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Peptides and behavior
Life Scieacae Vol . 20, pp . 195-204, 1977 . Printed in thn U. S . A.
Pergamon Preee
MINIREVIEW PEPTIDES AND BEHAVIOR David de Wied Rudolf Magnus Institute for Pharmacology Medical Faculty, University of Utrecht, Vondellaan 6, Utrecht, The Netherlands .
During the last decade a great number of experiments have disclosed the implication of pituitary and hypothalamic hormones in various brain functions . Such an involvement became apparent after observations of behavioral disturbances which occur in rats in which the adenohypophysis or the whole gland had been roved (1, 2), and in animals with hereditary diabetes insipidus which lack the ability to synthetize vasopresein (3) . Impaired behavior associated with the absence of pituitary principles can be restored readily by treatment with ACTH or vasopresein, but also with fragments of then® polypeptides which themselves ame devoid of the classical endocrine effects of their parent hormones . Thus, the hypothalamic pituitary complex appears to be a source of "neuropeptides" generated from hypothalamic and pituitary hormones which may be regarded as precursor molecules for these entities .
Short term and lon term behavioral effect of ACTH and vaso~ressin . St 1es in hypop ysectom zed rata revea the e qni cance of pituitary hormones on acquisition of learned behavior . Although removal of the pituitary gland leads to a general endocrine and metabolic disturbance in addition to physical debilitation, the behavioral deficiency which accompanies the absence of pituitary principles can be corrected by hormonally inert fragments of ACTH, MSH, lipotropin (B-LPH), and vasopresein . Thus impaired avoidance acquisition in the shuttle box of hypophysectomized rats responds to treatment with ACTH, a- and ß-MSH, ACTH 4-10, vasopresein end desglycinamide9-lysine$-vasopresein (DG-LVP) (2,4,5) . The action of peptides related to ACTH and those related to vasopresein is basically different with respect t$ the duration of the effect . Administration of ACTH 4-10 or lysine vasopresein (LVP) restores impaired avoidance acquisition of hypophysectoanized rats in the shuttle box (5) . Cessation of the treatment after one week when avoidance performance of the treated groups is at a high level, results in a progressive deterioration of avoidance behavior in animals receiving ACTH 4-10 despite shock reinforcement . In contrast, cessation of the treatment with LVP did not affect subsequent avoidance performance . Thus, peptides related to ACTH have a "short term" behavioral effect, those related to vasopresein a "long term" one. A similar qualitative difference was observed on the maintenance of active and passive avoidance behavior in intact rats (6-8) . Thus, a single injection of ACTH 4-10 delays extinction of a pole jumping avoidance response in intact rats for several hours, one of vasopresein for several days (8) . 195
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ß-LPH fra ents and avoidance behavior . The foregoing suggests that neuropeptides derived rom pituitary ACTH play an important role in adaptive behavioral mechanisms . It is possible that ACTH 4-10 represents the actual neurotropic effector of ACTH/MSH/9-LPH . It is also conceivable that other sequences of these pituitary hormones are essential in this respect . Attempts to isolate from the pituitary relatively small peptides related to these hormones which, like ACTH 4-10, would be able to restore the deficient learning behavior of hypophysectomized rats or affect the maintenance of avoidance behavior in intact rats (9-11), suggested the presence of more potent oligopeptides in hog pituitary material . The first peptide which was identified as a potentially potent behavioral agent was not related to ACTH and appeared to be DG-LVP (10) . Further studies, however, revealed the existence of a number of peptides possibly related to ß-LPH. The amino acid composition of one fraction obtained after trypsin digestion of one of the purified fractions (BC 7a) was strikingly similar to that of B-LPH 61-69 (11) . Behaviorally, it was stronger acting that ACTH 4-10 . Indeed, on a weight basis, 9-LPH 61-69 is ten times as active as ACTH 4-10 in delaying extinction of the pole jumping avoidance response . The same holds for ß-LPH 61-76 and ß-LPH 61-91 . ACTH 4-10 is identical to B-LPH 47-53 as part of B-MSH or to a-MSH 4-10 . Which one of ACTH, a-, B-MSH, ß-LPH acts as the precursor molecule of neuropeptides modulating adaptive behavior, is not yet known . The results so far indicate redundancy in behaviorally active sequences in these pituitary hormones . It is possible that other neuropeptides will be found eventually which may affect learned behavioral responses in a more potent and specific manner . Studies on degradation of ACTH, a- and ß-MSH and B-LPH by pituitary and brain enzymes may eventually reveal the nature and the behavioral activity of the various neuropeptides generated from these prohormones . ACTH on motivation and learnin . A plausible explanation for the short term of ect of ACTH and related peptides seems to be a temporary increase in motivation . Several studies support this hypothesis . Facilitation of acquisition of shuttle box avoidance behavior of rats trained at a low footshock level (12), facilitation of acquisition of food-rewarded behavior in a multiple Tmaze (13) suggest a motivational effect . Other studies point in the same direction . ACTH and related peptides delay extinction of active avoidance behavior and facilitate passive avoidance behavior (14-21), inhibit extinction of approach behavior motivated by food (22-27), and delay extinction of