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A comparison of the effects of anti-psychotic drugs on pituitary, striatal and limbic system post-synaptic dopamine receptors
Life Sciences, Vol . 23, pp . 605-610 Printed in the U.S .A .
Pergamon Press
A COMPARISON OF THE EFFECTS OF ANTI-PSYCHOTIC DRUGS ON PITUITARY, STRIATAL AND LIMBIC SYSTEM POST-SYNAPTIC DOPAMINE RECEPTORS H .Y . Meltzer, l ' 4 M . Simonovic, 2 V . Fang, 3 S . Piyakalamala 4 and M . Young 4 Depts . of Psychi~try,l Pharmacology and Physiological Sciences 2 and Medicine, Univ . of Chicago Pritzker School of Medicine and the Illinois State Psychiatric Institute . 4
SUMMARY Dopamine (DA) antagonists promote the secretion of prolactin (PRL) from the anterior pituitary gland by blocking the effects of DA at receptors in the pituitary itself . Thus, comparison of the properties of these receptors with DA receptors in the striatal, meso-limbic and meso-cortical regions is of interest . Evidence is presented that clozapine, RMI-81,582 (a morphanthridine derivative), trebenzomine (CI-686, a chromanamine derivative) and sultopride (a benzamide) have much weaker effects on human and rat PRL secretion than would be predicted by their anti-psychotic potency . The reverse is true of two other benzamides, sulpiride and metoclopramide . Classical neuroleptics of the phenothiazine, butyrophenone and thioxanthene types appear to affect rat and human PRL secretion in a manner which is mainly but not entirely consistent with their known effects on striatal and meso-limbic/meso-cortical postsynaptic DA receptors . Preliminary studies indicate presynaptic receptors which affect prolactin secretion are not present in rats . Supersensitivity may develop in the tubero-infundibular (TI) system after chronic neuroleptic treatment but altered sensitivity of these receptors was not found in schizophrenics given apomorphine . There is extensive evidence that the ability of neuroleptics to block postsynaptic DA receptors of the meso-limbic/meso-cortical, nigro-striatal and TI dopaminergic systems is relevant to their anti-psychotic, extrapyramidal, or PRL releasing effects, respectively (1) . Thus, there is a good correlation between the anti-psychotic effects of neuroleptics, and their ability to block DA-induced behaviors (1,2), to bind to DA receptors in vitro (3,4), or to stimulate PRL release (5,6) . There is good evidencethat the postsynaptic DA receptor of the TI neurons is in the pituitary, not in the hypothalamus (7) . In view of the evidence that the TI dopaminergic neurons topically inhibit PRL release from the anterior pituitary (8), the increase in serum PRL levels following neuroleptic administration has been proposed as an index of the anti-dopaminergic effects of these drugs (5,6) . Thus, the ability to augment PRL secretion in the rat is being used to predict anti-psychotic potential of new drugs and to predict their effect on human PRL secretion . Therefore, it is of interest to examine the similarities and differences between the receptors in the pituitary which mediate the effects of neuroleptics on PRL secretion and the neuroleptic receptors in the striatum, meso-limbic and meso-cortical regions . We have discussed some of these similarities and differences as revealed by studies of prolactin secretion previously (9) . We have now investigated several 0300-9653/78/0814-0605$02 .00/0 Copyright (c) 1978 Pergamon Press
606
Antipaychotic Drugs on DA Syatema
Vol . 23, No . 6, 1978
anti-psychotic drugs for which there is no correlation between anti-psychotic activity and PRL releasing effects . This paper will report briefly our findings with these drugs, review other recent reports of discrepencies between PRL stimulation and anti-psychotic activity, and then compare several known characteristics of pituitary DA receptors with those of postsynaptic DA receptors from other regions in the brain . Prolactin Secretion and Clinical Response We have repeatedly observed a significant positive correlation between the increase in serum PRL levels in patients and male rats and the antipsychotic effects of classical neuroleptic drugs (5,10) . However, there are a number of drugs for which this relationship does not hold . Clozapine can elevate plasma PRL levels in male rats (11) but it is five-to-ten times less In potent than would be expected on the basis of its anti-psychotic activity . contrast to classical neuroleptics, clozapine, even in high doses, failed to produce sustained elevations of serum PRL levels in humans although high doses produce small, short duration increases (4,12) . We have recently conducted clinical trials with two drugs, RMI-81,582 (2-chloro-11-3-dimethylaminopropylidene morphanthridine), and CI-686, the a-isomer of N,N2-trimethyl-3-chromanamine monohydrochloride (Fig . 1) (13) .
