechanisms of action might be sought which may be more related . to specific motivational variables . 0024-3205/79/181631-06502 .00/0 Copyright (c) 1979 Pergamon Press, Inc .
1632
Endorphins and Extinction
Vol . 24, No . 18, 1979
We now report that at comparable doses (1-10 ug/rat) the effects of alpha and gamma endorphin on rat behavioral paradigms are, in fact, dependent upon the test situation . Specifically, in a pole-jump avoidance task alpha endorphin inhibited extinction while gamma endorphin facilitates extinction, as reported by the De Wied group (2) . However, in an appetitively motivated drinking test, both endorphins inhibited extinction . These results suggest that the actions of the peptides on behavior depend upon the nature of the reinforcera maintaining the behavior . Methods For the pole jumping task the procedures of De Wied and coworkers w..re followed (1) . Eighteen male Wister albino rats weighing between 100 and 120 g were used . The rats were trained to jump onto a pole within 5 sec after presentation of a conditioned stimulus which consisted of illuminating six 28 V lights on one wall . Rats which failed to jump within 5 sec received 1 .2 to 1 .7 mA, D .C . of scrambled foot shock (shock was provided by a BRS/LVE constant power shock generator, model SGS-003) . The rats received 10 trials/ day with intertrial intervals of 40, 60, and 80 seconds presented in a random order . Ten rats were trained for 3 days in experiment 1 and eight rata were trained for 4 days in experiment 2 . Following acquisition all rats were given a ten trial extinction session. Following this first extinction trial each rat was injected with peptide or vehicle . The rata in experiment 1 (30 trials acquisition) received 1 ug of alpha endorphin and the rats in experiment 2 (40 trials acquisition) received 1 ug of gamma endorphin (both equal Extinction trials were then repeated again at 2 and 4 to 10 ug/kg) . hours after injection . Twenty-one male hooded rate (200-240 g) of the Long Evana strain were used in the drinking test . The apparatus consisted of a runway with two arms at a 60° angle ; each arm was 61 cm in length 12 .5 cm in width and 15 cm in height . The runway was constructed of aluminum with a floor of brass rode 2 .0 cm apart and a removable clear plexiglass roof . At one end of the arm a metal drinking tube protruded 3 cm into the arm. Contact with this tube registered an audible click . The rats were water deprived for 24 hours and on day 2 training began . Each rat received one trial per day for 7 consecutive days . A trial began with the placing of the rat facing the back wall in the long arm of the maze . Latency to run to the end of the opposite arm and to lick the water tube was recorded to the nearest second . The rat was allowed to drink for a total duration of 30 sec . Following each daily session, the rats were allowed to drink for 30 min., and thus were 23 .5 hr . water deprived before each daily test . Extinction testing was studied on the eighth day . Here the drinking tube remained in place but did not contain water. During the first extinction trial the rats were allowed to lick the dry tube in two separate bouts ; they were removed 30 seconds after the second bout . The rats were then randomly separated into three experimental groups and injected with either 10 ug per rat of alpha endorphin, 10 ug per rat of gamma endorphin (both equal to 40 ug/kg) or vehicle . All drugs were dissolved in physiological saline and injected subcutaneously in a volume of 0 .5 ml . Three subsequent extinction trials were performed every two hours. Data were subjected to a Kruskal-Wallis analysis of variance and/or a Mann-Whitney U-test (7) .