sexually motivated approach behavior (28) . It further appeared that a-MSH facilitates reversal learning (29), that ACTH 1-24 improves discrimination learning (21), and that ACTH 4-10 attenuates carbon dioxide-induced amnesia for a passive avoidance response (30) . These studies indicate that ACTH may also affect learning and retrieval processes although motivational effects cannot be excluded . Vasopressin and memory processes . Vasopressin is physiologically involved in memory processes . Rats of the Brattleboro strain with a genetic defect in the synthesis of vasopressin are inferior in maintaining active and passive avoidance behavior (31) . Memory impairment in these animals is most readily detected in a simple one trial passive avoidance procedure (3) . Rats homozygous for diabetes insipidus (HO-DI) in contrast to heterozygous littermates (HE-DI) fail to exhibit passive avoidance behavior when tested 24, 48 or 72 hours after shock exposure . Treatment immediately after
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the learning trial with arginine8-vasopressin (AVP) or DG-LVP restores the behavior of these animals . .HO-DI rats do avoid without vasopressin treatment when tested immediately after the learning trial indicating that memory rather than learning processes are disrupted in the absence of vasopressin. Intraventricülar administration of vasopressin antiserum which binds vasopressin in the CSF elicits the same behavioral disturbance and prevents passive avoidance behavior . This is not the case when the antiserum is administered syst~aically (32) . Learning is not affected in this situation either since full passive avoidance behavior is found if animals are tested within 3 hours after the learning trial . Evidence for an effect of vasopressin on memory processes can also be derived from studies on amnesia. Lands et al . (33) reported that DG-LVP protects against puromycin-induced memory loss in mice . Other neurohypophyseal hormones and fragments of these Peptides have similar effects (34) . Amnesia for a one trial passive avoidance response in rate as induced by C02 or electroconvuleive shock is reversed by DG-LVP when injected immediately after the learning trial or one hour prior to the retention test . Rigter et al . (30) suggested that vasopressin prc®otes memory consolidation or retrieval processes .
H thalamic and ituitar hormones as recursor molecules for neuro a tides . A large n er o pept a rmones appears to sty rom precursor molecules from which the hormonal principle is released enzymatically . Angiotensin II (35) and insulin (36) are well known examplesi evidence for a similar mechanism ie e~erging for vasopressin (37), gastrin (38), parathyroid hormone (39), ACTH (38), and growth hormone (40) . Pituitary hormones may in turn be precursor molecules for neuropeptides . ACTH and 9-LPH are synthetized in the anterior and intermediate lobe of the pituitary. In the intermediate lobe, ACTH acts as the precursor molecule for aMSH and ACTH 18-39, while B-LPH is the prohormone for 7-LPH and a C-terminal peptide and ß-MSH (41) . Thus, the intermediate lobe contains specific enzymes for the generation of oligopeptides which exert effects different from those of their parent hormones, e .q . MSH-activity in case of a- and ß-MSH, "opiate-like" activity in case of the C-fragment of ß-LPH (42) . Recent reports have shown that in the brain (43-45) and in the pituitary (46,47) there exist endogenous peptides with opiate-like activity . One of the brain peptides was isolated and the structure determined . It appeared to be a pentapeptide (met-enkephalin), the structure appearing identical to ß-LPH 61-65 . A related opiatelike peptide which was recently isolated from hog hypothalamic neurohypophyseal tissue, a-endorphin, appeared to be identical to B-LPH, of which met-enkephalin is the N-terminal pentapeptide (48) . The C-fragment of 9-LPH which is released from lipotropin by mild digestion with trypsin in vitro (42,49) and which represents 9-LPH 61-91, appeared to have an even higher affinity for brain opiate binding sites than did smaller sequences . Since B-LPH is without effect in this respect, the active C-fragment and related peptides probably are generated from this pituitary hormone by enzymes present in either the pituitary or the brain . The hypothalamus exhibits similar enzymatic control in the generation of oligopeptides with intrinsic activities dissimilar to that of the neurohypophyseal hormones . The discoveries that H-Pro Leu-Gly-NH2 (PLG or MIF) is the active peptide which inhibits the release of MSH from the pituitary gland (50,51) and that it is released enzymatically from oxytocin (50,52), showed for the first time that a peptide hormone can release an active moiety with ef-
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fects unlike those of the parent hormone . Our results, which showed that ACTH 4-7 is as active as the whole ACTH molecule in affecting acquisition and extinction and that N-terminal fragments of vasopressin affect the consolidation of learned responses, were the first to indicate dissociation between endocrine and behavioral effects of hypothalamic and pituitary hormones . The memory consolidating effect of vasopressin is mainly located in the N-terminal covalent ring structure preasinamide . Following intraventricular administration, it is nearly as active as AVP in increasing resistance to extinction of a pole jumping avoidance response in contrast to the C-terminal tripeptide H-Pro-Arg-Gly-NH (PAG) . The protective effect of neurohypbphyseal hormones on puromycin-induced amnesia in mice (33) is however located mainly in the C-terminal fragments of these polypeptides (34) .