CH3 nKcH3)2
HCI
CI - 686
RMI - 81582 Fig . 1
Both of these drugs appeared to be effective anti-psychotic drugs in most of the acute and chronic schizophrenics who were studied . Both compounds produced effects on rat and human serum PRL levels which differ from those produced by classical neuroleptics . As an anti-psychotic, RMI-81,582 appears Yet, we found it to be to be 4-8 times more potent than chlorpromazine (CPZ) . 10-15 times less potent than CPZ in elevating rat plasma PRL levels with regard to threshold doses . The magnitude of the peak effect of RMI-81,582 on PRL Four of eleven patients treated chronically secretion was comparable to CPZ . with RMI-81,582, showed no rise in morning (steady-state) serum PRL levels . In six other patients, an initial increase in steady-state serum PRL levels was seen, but as the dose was increased, serum PRL levels returned to placebo levels . This pattern of effect on serum PRL levels has never been seen with classical DA receptor blockers (10) . Only one RMI-81,582-treated subject had a sustained increase in steady-state serum PRL levels . No correlation was observed between the anti-psychotic effect of RMI-81,582 and its effect on serum PRL levels in this series of patients . RMI-81,582 is much less potent than CPZ in antagonizing 3 H-spiroperidol binding to calf striatal DA receptors in vitro (Yamamura, H . and Ursillo, R ., ng reports regarding the personal communication) . There are
con~l~c
Vol . 23, No . 6, 1978
Antipaychotic Druga on DA Syetema
607
comparative potency of clozapine and CPZ to inhibit neuroleptic binding in vitro (3,14,15) relative to their anti-psychotic effects . The ability o~ clozapine and RMI-81,582 to stimulate rat prolactin secretion may suggest an anti-dopaminergic effect other than receptor blockade although a mechanism independent of DA could account for their ability to weakly stimulate PRL secretion in rats and man (11,13) . CI-686 is comparable to CPZ with respect to its anti-psychotic potency (13) but the threshold dose for this compound to stimulate rat PRL secretion was 30 times greater than that of CPZ . CI-686 had no effect on human steady state erum PRL levels . In addition, CI-686 did not compete effectively with l~C-spiroperidol for binding to DA receptors in calf striatal tissue (Seeman, P ., personal communication) . CI-686 also has minimal effects on turnover of brain DA (Stanley, M . and Wilk, S ., personal communication) . These results suggest that this drug may be producing its anti-psychotic effects by a non-dopaminergic mechanism . The minimal effect of CI-686 on rat plasma PRL levels is inconclusive evidence that it may affect dopaminergic activity in the hypothalamus . The anti-psychotic properties and prolactin stimulating properties of the benzamide series of drugs are also poorly correlated . Metoclopramide is a potent stimulus to prolactin secretion in man and rats but has been reported not to have anti-psychotic properties (see ref . 9) . Sulpiride is anti-psychotic but only about half as potent as CPZ (16) . Yet, we have found that threshold dose of sulpiride for stimulation of PRL secretion in male rats is slightly less than 0 .05 mg/kg, whereas that for CPZ is 1 .5 mg/kg, a 30-fold difference . These results suggest that with regard to PRL stimulation in male rats, sulpiride is about 30 times more potent than CPZ . On the other hand, it has been reported that sultopride, a neuroleptic of the benzamide type, did not elevate human serum PRL levels even though it is an anti-psychotic (17) . The results presented here now indicate fairly conclusively that there is a second group of anti-psychotic drugs, including clozapine, RMI-81,582, CI-686 and the benzamides for which the relationship between anti-dopaminergic activity, anti-psychotic activity and prolactin stimulation is quantitatively and probably