1633
Endorphins and Extinction
Vol . 24, No . 18, 1979
Reaulta As already reported by De Wied et al (2), alpha and gamma endorphin produce apparently opposite effects on the extinction of the pole jump task (Table I) . According to the protocol of those reports (2) alpha endorphin (1 yg/rat ; subcutaneous injection) delayed extinction of rate trained three days, while gamma endorphin at the same does facilitated extinction of rata trained for 4 days . Ia the present study, rate receiving 3 days training (30 acquisition trials) continued to jump significantly more to the conditioned stimulus when tented at 2 hours after receiving alpha endorphin (Mann-Whitney U - 0, p < 0.01) but by 4 hours were not significantly different from controls injected with only the saline vehicle. Conversely, rate given 4 days training (40 acquisition trials) jumped significantly fewer times/session than saline injected rata when tested at both 2 and 4 hrs after reThese ceiving gamma endorphin (Mann-Whitney U ~ 0 .5, p < 0 .02) . results closely reproduce those reported by De Wied et al (2) and indicate that peripherally injected peptides can influence animal behavior over long periods encompassing several hours . However, the effects are dependent upon training exposure, and in these tests the differences between the actions of the peptides depends upon the duration of the acquisition phase of the training . Alpha endorphin has the effect of delaying extinction to a degree equalled by ten additional acquisition trials (1 additional acquisition day) while gamma endorphin has the effect of accelerating extinction to the degree exhibited by the less fully trained rate . In the De Wied experiments (2) gamma endorphin did not alter the 3-day extinction nor did alpha endorphin alter 4-day extinction . Table I Effects of Alpha Endorphin and Gamma Endorphin on Extinction of Active Avoidance Behavior Groupe
(n)
Training
No . of Positive Responses in 10 trials of Extinction 0 hra .
Saline 0.5 ml Alpha endorphin 1 ug/rat Saline 0 .5 ml Gamma endorphin 1 ug/rat
+2 hrst
+ 4 hra
(5)
3 days
8 .Ott (7-10)
2 .0 (1-5)
(0-2)
(5)
3 days
8 .0 (8-9)
9 .0 * (8-10)
7 .0 (0-8)
(4)
4 days
9 .0 (9-10)
8 .5 (7-10)
8.5 (7-10)
(4)
4 days
9 .0 (8-10)
3 .0 (1-7)
1 .0* (0-5)
t Peptide or saline was injected immediately after this first
extinction session Two more extinction sessions followed 2 and 4 hours after injection tt tiedian and range in parenthesis * Aeterick indicates significant (p < 0 .05) difference from saline
1634
Endorphins and Extinction
Vol . 24, No .
18, 1979
Administration of alpha and gamma endorphin (10 ug/rat) also produced significant effects on extinction when water deprived rats were examined in a runway in which they had previously learned to find water . Rats given only saline injections (Fig . 1) showed a time-dependent steady increase in the latency to approach the dry tube over the three extinction sessions . This trend was significant : Xr= 15 .34, df-3 P < 0 .01 (Friedman analysis of variance) . In contrast, rats receiving either alpha or gamma endorphin continue to approach the dry tube as quickly as they had on acquisition trials, even though being permitted contact with the dry tube . In this teat, both peptides produced identical actions, equally enhancing the resistance to extinction, and these effects lasted for at least 6 hours . A KrusalWallis one-way analysis of variance showed a significant difference between the groups at extinction III and IV (p < 0 .02) with both alpha and gamma endorphin showing significantly shorter latencies than the saline group (Mann-Whitney U _< 5, p < 0 .01) . These same results with gamma endorphin were replicated using Wistar albino rats in the same test and apparatus .
InJ~eNon
D~ fnjMian
Figure 1 Median latency to touch a dry water tube during successive extinction sessions . Peptides were injected (40 ug/kg) immediately after the first extinction session . Asterick indicates significant difference from saline group ; ** p < O.Oh n~7 in each group .