Neuro e tides and the develo ent of tolerance and h sical development to narcotic ana gesics . Another interesting an proba ly related . observation is the demonstration that fragments of neuro hypophyseal hormones facilitate the development of both resistance to the analgesic effect of and physical dependence on narcotic analgesics . Krivoy et al .(53) showed that chronic treatment of mice with high amounts of DG-LVP facilitated the development of resistance to the analgesic action of morphine . This polypeptide does not it self exert hyperalgesia and does not compete with morphine for the opiate receptor in rat brain synaptosomal plasma membranes (54) . The implication of vasopressin in the development of tolerance to narcotic analgesics was subsequently demonstrated in brattleboro rats . It was found that the response to the hot plate in HE-DI rats treated daily with analgesic amounts of morphine, gradually diminished until full tolerance had developed after the fifth injection . The response in HO-DI rats, treated in the same way was however saved even after 8 consecutive days of treatment with morphine (55) . Administration of AVP or DG-LVP immediately after the daily trial on the hot plate restored the development of tolerance to morphine in HO-DI rats . Subsequent experiments were performed, using body weight loss and change in body temperature in response to naloxone as indices of physical dependence, in rats treated chronically with morphine . It appeared that oxytocin was markedly more potent than vasopressin in facilitating physical dependence to morphine (56) . This activity appeared to reside in the C-terminal tüpeptide PLG . This peptide was as potent as oxytocin while tocinamide was ineffective . Interestingly, these results compare favourably with those obtained in the amnesia test of Walter et al .(34) . In this test, PLG was one of the most effective peptides in protecting against puromycin-induced amnesia in mice, while tocinamide had only weak activity . This suggests that neurohypophyseal hormones operate at different levels to affect memory processes .
Neuropeptides affecting sleep . Peptides affecting sleep have also been detected in the brain . Rabbits, kept asleep by stimulation of the thalamic sleep centre, produce a hypnogenic substance which elicits delta activities in the EEG, reduces motor activity, heart rate and respiration following infusion into the meso-diencephalic ventricular system . This so-called "delta sleep factor" seems to be an oligopeptide (57,58) . The structure of the peptide is not known but it is tempting to speculate that the hypothalamicpituitary complex is the source of this peptide ; the more so since ,hormones from this complex are involved in sleep-waking patterns .
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Several peptide hormones affect sleep-waking patterns in various species . Cats given growth hormone (GH) but not thyrotropin (TSH) showed a s®lective elevation of paradoxical sleep (PS) episodes for 3 hours after injection (59) . The greatly increased secretion of GH during slow wave sleep in man (60) according . to Stern et al . (59) may play a role in the occurrence of PS . Hypophysectomized rata have shorter PS episodes and lack the normal circadian rhythmicity of PS (61) . PS is disturbed in the chronic pontine cat without hypothalamus and pituitary (62) but only for 5 days or more after the operation. These disturbances can be restored with various pituitary principles . Hypophysectomized rabbits spent a greater proportion of time in slow wave sleep with slightly less time in PS than intact animals, although spontaneous PS episodes and PS induced by electrical stimulation of the brain both occurred readily in the absence of the pituitary gland (63) . Recent electrophysiological studies in free moving Brattleboro rats have shown that the frequency content of rhythmic slow activity (RSA) of HO-DI rats during PS substantially deviates from the activity of .their heterozygous littermates (64) . Differences were mostly confined to "average" and "peak" frequencies which in HO-DI rats were approximately one C/S lower than those of HE-DI animals . Thus, PS fails to produce normal theta frequency in the absence of vasopreasin indicating a qualitatively different PS . Administration of Vasopreasin and Vasopreasin fragments restores the distribution of hippocampal theta frequencies in HO-DI rats . The same peptides but also ACTH 4-10 enhance the generation of higher frequencies during PS in HE-DI and homozygous normal Brattleboro rats . Conversely, the intracerebroventricular administration of vasopressin antiserum which binds Vasopreasin present in the CSF, elicits the same differences in RSA during PS as found in HO-DI rats . In addition,[D-Phe7] ACTH 4-10 which facilitates extinction of active avoidance behavior (18) thus exerting an effect opposite to that of [L-Phe 7] ACTH 4-10, also induces lower theta frequencies during PS . The disturbed RSA during PS may be related to consolidation deficits which are observed in rats which lack Vasopreasin . Deprivation of PS interferes with the consolidation of learned responses (65-67) . Drugs which facilitate m~aory formation promote theta activity in the poatlearninq period (68) . This suggests that changes in excitability in the hippocampal theta activity generating substrate are related to memory consolidation . Trans rt of neuro tides to the sites of action . Although the systemic a inistration o ACTH ragments a Vaeopressin fragments elicits the various behaviors reported above, intracerebroVentricular administration is much more effective . Thus, using this route, between 200 and 1000 times less of ACTH 4-10, AVP or preseinamide is needed to delay extinction of pole jumping avoidance behavior . In addition, some behaviors are elicited only after intracerebral administration . Fox example, in a variety of mammals ACTH induces a stretching and yawning syndra~me (SYS) after intracranial administration (69,70) . In the rat, the onset of the syndrome is preceded by display of increased grooming (71,72) . This effect which is located in the N-terminal part of the ACTH molecule, .cannot .be elicited following systemic administration : These observations and the presence of ACTH (73), Vaeopressin and vasotocin (74-77) and of .prolactin (78) in the CSF suggest that pituitary hormones are transported directly to the brain . Morphological observations point to a connection between neurosecretory cells and the ependyma of the infundibular recess of the third ventricle .