qualitatively different than for the classical neuroleptics . Prol actin Secretion and Presynaptic Rec e~ors In addition to postsynaptic DA receptors, evidence has been presented for presynaptic, or regulatory DA receptors (18) . The activation of postsynaptic striatal DA receptors causes stimulation of dopaminergic activity, while the activation of presynaptic ones inhibits the activity of DA neurons through a local feedback mechanism . It has been postulated that a very low dose of an àgonist which possesses greater affinity for presynaptic than for postsynaptic DA receptors would inhibit the activity of nigra-striatal DA neurons, thus producing an effect similar to that caused by the blockade of postsynaptic DA receptors . In order to investigate the existence of such presynaptic DA receptors in the TI dopaminergic system, we have administered intravenous apomorphine, a DA agonist, in doses ranging from 0 .0005 to 0 .01 mg/kg, to male rats with indwelling venous catheters . We did not observe any rise in rat plasma PRL levels 10, 30 and 60 minutes after any dose . Higher doses inhibit PRL secretion . We have also not observed any early increases in serum PRL levels in humans given doses of apomorphine which eventually decrease PRL secretion . The existence of presynaptic DA receptors in the TI dopaminergic system might have been revealed by early increases in PRL levels when tissue levels of apomorphine were low . However, the failure of these studies to demonstrate findings consistent with the theory of auto-receptors does not preclude their existence in other DA neurons or that other experimental
608
Antipeychotic Drugs on DA Systems
Vol . 23, No . 6, 1978
conditions might reveal their presence in TI neurons . Lal et al . (19) presented evidence consistent with presynaptic DA receptors i~the hypothalamus of rats withdrawn from chronic haloperidol treatment . Pituitary Hormone Secretion and Supersen sitivity It has been reported that chronic interference with dopaminergic transmission, either through lesions, receptor blockade or inhibition of DA synthesis, induces supersensitivity in brain, as well as pituitary DA receptors (20) . Thus, Lal et al . (19) have reported that following chronic haloperidol treatment, rat serumPRL levels were significantly decreased, and that a dose of apomorphine which inhibited PRL secretion in control rats produced a more profound decrease in plasma PRL levels in the rats exposed to chronic haloperidol treatment . These findings were interpreted as evidence for development of supersensitivity in postsynaptic DA receptors . Cheung and Weiner (21) reported enhanced suppression of PRL secretion by apomorphine in rats with chronic (14 days) but not acute (1 day) lesions of the medial basal hypothalamus . On the other hand, we found that the ability of apomorphine to inhibit CPZstimulated PRL release in male rats was not greater in rats subjected to chronic treatment with CPZ (5) . Similar results were obtained by Ravitz and Moore (22) . We have found that apomorphine (0 .01 and 0 .05 mg/kg i .p .) produced significantly greater inhibition of 5-hydroxytryptophan-stimulated PRL secretion in rats who were withdrawn from chronic CPZ treatment (data not presented) . Annunziato and Moore (23) reported recently that inhibition of DA synthesis by frequent injections of alpha-methyl-p-tyrosine (AMPT1 for 10 days enhanced slightly, but significantly, the ability of apomorphine to suppress the rise in PRL following AMPT administration . The ability of apomorphine, a dopamine agonist, to increase serum growth hormone (GH) levels and to decrease serum PRL levels can be used as a crude guide to the sensitivity of DA receptors in the hypothalamus (GH) and pituitary (PRL) to DA agonists . Apomorphine, 0 .75 mg, was given subcutaneously to 19 normal volunteers (NV), 6 acute schizophrenics (AS) and 15 chronic schizophrenics (CS) who had indwelling venous catheters from which three baseline samples were obtained over a 20 minute period . There was no difference in the percentage decrease in PRL levels or increase in GH levels from baseline during a 3 hour period following apomorphine for AS and CS compared to NV . Analyses are under way to determine any relationship between the magnitude of the GH or PRL response in the AS and CS and previous treatment with neuroleptics, therapeutic response to neuroleptics, tardive dyskinesia, or other measures of dopaminergic activity . Thus far, we have not replicated the results of other investigators who have observed an excessive apomorphine-induced GH response in CS who did not respond to neuroleptics (24), a decreased GH response in CS as a group (25), or an excessive GH response in AS (26) . Prolactin Secretion and Tolerance There is no evidence that chronic treatment with neuroleptics results in the development of tolerance to anti-psychotic effects of these drugs (1) . We have found that no tolerance develops to the ability of neuroleptics to stimulate PRL secretion in man (10) . Conclusions The data presented here indicate that increasing numbers of differences, both qualitative and quantitative, have been found between the anti-psychotic effects of a small minority of anti-psychotic drugs and the ability of these drugs to stimulate rat or human prolactin secretion . In view of the great similarity of effects of classical neuroleptics on PRL release and striatal and
Vol . 23, No . 6, 1978
Antipaychotic Drugs on DA Systems
609
meso-limbic DA-dependent processes, it is likely that there are very close similarities in the post-synaptic DA recepto s of the latter two systems and the pituitary . Therefore, the anti-psychotic action or PRL-releasing effect of drugs such as clozapine, RMI-81,852, CI-686, and the benzamides may be based upon some effect other than DA receptor blockade . Acknowledge ments The assistance of D . Goode ând M . Strahilevitz is gratefully acknowledged . Supported by ADAMHA grants MH 29,206 and 30,938 . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 .
H .Y . MELTZER and S .M . STAHL, Schiz . Bull . 2 19-76 (1976) . D . H . YORK, in Bio epic Amine Rece tors, L .L . Iversen, S .D . Iversen and S .H . Snyder, e s ., pp . -61, lenum Press, New York and London (1975) . P . SEEMAN, T . LU, M . CHAN -WONG, and K . WONG, Nature 261 717-718 (1.976) . D .R . BURT, S .J . ENNA, I . CREESE, and S .H . SNYDER, Proc . Nat . Acad . Sci . USA 72 4655-4659 (1975) . H .Y . -FIELTZER, D .J . GOODE, and V .S . FANG, in A Review of Psychopharmacology . M .A . Lipton, A . DiMascio and K . F . Killam, pp . 509-530, Raven Press, New York (1978) . J . CLEMENS, E . SüALSTIG, and B . SAWYER, Psychopharmacologia 40 123 (1974) . G .M . BROWN, P . SEEMAN, and T . LU, Endocrinology 99 1407-14101976) . J . METTES and J . CLEMENS, Vitam . and Horm . 30 165-221 (1972) . H .Y . MELTZER, V .S . FIWG, R .G . FESSLER, ~~i . STHONOVIC, and D . STANISIC, in Animal ~--lodels in Ps chiatr and Neurolo , I . Hanin and E . Usdin, eds ., pp . 4 -454, ergamon Press, Oxford and New York (1977) . H .Y . ~~1ELTZER and V .S . FANG, Arch . Gen . Psych . 33 279-286 (1976) . H .Y . MELTZER, S . DANIELS, and V .S . FANG, Life Sci . 17 339-342 (1975) . H .Y . MELTZER, D .J . GOODE, and V .S . FANG, Arch . Gen . Psych . (in press) . H .Y . MELTZER, D .J . GOODE, M . YOUNG, M . STRAHILEVITZ, I . CREESE and S .H . SNYDER, Presented at the American Psychiatric Assn ., Atlanta, Ga ., ~iay, 1978 . I . CREESE, D . R . BURT, and S . H . SNYDER, Science 192 481-483 (1976) . J . LEYSEN, W . GOMMEREN, and P . LADURON, BiochemPharmacol . . 27 307-316 (1978) . M . TORU, Y . SMINAZONO, M . MIYASAKA, T . KOKUBO, Y . MORI, and T. HASU, J . Clin . Pharm . 