Life Sciences, Vol . 23, pp .

605-610 Pergamon Press

Printed in the U.S .A .

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 morphan-
thridine 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 neuro-
leptics 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 . Super-
sensitivity 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 anti-
psychotic 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
potent than would be expected on the basis of its anti-psychotic activity . In
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
HCI
nKcH3)2

RMI - 81582 CI - 686

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
to be 4-8 times more potent than chlorpromazine (CPZ) . Yet, we found it to be
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
secretion was comparable to CPZ . Four of eleven patients treated chronically
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 .,
personal communication) . There are con~l~c ng reports regarding the
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 trans-

mission, 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 haloper-
idol 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 CPZ-
stimulated 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 .

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