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Using imurunochemical techniques, Goldsmith and Zimmeruran (79) and Zimmerman et al .(80) demonstrated that neuronal processes containing granules with neurophysin and vasopressin are present not only close to portal capillary loops, but also protrude in the third ventricle . Although hypothalamic limbic pathways .have been suggested as an integral subsystem of a peptidergic neurosecretory system (81,82), the CSF may be the preferred route for the behavioral effects of neurohypophyseal hormones to reach the sites of action in the brain . The demonstration that intraventricular administration of vasopressin antiserum prevents passive avoidance behavior (32) supports this hypothesis . The actual mode of transport of pituitary hormones to the brain is not known and remains a matter for speculation . Various possibilities have been offered, such as retrograde transport along the pituitary stalk or the existence of basilar cisterns which may be connected with the CSF in the adenohypophysis close to the hormoneproducinq cells (73) and transport via the blood . Szentagothai et al .(83) already suggested a microcirculation which would carry hormonal substances from the pituitary to the brain . Recent evidence for such a connection was obtained by Ambach and Palkovits (84) who showed that the nucleus periventricularis receives blood from the anterior hypophyseal artery . The brain itself may also be the production site of neuropeptides . Vasopresain and oxytocin are produced in the supraoptic and paraventricular nuclei of the hypothalamus . Recently, localization of compounds related to a-MSH have been detected in various regions in the brain by immunolocalization (85,86,87) .In addition, immunoreactive a-MSH is still present throughout the brain 3 weeks after hypophysectomy (87) . That these centrally occurring peptides are not the only source of neuropeptides is suggested by our observations on the deficient avoidance beha= vior of hypophysectomized rats which can be readily corrected by the administration of relatively small amounts of ACTH-like peptides (2) . Concludin remarks . Pituitary peptides related to ACTH, MSH, ßLPH and vasopress n appear to affect motivational, learning and memory processes . Other peptides originating from the brain have central nervous system effects . For detailed information on the central effects of hypophysiotropic hormones, the reader is referred to the excellent review by Prang~ et al .(88) . In general, the various releasing hormones have not been connected to specific behaviors except for LHRH . This decapeptide facilitates lordosis behavior in ovariectomized and hypophysectomized rats (89,90) and accelerates ejaculation in intact and in castrated rats maintained on testosterone (91) . Angiotensin II elicits drinking in rat (92) and substance P, whose structure was recently characterized (93) and which may be regarded as an excitatory transmitter (94), abolishes the abstinence syndrome in morphinized mice and reduces aggressiveness in the same species (95) . The field is rapidly expanding and one may expect a vast increase in information within the coming years . It is already clear that the hypothalamic-pituitary complex produces large numbers of neuropeptides carrying specific information to brain structures involved in the behavioral repertoire of the organism . Findings so far indicate the existence of neuropeptides which affect learning, memory and motivation, neuropeptides with opiate-like activity, and neuropeptides affecting sleep, thirst, aggression (95,96) and the development of tolerance and physical dependence .
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60 . Y .Takahashi, D .M .Ripnis and W .H .Daughaday, J . Clin . Invest ._47, 2079-2090 (1968) . 61 . J .L .Valatx, G .Chouver and M .Jouvet, Pro rasa in Brain Research, D. e nus, B .Bohus a eds . W.H .Gispen, Tj .B .van Wimersma Gre Wied, 42, 115-120 . Elsevier, Amsterdam (1975) . 62 . M.Jouvét, As acts Anatoaao-fonctionelles de la Ph siolo ie du Sommeil, CNRS Paris, - 9 196 63 . H .G .Spies, D .I .Whitmoyer and Ch .H .Sawyer, Brain Res . _18, 155164 (1970) . 64 . I .Urban and D . de Wied, Brain Res . 97, 362-366 (1975) . 65 . P .Leconte and V.Bloch, C .R .Acad .Sci~Paris) Ser .D , 271, 226-229 (1970) . 66 . W.C .Stern, ~Ph sio~l . Behav . _7, 345-352 (1971) . 67 . W.Fishbein, Physiol~v . 6, 279-282 (1971) . 68 : V .G .Longo and A.Loizzo, Pharmacology and the Future of Man , eds . ~F .E .Bloom and G .H .Acheson, _4, Brain Nerves and Synapses . Rarqer, Basel, 46-54 (1973) . 69 . W.Ferrari, G .L .Gessa and L .Vargiu, Ann . N .Y . Acad . Sci . _104, 330-345 (1963) . 70 . G .L .Gessa, M .Pisano, L .Vargiu, F .Crabai and W.Ferrari, Rev . Can. Biol . 26, 229-236 (1967) . 71 . R .Izumi, J .Dônaldson and A .Barbeau, Life Sci . _12, 203-210 (1973) . 72 . W.H .Gispen, V .M .Wiegant, H .M .Greven and D . de Wied, Life Sci . 17, 645-652 (1975) . 73 . J .P .Allen, J .W .Kendall, R .McGilvra and C .Vancura, J . Clin . En docr . 38, 586-593 (1974) . 74 . H .Hellér, S .H .Hasan and A .Q .Saifi, J .Endocr . _41, 273-280 (1968) . 