12 221-229 (1972) . R . ROPER, Presentéd at the American Psychiatric Assn ., Atlanta, Ga ., May,1978 . A . CARLSSON, W . KEHR, M . LINDQVIST, T . MAGNUSSON, C .V . ATACK, Pharmacol . Rev . 24 371-384 (1972) . H. LAL, W . BROWN, R . DRAWBAUGH, M . HYNES, and G . BROWN, Life Sci . 20 101-106 (1977) . K, E . MOORE and J .E . THORNBURG, in Advances in Neurology, 9, 93-104 (1975) . C .Y . CHEUNG and R .I . WEINER, Endocrinology 99 914-916 (1976) . A .J . RAVITZ and K .E . t~100RE, J . Pharm . Pharmâc . 29 384-385 (1977) . L . ANNUNZIATO and K .E . MOORE, Life Sci . 21 1845-1850 (1977) . J . ROTROSEN, B .M . ANGRIST, S . GERSHON, E .J. SACHAR and F . HALPERN, Psychopharmacology 51 1-7 (1976) . C .A . TAMMINGA, R .C .~MITH, G . PANDEY, L .A . FROHMAN and J .M . DAVIS, Arch . Gen . Psych . 36 1199-1203 (1977) . G .N . PANDEY, D.L . GARVER, C . TANRIINGA, S . ERICSON, S .I . ALI and J .M . DAVIS, Amer . J . Psychiatry 134 518-522 (1977) .
Pergamon Press
A COMPARISON OF THE EFFECTS OF ANTI-PSYCHOTIC DRUGS ON PITUITARY, STRIATAL AND LIMBIC SYSTEM POST-SYNAPTIC DOPAMINE RECEPTORS H .Y . Meltzer, l ' 4 M . Simonovic, 2 V . Fang, 3 S . Piyakalamala 4 and M . Young 4 Depts . of Psychi~try,l Pharmacology and Physiological Sciences 2 and Medicine, Univ . of Chicago Pritzker School of Medicine and the Illinois State Psychiatric Institute . 4
SUMMARY Dopamine (DA) antagonists promote the secretion of prolactin (PRL) from the anterior pituitary gland by blocking the effects of DA at receptors in the pituitary itself . Thus, comparison of the properties of these receptors with DA receptors in the striatal, meso-limbic and meso-cortical regions is of interest . Evidence is presented that clozapine, RMI-81,582 (a morphanthridine derivative), trebenzomine (CI-686, a chromanamine derivative) and sultopride (a benzamide) have much weaker effects on human and rat PRL secretion than would be predicted by their anti-psychotic potency . The reverse is true of two other benzamides, sulpiride and metoclopramide . Classical neuroleptics of the phenothiazine, butyrophenone and thioxanthene types appear to affect rat and human PRL secretion in a manner which is mainly but not entirely consistent with their known effects on striatal and meso-limbic/meso-cortical postsynaptic DA receptors . Preliminary studies indicate presynaptic receptors which affect prolactin secretion are not present in rats . Supersensitivity may develop in the tubero-infundibular (TI) system after chronic neuroleptic treatment but altered sensitivity of these receptors was not found in schizophrenics given apomorphine . There is extensive evidence that the ability of neuroleptics to block postsynaptic DA receptors of the meso-limbic/meso-cortical, nigro-striatal and TI dopaminergic systems is relevant to their anti-psychotic, extrapyramidal, or PRL releasing effects, respectively (1) . Thus, there is a good correlation between the anti-psychotic effects of neuroleptics, and their ability to block DA-induced behaviors (1,2), to bind to DA receptors in vitro (3,4), or to stimulate PRL release (5,6) . There is good evidencethat the postsynaptic DA receptor of the TI neurons is in the pituitary, not in the hypothalamus (7) . In view of the evidence that the TI dopaminergic neurons topically inhibit PRL release from the anterior pituitary (8), the increase in serum PRL levels following neuroleptic administration has been proposed as an index of the anti-dopaminergic effects of these drugs (5,6) . Thus, the ability to augment PRL secretion in the rat is being used to predict anti-psychotic potential of new drugs and to predict their effect on human PRL secretion . Therefore, it is of interest to examine the similarities and differences between the receptors in the pituitary which mediate the effects of neuroleptics on PRL secretion and the neuroleptic receptors in the striatum, meso-limbic and meso-cortical regions . We have discussed some of these similarities and differences as revealed by studies of prolactin secretion previously (9) . We have now investigated several 0300-9653/78/0814-0605$02 .00/0 Copyright (c) 1978 Pergamon Press