Discussion The present results confirm the findings of De Wied and associates in demonstrating that the subcutaneous injection of small amounts of endorphin analogues can alter the behavior of rats during extinction (1,2) . Here alpha endorphin increased resistance to extinction of an active avoidance task (pole-jump), but gamma endorphin decreased resistance to extinction . These behavioral effects are particularly interesting because the doses required are very small (1-10 g) and the behavioral change is still manifest several hours after the injection . That peptide-like compounds in
Vol . 24, No . 18, 1979
Endorphins and Extinction
163 5
small doses can significantly alter behavior has been demonstrated previously for angiotenain in drinking (8) and lutenizing hormone releasing factor in sexual behavior (9) and suggests that new dimensions must be considered in the study of behavioral pharmacology . In addition the present study extends the results of De Wied and associates by examining the effects of alpha and gamma endorphin on extinction of an appetitive task . Here, both alpha and gamma endorphin increased resistance to extinction in a runway task for water . These results make any simple interpretations in terms of neuroleptic activity difficult to accept . For example, alpha endorphin facilitates extinction of avoidance tasks and thus according to De Wied carries behavioral information opposite to that of gamma endorphin . Using these reaulte De Wied and associates have speculated about the possibility of an endogenous neuroleptic with a chemical structure related to gamma endorphin (6) . The fact that both alpha and gamma endorphin delay extinction in an appetitive task suggest that these interpretations as regards an opposite mode of action for these two peptides must be re-evaluated . One possible interpretation of the results on extinction of an avoidance response is that alpha and gamma endorphin are acting on some emotional substrate that is specific to aversive situations . Alpha and gamma endorphin also have opposite effects on passive avoidance behavior with alpha endorphin facilitating and gamma endorphin attenuating the retention of the avoidance response (1,2) . These reaulte are consistent to the interpretation discussed by De Wied where alpha endorphin "temporarily increases the motivational value of environmental stimuli, e .g ., aversive stimulation" (1) . Gamma endorphin would then presumably produce the opposite effect, i .e ., decreasing "fear" motivation . This interpretation would explain the delay in extinction seen in the appetitive experiment with gamma endorphin since it is established that anxiolytic drugs will prolong extinction (11) . However, it is not clear how an increase in "fear" produced by alpha endorphin would also delay extinction in an appetitive task . One possibility would be that the endorphins are also interacting with a motivational state specific to water reinforcement . Some evidence exists that suggests that peripheral injection of morphine and ß-endorphins can stimulate vasopressin release (12,13) and this in turn could alter water balance and thirst itself . Whether the differential effects on extinction in appetitive and aversive tasks found in the present experiments will extend to the use of other reinforcers remains to be determined . Finally, it is still of great interest to determine the Although physiological site and mechanism of action of these peptides . De Wied and associates seem to have eliminated any peripheral endo crinological mediation, and their results with intraventricular injections suggest a central action, (1,2) no studies to date have shown whether these peptides are acting directly upon the brain. Although the long term behavioral effects can be explained by an action of the drug on a particular behavioral contingency during a specified and possibly short period of time, further studies are needed to define where and how these peptides are producing their behavioral effects .
Endorphins and Extinction
1636
Vol . 24, No . 18, 1979
Acknowledgements The authors would like to thank Drs . Nicholas Ling and Roger Guillemin for the preparation of the synthetic endorphins . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 .
B . DE WIED, B . BONUS, J .M . VAN REE, and I . URBAN, J . Pharm . Exp . Ther . _204 570-580 (1978) . D . DE WIED, G . L . ROVACS, B . BONUS, M . M . VAN REE, and H .M . GREVEN, Eur . J . Pharm . 49 427-436 (1978) . H . RIGTER, Science 200 83-85 (1978) . D . DE WIED, Soc . Exp . Biol . Med . _122 28-32 (1966) . B . BONUS and D . DE WIED, Science _153 318-320 (1966) . D . DE WIED, B . BONUS, J . M . VAN REE, G . L . KOVACS, and H .M . GREVEN, Lancet _1 1046 (1978) . S . SIEGEL, Nonparametric statistics , McGraw-Hill, New York (1956) . J .T . FITZSIMONS and B .J . SIMONS, J . Physiol (London) _203 45-57 (1969) . R .L . MOSS and S .M . McCANN, Science _181 177-179 (1973) . D . DE WIED, _The Neurosciences , Third Study Program , Eds . F .O . Schmitt and F .G . Worden, pps . 653-666, MIT Press, Cambridge (1974) . J .A . GRAY, J . Comp . Physiol . Psychol . 6 9 55-64 (1969) . R .C . DE BODO, J . Pharm . Exp . Ther . _82 74-85 (1944) L-F . TSENG, H .H . LOH, C .H . LI . Int . J . Peptid e Res . _12 173-176 (1978) .