75 . H .Vorherr, M .W .B .Bradbury, M.Hoghouqhi and C .R .Rleeman, Endo crinology 83, 246-250 (1968) . 76 . K .R .Gupta, Lancet 1, 581 (1969) . 77 . S .Pavel, J .C11n .Endocr . 31, 369-371 (1970) . 78 . J .Assies and J .L .Tou er,l~bstract No .116, 58th Annual Meeting of the Endocrine Societ , San Francisco, June 1976 . 79 . P .C .Gol smith and E .A .Zimmerman, 57th Meetin of the Endocrine Society , suppl . to Vol . 96, A 377 1 7 80 . E .A .Zimmerman, G .P .Kozlowski and D .E .Scott, Brain-Endocrine Interaction II , eds . R .M .Rnigge, D .E .Scott, H .Robayashi and S . Ishü , 123-134 . Karqer, Basel (1975) . 81 . G .Sterba, Zoo1 .J .Physiol . 78, 409-423 (1974) . 82 . J .B .Martin, L .P .Renaud and P .Brazesu ., Lancet _II, 393-395 (1975) . 83 . J .Szentâgothai, B .Flerk6, B .Mess and B .Halâsz, H ~othalamic control of tt~e anterior ituita An ex erimenta -mor o ical study . Akad iai Kiad , Budapest 196 84 . G .Ambach and M.Palkovits, Acta Morph. Acad .~Sci . Hung . 23, 2149 (1975) . 85 . D :Rudman, J .W .Scott, A .E .Del Rio and S .Sheen, Amer .J .Physiol . 226, 682-686 (1974) . 86 . D .F .Swaab, Abstract no .285, V International Con rasa of Endocrinology , Hamburg, July 197 . 87 . C .Oliver, R.L .Eskay and J .C .Porter, Abstract no .594, V International Con rasa of Endocrinolo , Hamburq,July 1976 . 88 . A.J .Prange, Jr ., C .B .Nemero f, M .A . Lipton, G .R . Breese and I .C .Wilson, Handbook of Ps cho harmacolo , eds . L .L .Iversen, S .D . Iversen and S .H .Sn er, P enum Press, New York, in press . 89 . R .L . Moss and S .M . McCann, Science 181, 177-179 (1973) .
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90, D .W . Pfaff, Science 182, 1148-1149 (1973) . 91, R .L . Moss, S .M . McCânn and C .A . Dudley, Progress in Brain Re search, eds . W .H . Gispen, Tj .B .van Wimersma Greidanus, B .Bohus an~D. de Wied, 42, 37-46 . Elsevier, Amsterdam (1975) . 92, A .N . Epstein, J .T. Fitzsimons and B,J . Situons, J . Physiol . _196, 98-104 (1968) . 93 . S .E . Leeman and E .A . Mroz, Life Sci . 15, 2033-2044 (1975) . 94 . M . Otsuka, S . Konishi and T . Takahashi, Fed . Proc . 34, 19221928 (1975) . 95, P . Stern and S . HadzoviL', Arch . Int . Pharmacodyn . _202, 259-262 (1973) . 96 . P .F . Brain, N,W. Nowell and A . Wouters, Physiol, Behav . 6, 27_ 29 (1971) .
Pergamon Preee
MINIREVIEW PEPTIDES AND BEHAVIOR David de Wied Rudolf Magnus Institute for Pharmacology Medical Faculty, University of Utrecht, Vondellaan 6, Utrecht, The Netherlands .
During the last decade a great number of experiments have disclosed the implication of pituitary and hypothalamic hormones in various brain functions . Such an involvement became apparent after observations of behavioral disturbances which occur in rats in which the adenohypophysis or the whole gland had been roved (1, 2), and in animals with hereditary diabetes insipidus which lack the ability to synthetize vasopresein (3) . Impaired behavior associated with the absence of pituitary principles can be restored readily by treatment with ACTH or vasopresein, but also with fragments of then® polypeptides which themselves ame devoid of the classical endocrine effects of their parent hormones . Thus, the hypothalamic pituitary complex appears to be a source of "neuropeptides" generated from hypothalamic and pituitary hormones which may be regarded as precursor molecules for these entities .
Short term and lon term behavioral effect of ACTH and vaso~ressin . St 1es in hypop ysectom zed rata revea the e qni cance of pituitary hormones on acquisition of learned behavior . Although removal of the pituitary gland leads to a general endocrine and metabolic disturbance in addition to physical debilitation, the behavioral deficiency which accompanies the absence of pituitary principles can be corrected by hormonally inert fragments of ACTH, MSH, lipotropin (B-LPH), and vasopresein . Thus impaired avoidance acquisition in the shuttle box of hypophysectomized rats responds to treatment with ACTH, a- and ß-MSH, ACTH 4-10, vasopresein end desglycinamide9-lysine$-vasopresein (DG-LVP) (2,4,5) . The action of peptides related to ACTH and those related to vasopresein is basically different with respect t$ the duration of the effect . Administration of ACTH 4-10 or lysine vasopresein (LVP) restores impaired avoidance acquisition of hypophysectoanized rats in the shuttle box (5) . Cessation of the treatment after one week when avoidance performance of the treated groups is at a high level, results in a progressive deterioration of avoidance behavior in animals receiving ACTH 4-10 despite shock reinforcement . In contrast, cessation of the treatment with LVP did not affect subsequent avoidance performance . Thus, peptides related to ACTH have a "short term" behavioral effect, those related to vasopresein a "long term" one. A similar qualitative difference was observed on the maintenance of active and passive avoidance behavior in intact rats (6-8) . Thus, a single injection of ACTH 4-10 delays extinction of a pole jumping avoidance response in intact rats for several hours, one of vasopresein for several days (8) . 195