606
Antipaychotic Drugs on DA Syatema
Vol . 23, No . 6, 1978
anti-psychotic drugs for which there is no correlation between anti-psychotic activity and PRL releasing effects . This paper will report briefly our findings with these drugs, review other recent reports of discrepencies between PRL stimulation and anti-psychotic activity, and then compare several known characteristics of pituitary DA receptors with those of postsynaptic DA receptors from other regions in the brain . Prolactin Secretion and Clinical Response We have repeatedly observed a significant positive correlation between the increase in serum PRL levels in patients and male rats and the antipsychotic effects of classical neuroleptic drugs (5,10) . However, there are a number of drugs for which this relationship does not hold . Clozapine can elevate plasma PRL levels in male rats (11) but it is five-to-ten times less In potent than would be expected on the basis of its anti-psychotic activity . contrast to classical neuroleptics, clozapine, even in high doses, failed to produce sustained elevations of serum PRL levels in humans although high doses produce small, short duration increases (4,12) . We have recently conducted clinical trials with two drugs, RMI-81,582 (2-chloro-11-3-dimethylaminopropylidene morphanthridine), and CI-686, the a-isomer of N,N2-trimethyl-3-chromanamine monohydrochloride (Fig . 1) (13) .
CH3 nKcH3)2
HCI
CI - 686
RMI - 81582 Fig . 1
Both of these drugs appeared to be effective anti-psychotic drugs in most of the acute and chronic schizophrenics who were studied . Both compounds produced effects on rat and human serum PRL levels which differ from those produced by classical neuroleptics . As an anti-psychotic, RMI-81,582 appears Yet, we found it to be to be 4-8 times more potent than chlorpromazine (CPZ) . 10-15 times less potent than CPZ in elevating rat plasma PRL levels with regard to threshold doses . The magnitude of the peak effect of RMI-81,582 on PRL Four of eleven patients treated chronically secretion was comparable to CPZ . with RMI-81,582, showed no rise in morning (steady-state) serum PRL levels . In six other patients, an initial increase in steady-state serum PRL levels was seen, but as the dose was increased, serum PRL levels returned to placebo levels . This pattern of effect on serum PRL levels has never been seen with classical DA receptor blockers (10) . Only one RMI-81,582-treated subject had a sustained increase in steady-state serum PRL levels . No correlation was observed between the anti-psychotic effect of RMI-81,582 and its effect on serum PRL levels in this series of patients . RMI-81,582 is much less potent than CPZ in antagonizing 3 H-spiroperidol binding to calf striatal DA receptors in vitro (Yamamura, H . and Ursillo, R ., ng reports regarding the personal communication) . There are
con~l~c
Vol . 23, No . 6, 1978
Antipaychotic Druga on DA Syetema
607
comparative potency of clozapine and CPZ to inhibit neuroleptic binding in vitro (3,14,15) relative to their anti-psychotic effects . The ability o~ clozapine and RMI-81,582 to stimulate rat prolactin secretion may suggest an anti-dopaminergic effect other than receptor blockade although a mechanism independent of DA could account for their ability to weakly stimulate PRL secretion in rats and man (11,13) . CI-686 is comparable to CPZ with respect to its anti-psychotic potency (13) but the threshold dose for this compound to stimulate rat PRL secretion was 30 times greater than that of CPZ . CI-686 had no effect on human steady state erum PRL levels . In addition, CI-686 did not compete effectively with l~C-spiroperidol for binding to DA receptors in calf striatal tissue (Seeman, P ., personal communication) . CI-686 also has minimal effects on turnover of brain DA (Stanley, M . and Wilk, S ., personal communication) . These results suggest that this drug may be producing its anti-psychotic effects by a non-dopaminergic mechanism . The minimal effect of CI-686 on rat plasma PRL levels is inconclusive evidence that it may affect dopaminergic activity in the hypothalamus . The anti-psychotic properties and prolactin stimulating properties of the benzamide series of drugs are also poorly correlated . Metoclopramide is a potent stimulus to prolactin secretion in man and rats but has been reported not to have anti-psychotic properties (see ref . 9) . Sulpiride is anti-psychotic but only about half as potent as CPZ (16) . Yet, we have found that threshold dose of sulpiride for stimulation of PRL secretion in male rats is slightly less than 0 .05 mg/kg, whereas that for CPZ is 1 .5 mg/kg, a 30-fold difference . These results suggest that with regard to PRL stimulation in male rats, sulpiride is about 30 times more potent than CPZ . On the other hand, it has been reported that sultopride, a neuroleptic of the benzamide type, did not elevate human serum PRL levels even though it is an anti-psychotic (17) . The results presented here now indicate fairly conclusively that there is a second group of anti-psychotic drugs, including clozapine, RMI-81,582, CI-686 and the benzamides for which the relationship between anti-dopaminergic activity, anti-psychotic activity and prolactin stimulation is quantitatively and probably qualitatively different than for the classical neuroleptics . Prol actin Secretion and Presynaptic Rec e~ors In addition to postsynaptic DA receptors, evidence has been presented for presynaptic, or regulatory DA receptors (18) . The activation of postsynaptic striatal DA receptors causes stimulation of dopaminergic activity, while the activation of presynaptic ones inhibits the activity of DA neurons through a local feedback mechanism . It has been postulated that a very low dose of an àgonist which possesses greater affinity for presynaptic than for postsynaptic DA receptors would inhibit the activity of nigra-striatal DA neurons, thus producing an effect similar to that caused by the blockade of postsynaptic DA receptors . In order to investigate the existence of such presynaptic DA receptors in the TI dopaminergic system, we have administered intravenous apomorphine, a DA agonist, in doses ranging from 0 .0005 to 0 .01 mg/kg, to male rats with indwelling venous catheters . We did not observe any rise in rat plasma PRL levels 10, 30 and 60 minutes after any dose . Higher doses inhibit PRL secretion . We have also not observed any early increases in serum PRL levels in humans given doses of apomorphine which eventually decrease PRL secretion . The existence of presynaptic DA receptors in the TI dopaminergic system might have been revealed by early increases in PRL levels when tissue levels of apomorphine were low . However, the failure of these studies to demonstrate findings consistent with the theory of auto-receptors does not preclude their existence in other DA neurons or that other experimental
608
Antipeychotic Drugs on DA Systems
Vol . 23, No . 6, 1978