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ß-LPH fra ents and avoidance behavior . The foregoing suggests that neuropeptides derived rom pituitary ACTH play an important role in adaptive behavioral mechanisms . It is possible that ACTH 4-10 represents the actual neurotropic effector of ACTH/MSH/9-LPH . It is also conceivable that other sequences of these pituitary hormones are essential in this respect . Attempts to isolate from the pituitary relatively small peptides related to these hormones which, like ACTH 4-10, would be able to restore the deficient learning behavior of hypophysectomized rats or affect the maintenance of avoidance behavior in intact rats (9-11), suggested the presence of more potent oligopeptides in hog pituitary material . The first peptide which was identified as a potentially potent behavioral agent was not related to ACTH and appeared to be DG-LVP (10) . Further studies, however, revealed the existence of a number of peptides possibly related to ß-LPH. The amino acid composition of one fraction obtained after trypsin digestion of one of the purified fractions (BC 7a) was strikingly similar to that of B-LPH 61-69 (11) . Behaviorally, it was stronger acting that ACTH 4-10 . Indeed, on a weight basis, 9-LPH 61-69 is ten times as active as ACTH 4-10 in delaying extinction of the pole jumping avoidance response . The same holds for ß-LPH 61-76 and ß-LPH 61-91 . ACTH 4-10 is identical to B-LPH 47-53 as part of B-MSH or to a-MSH 4-10 . Which one of ACTH, a-, B-MSH, ß-LPH acts as the precursor molecule of neuropeptides modulating adaptive behavior, is not yet known . The results so far indicate redundancy in behaviorally active sequences in these pituitary hormones . It is possible that other neuropeptides will be found eventually which may affect learned behavioral responses in a more potent and specific manner . Studies on degradation of ACTH, a- and ß-MSH and B-LPH by pituitary and brain enzymes may eventually reveal the nature and the behavioral activity of the various neuropeptides generated from these prohormones . ACTH on motivation and learnin . A plausible explanation for the short term of ect of ACTH and related peptides seems to be a temporary increase in motivation . Several studies support this hypothesis . Facilitation of acquisition of shuttle box avoidance behavior of rats trained at a low footshock level (12), facilitation of acquisition of food-rewarded behavior in a multiple Tmaze (13) suggest a motivational effect . Other studies point in the same direction . ACTH and related peptides delay extinction of active avoidance behavior and facilitate passive avoidance behavior (14-21), inhibit extinction of approach behavior motivated by food (22-27), and delay extinction of sexually motivated approach behavior (28) . It further appeared that a-MSH facilitates reversal learning (29), that ACTH 1-24 improves discrimination learning (21), and that ACTH 4-10 attenuates carbon dioxide-induced amnesia for a passive avoidance response (30) . These studies indicate that ACTH may also affect learning and retrieval processes although motivational effects cannot be excluded . Vasopressin and memory processes . Vasopressin is physiologically involved in memory processes . Rats of the Brattleboro strain with a genetic defect in the synthesis of vasopressin are inferior in maintaining active and passive avoidance behavior (31) . Memory impairment in these animals is most readily detected in a simple one trial passive avoidance procedure (3) . Rats homozygous for diabetes insipidus (HO-DI) in contrast to heterozygous littermates (HE-DI) fail to exhibit passive avoidance behavior when tested 24, 48 or 72 hours after shock exposure . Treatment immediately after
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the learning trial with arginine8-vasopressin (AVP) or DG-LVP restores the behavior of these animals . .HO-DI rats do avoid without vasopressin treatment when tested immediately after the learning trial indicating that memory rather than learning processes are disrupted in the absence of vasopressin. Intraventricülar administration of vasopressin antiserum which binds vasopressin in the CSF elicits the same behavioral disturbance and prevents passive avoidance behavior . This is not the case when the antiserum is administered syst~aically (32) . Learning is not affected in this situation either since full passive avoidance behavior is found if animals are tested within 3 hours after the learning trial . Evidence for an effect of vasopressin on memory processes can also be derived from studies on amnesia. Lands et al . (33) reported that DG-LVP protects against puromycin-induced memory loss in mice . Other neurohypophyseal hormones and fragments of these Peptides have similar effects (34) . Amnesia for a one trial passive avoidance response in rate as induced by C02 or electroconvuleive shock is reversed by DG-LVP when injected immediately after the learning trial or one hour prior to the retention test . Rigter et al . (30) suggested that vasopressin prc®otes memory consolidation or retrieval processes .