conditions might reveal their presence in TI neurons . Lal et al . (19) presented evidence consistent with presynaptic DA receptors i~the hypothalamus of rats withdrawn from chronic haloperidol treatment . Pituitary Hormone Secretion and Supersen sitivity It has been reported that chronic interference with dopaminergic transmission, either through lesions, receptor blockade or inhibition of DA synthesis, induces supersensitivity in brain, as well as pituitary DA receptors (20) . Thus, Lal et al . (19) have reported that following chronic haloperidol treatment, rat serumPRL levels were significantly decreased, and that a dose of apomorphine which inhibited PRL secretion in control rats produced a more profound decrease in plasma PRL levels in the rats exposed to chronic haloperidol treatment . These findings were interpreted as evidence for development of supersensitivity in postsynaptic DA receptors . Cheung and Weiner (21) reported enhanced suppression of PRL secretion by apomorphine in rats with chronic (14 days) but not acute (1 day) lesions of the medial basal hypothalamus . On the other hand, we found that the ability of apomorphine to inhibit CPZstimulated PRL release in male rats was not greater in rats subjected to chronic treatment with CPZ (5) . Similar results were obtained by Ravitz and Moore (22) . We have found that apomorphine (0 .01 and 0 .05 mg/kg i .p .) produced significantly greater inhibition of 5-hydroxytryptophan-stimulated PRL secretion in rats who were withdrawn from chronic CPZ treatment (data not presented) . Annunziato and Moore (23) reported recently that inhibition of DA synthesis by frequent injections of alpha-methyl-p-tyrosine (AMPT1 for 10 days enhanced slightly, but significantly, the ability of apomorphine to suppress the rise in PRL following AMPT administration . The ability of apomorphine, a dopamine agonist, to increase serum growth hormone (GH) levels and to decrease serum PRL levels can be used as a crude guide to the sensitivity of DA receptors in the hypothalamus (GH) and pituitary (PRL) to DA agonists . Apomorphine, 0 .75 mg, was given subcutaneously to 19 normal volunteers (NV), 6 acute schizophrenics (AS) and 15 chronic schizophrenics (CS) who had indwelling venous catheters from which three baseline samples were obtained over a 20 minute period . There was no difference in the percentage decrease in PRL levels or increase in GH levels from baseline during a 3 hour period following apomorphine for AS and CS compared to NV . Analyses are under way to determine any relationship between the magnitude of the GH or PRL response in the AS and CS and previous treatment with neuroleptics, therapeutic response to neuroleptics, tardive dyskinesia, or other measures of dopaminergic activity . Thus far, we have not replicated the results of other investigators who have observed an excessive apomorphine-induced GH response in CS who did not respond to neuroleptics (24), a decreased GH response in CS as a group (25), or an excessive GH response in AS (26) . Prolactin Secretion and Tolerance There is no evidence that chronic treatment with neuroleptics results in the development of tolerance to anti-psychotic effects of these drugs (1) . We have found that no tolerance develops to the ability of neuroleptics to stimulate PRL secretion in man (10) . Conclusions The data presented here indicate that increasing numbers of differences, both qualitative and quantitative, have been found between the anti-psychotic effects of a small minority of anti-psychotic drugs and the ability of these drugs to stimulate rat or human prolactin secretion . In view of the great similarity of effects of classical neuroleptics on PRL release and striatal and
Vol . 23, No . 6, 1978
Antipaychotic Drugs on DA Systems
609
meso-limbic DA-dependent processes, it is likely that there are very close similarities in the post-synaptic DA recepto s of the latter two systems and the pituitary . Therefore, the anti-psychotic action or PRL-releasing effect of drugs such as clozapine, RMI-81,852, CI-686, and the benzamides may be based upon some effect other than DA receptor blockade . Acknowledge ments The assistance of D . Goode ând M . Strahilevitz is gratefully acknowledged . Supported by ADAMHA grants MH 29,206 and 30,938 . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 .
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