H thalamic and ituitar hormones as recursor molecules for neuro a tides . A large n er o pept a rmones appears to sty rom precursor molecules from which the hormonal principle is released enzymatically . Angiotensin II (35) and insulin (36) are well known examplesi evidence for a similar mechanism ie e~erging for vasopressin (37), gastrin (38), parathyroid hormone (39), ACTH (38), and growth hormone (40) . Pituitary hormones may in turn be precursor molecules for neuropeptides . ACTH and 9-LPH are synthetized in the anterior and intermediate lobe of the pituitary. In the intermediate lobe, ACTH acts as the precursor molecule for aMSH and ACTH 18-39, while B-LPH is the prohormone for 7-LPH and a C-terminal peptide and ß-MSH (41) . Thus, the intermediate lobe contains specific enzymes for the generation of oligopeptides which exert effects different from those of their parent hormones, e .q . MSH-activity in case of a- and ß-MSH, "opiate-like" activity in case of the C-fragment of ß-LPH (42) . Recent reports have shown that in the brain (43-45) and in the pituitary (46,47) there exist endogenous peptides with opiate-like activity . One of the brain peptides was isolated and the structure determined . It appeared to be a pentapeptide (met-enkephalin), the structure appearing identical to ß-LPH 61-65 . A related opiatelike peptide which was recently isolated from hog hypothalamic neurohypophyseal tissue, a-endorphin, appeared to be identical to B-LPH, of which met-enkephalin is the N-terminal pentapeptide (48) . The C-fragment of 9-LPH which is released from lipotropin by mild digestion with trypsin in vitro (42,49) and which represents 9-LPH 61-91, appeared to have an even higher affinity for brain opiate binding sites than did smaller sequences . Since B-LPH is without effect in this respect, the active C-fragment and related peptides probably are generated from this pituitary hormone by enzymes present in either the pituitary or the brain . The hypothalamus exhibits similar enzymatic control in the generation of oligopeptides with intrinsic activities dissimilar to that of the neurohypophyseal hormones . The discoveries that H-Pro Leu-Gly-NH2 (PLG or MIF) is the active peptide which inhibits the release of MSH from the pituitary gland (50,51) and that it is released enzymatically from oxytocin (50,52), showed for the first time that a peptide hormone can release an active moiety with ef-
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fects unlike those of the parent hormone . Our results, which showed that ACTH 4-7 is as active as the whole ACTH molecule in affecting acquisition and extinction and that N-terminal fragments of vasopressin affect the consolidation of learned responses, were the first to indicate dissociation between endocrine and behavioral effects of hypothalamic and pituitary hormones . The memory consolidating effect of vasopressin is mainly located in the N-terminal covalent ring structure preasinamide . Following intraventricular administration, it is nearly as active as AVP in increasing resistance to extinction of a pole jumping avoidance response in contrast to the C-terminal tripeptide H-Pro-Arg-Gly-NH (PAG) . The protective effect of neurohypbphyseal hormones on puromycin-induced amnesia in mice (33) is however located mainly in the C-terminal fragments of these polypeptides (34) .
Neuro e tides and the develo ent of tolerance and h sical development to narcotic ana gesics . Another interesting an proba ly related . observation is the demonstration that fragments of neuro hypophyseal hormones facilitate the development of both resistance to the analgesic effect of and physical dependence on narcotic analgesics . Krivoy et al .(53) showed that chronic treatment of mice with high amounts of DG-LVP facilitated the development of resistance to the analgesic action of morphine . This polypeptide does not it self exert hyperalgesia and does not compete with morphine for the opiate receptor in rat brain synaptosomal plasma membranes (54) . The implication of vasopressin in the development of tolerance to narcotic analgesics was subsequently demonstrated in brattleboro rats . It was found that the response to the hot plate in HE-DI rats treated daily with analgesic amounts of morphine, gradually diminished until full tolerance had developed after the fifth injection . The response in HO-DI rats, treated in the same way was however saved even after 8 consecutive days of treatment with morphine (55) . Administration of AVP or DG-LVP immediately after the daily trial on the hot plate restored the development of tolerance to morphine in HO-DI rats . Subsequent experiments were performed, using body weight loss and change in body temperature in response to naloxone as indices of physical dependence, in rats treated chronically with morphine . It appeared that oxytocin was markedly more potent than vasopressin in facilitating physical dependence to morphine (56) . This activity appeared to reside in the C-terminal tüpeptide PLG . This peptide was as potent as oxytocin while tocinamide was ineffective . Interestingly, these results compare favourably with those obtained in the amnesia test of Walter et al .(34) . In this test, PLG was one of the most effective peptides in protecting against puromycin-induced amnesia in mice, while tocinamide had only weak activity . This suggests that neurohypophyseal hormones operate at different levels to affect memory processes .
Neuropeptides affecting sleep . Peptides affecting sleep have also been detected in the brain . Rabbits, kept asleep by stimulation of the thalamic sleep centre, produce a hypnogenic substance which elicits delta activities in the EEG, reduces motor activity, heart rate and respiration following infusion into the meso-diencephalic ventricular system . This so-called "delta sleep factor" seems to be an oligopeptide (57,58) . The structure of the peptide is not known but it is tempting to speculate that the hypothalamicpituitary complex is the source of this peptide ; the more so since ,hormones from this complex are involved in sleep-waking patterns .
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Several peptide hormones affect sleep-waking patterns in various species . Cats given growth hormone (GH) but not thyrotropin (TSH) showed a s®lective elevation of paradoxical sleep (PS) episodes for 3 hours after injection (59) . The greatly increased secretion of GH during slow wave sleep in man (60) according . to Stern et al . (59) may play a role in the occurrence of PS . Hypophysectomized rata have shorter PS episodes and lack the normal circadian rhythmicity of PS (61) . PS is disturbed in the chronic pontine cat without hypothalamus and pituitary (62) but only for 5 days or more after the operation. These disturbances can be restored with various pituitary principles . Hypophysectomized rabbits spent a greater proportion of time in slow wave sleep with slightly less time in PS than intact animals, although spontaneous PS episodes and PS induced by electrical stimulation of the brain both occurred readily in the absence of the pituitary gland (63) . Recent electrophysiological studies in free moving Brattleboro rats have shown that the frequency content of rhythmic slow activity (RSA) of HO-DI rats during PS substantially deviates from the activity of .their heterozygous littermates (64) . Differences were mostly confined to "average" and "peak" frequencies which in HO-DI rats were approximately one C/S lower than those of HE-DI animals . Thus, PS fails to produce normal theta frequency in the absence of vasopreasin indicating a qualitatively different PS . Administration of Vasopreasin and Vasopreasin fragments restores the distribution of hippocampal theta frequencies in HO-DI rats . The same peptides but also ACTH 4-10 enhance the generation of higher frequencies during PS in HE-DI and homozygous normal Brattleboro rats . Conversely, the intracerebroventricular administration of vasopressin antiserum which binds Vasopreasin present in the CSF, elicits the same differences in RSA during PS as found in HO-DI rats . In addition,[D-Phe7] ACTH 4-10 which facilitates extinction of active avoidance behavior (18) thus exerting an effect opposite to that of [L-Phe 7] ACTH 4-10, also induces lower theta frequencies during PS . The disturbed RSA during PS may be related to consolidation deficits which are observed in rats which lack Vasopreasin . Deprivation of PS interferes with the consolidation of learned responses (65-67) . Drugs which facilitate m~aory formation promote theta activity in the poatlearninq period (68) . This suggests that changes in excitability in the hippocampal theta activity generating substrate are related to memory consolidation . Trans rt of neuro tides to the sites of action . Although the systemic a inistration o ACTH ragments a Vaeopressin fragments elicits the various behaviors reported above, intracerebroVentricular administration is much more effective . Thus, using this route, between 200 and 1000 times less of ACTH 4-10, AVP or preseinamide is needed to delay extinction of pole jumping avoidance behavior . In addition, some behaviors are elicited only after intracerebral administration . Fox example, in a variety of mammals ACTH induces a stretching and yawning syndra~me (SYS) after intracranial administration (69,70) . In the rat, the onset of the syndrome is preceded by display of increased grooming (71,72) . This effect which is located in the N-terminal part of the ACTH molecule, .cannot .be elicited following systemic administration : These observations and the presence of ACTH (73), Vaeopressin and vasotocin (74-77) and of .prolactin (78) in the CSF suggest that pituitary hormones are transported directly to the brain . Morphological observations point to a connection between neurosecretory cells and the ependyma of the infundibular recess of the third ventricle .
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Using imurunochemical techniques, Goldsmith and Zimmeruran (79) and Zimmerman et al .(80) demonstrated that neuronal processes containing granules with neurophysin and vasopressin are present not only close to portal capillary loops, but also protrude in the third ventricle . Although hypothalamic limbic pathways .have been suggested as an integral subsystem of a peptidergic neurosecretory system (81,82), the CSF may be the preferred route for the behavioral effects of neurohypophyseal hormones to reach the sites of action in the brain . The demonstration that intraventricular administration of vasopressin antiserum prevents passive avoidance behavior (32) supports this hypothesis . The actual mode of transport of pituitary hormones to the brain is not known and remains a matter for speculation . Various possibilities have been offered, such as retrograde transport along the pituitary stalk or the existence of basilar cisterns which may be connected with the CSF in the adenohypophysis close to the hormoneproducinq cells (73) and transport via the blood . Szentagothai et al .(83) already suggested a microcirculation which would carry hormonal substances from the pituitary to the brain . Recent evidence for such a connection was obtained by Ambach and Palkovits (84) who showed that the nucleus periventricularis receives blood from the anterior hypophyseal artery . The brain itself may also be the production site of neuropeptides . Vasopresain and oxytocin are produced in the supraoptic and paraventricular nuclei of the hypothalamus . Recently, localization of compounds related to a-MSH have been detected in various regions in the brain by immunolocalization (85,86,87) .In addition, immunoreactive a-MSH is still present throughout the brain 3 weeks after hypophysectomy (87) . That these centrally occurring peptides are not the only source of neuropeptides is suggested by our observations on the deficient avoidance beha= vior of hypophysectomized rats which can be readily corrected by the administration of relatively small amounts of ACTH-like peptides (2) . Concludin remarks . Pituitary peptides related to ACTH, MSH, ßLPH and vasopress n appear to affect motivational, learning and memory processes . Other peptides originating from the brain have central nervous system effects . For detailed information on the central effects of hypophysiotropic hormones, the reader is referred to the excellent review by Prang~ et al .(88) . In general, the various releasing hormones have not been connected to specific behaviors except for LHRH . This decapeptide facilitates lordosis behavior in ovariectomized and hypophysectomized rats (89,90) and accelerates ejaculation in intact and in castrated rats maintained on testosterone (91) . Angiotensin II elicits drinking in rat (92) and substance P, whose structure was recently characterized (93) and which may be regarded as an excitatory transmitter (94), abolishes the abstinence syndrome in morphinized mice and reduces aggressiveness in the same species (95) . The field is rapidly expanding and one may expect a vast increase in information within the coming years . It is already clear that the hypothalamic-pituitary complex produces large numbers of neuropeptides carrying specific information to brain structures involved in the behavioral repertoire of the organism . Findings so far indicate the existence of neuropeptides which affect learning, memory and motivation, neuropeptides with opiate-like activity, and neuropeptides affecting sleep, thirst, aggression (95,96) and the development of tolerance and physical dependence .
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