- Email: [email protected]
Clozapine induces hyperphagia in undeprived rats
Life Sciencae Vol . 21, pp " 1747-1750 Printed is the II .S .A .
Pnrgamon Preen
CLOZAPINE INDIICES HYPERPBAGIA IN IINDEPßIVED RATS Seymour M. Antalman~, Cynthia A. Black,
and Neil $ . Raalaad+
*Department of Psychiatry IIniversity of Pittsburgh, School of Medicine, Western Psychiatric Institute and Clinic and +Psychobiology Program, Department of Psychology, 15260 Pittsburgh, PA (Eacaived in final form October 14, 1977) Summary Rats given hither intragastric or iatraventricular injections of clozapine showed a dosa"-dependent increase in food intake . Of all the neurolnptica currently under study in the clinic and the laboratory the dibenzodiaznpine clozapine is easily the moat puzzling . Although it is generally agreed that this agent is largely devoid of extra pyramidal effects (1) there ie little agreement regarding its biochemical actions . For inataace, .although the lack of eatrapyramidal effects of clozapine have bees attributed to its' aaticholisergic properties (17, this Even when these properties have contention has been refuted by others (2) . been controlled for, it still fails to azhibit the profile of the more classical neuroleptic agents (2), Further, while some results suggest that clozapine has a marked and preferential influence oa mesolimbic dopamine (3,4) other data (5,6) contradict these conclusions, The action of clozapine in the tubaroinfundibular dopamine system ie likewise an enigma since it has bean shown to have inconsistant effects~oa prolactin secretion (7,8), Most of the existing behavioral data on clozapine relate to its inability to iaduca catalepsy or to eatagonisn the effects of amphetamine and apomorphine (1,2) as the more traditional nnuroleptics are able tc do . We would aoa like The to report that clozapine can induce hyperphagia is undeprived rate . present study originated in the observation made several years ago (Antelman and Szachtman, unpublished observations) that clozapine, in contrast to other neurolnptica tested, enhanced rather than attenuated tail-pinch-induced eating . Methods Male albino rate (Zivic-Miller, Pittsburgh) weighing 250-350 gms ware used in these studies . Animals were individually housed in wire mesh cages with Colony room lights were food (Purina pellets) and water available ad libitum. oa from 0700-1900 hrs and feeding tests warn conducted is the how cages between 1300 and 1600 hra . Rate are usually quiet at this time and show little Fending teats were two hours in duration and began spontaneous feeding. immediately following injection. Food intake was aeasured by weighing food before and after testing . Weight of food after testing included spillage of crumbs collected oa paper placed under the animals' cages .
1747
1748
Clozapine Induces Hyperphagia
Vol . 21, No . 12, 1977
Clozapine was dissolved in .2N HC1 and pH was adjusted to 5 .5-6 .5 by the addition of 1 N NaOH . Feeding tests were carried out following both peripheral and central injections of the drug . Intragastric injections in a volume of lcc/kg were given through a curved metal tube inserted into the throat . Central injections all of a 5y1 volume were made through an indwelling lateral ventricular steel cannula (steraotaxic coordinates : 1 .5 mm lateral to bregma directly on the coronal suture, and 4 .25 mm from the top of the skull) . Statistical significance was assessed using a 2-tailed t-test . Results and-Discuesion The results (shown in Table 1) indicate that both peripheral and central injections of Clozapine produced dose-dependent increases in food intake compared to vehicle~tre8ted animals, Rate typically took a single meal . No differences in water intake were noted . TABLE 1 Effect of Peripheral and Central Injections of Clozapine on Food Intake In The Rat Treatment
Peripheral
Central
Dose
N
Food Intake+ (grams)
Statistical Significance
Vehicle
8
0 .78 + 0.23
lOmg/kg
8
4 .97 + 0.61
P < 0 .001
15mg/kg
8
5 .18 + 1 .06
P t 0 .002
20mg/kg
8
6 .59 + 0.76
P < 0 .001
Vehicle
6
0,81 + 0.30
0.04y:g/5~1
6
1,58 + 0 .53
*N .S .
0 .20pg/5p1
6
1 .82 + 0.49
N .S .
l~g/5~1
6
2 .06 + 0 .17
P < 0.01
5~g/5p1
6
2 .15 + 0 .50
P < 0 .02
25pg/5}il
6
2 .50 + 0 .41
P ~ 0 .01
50y:g/Spl
6
3 .24 + 0 .70
P < 0 .01
+Mean + S .E . *Not significantly different from vehicle-treated controls . So far as we are aware this is the first report indicating that Clozapine can increase food intake . However, pheaothiazine neuroleptics such as chlorpromazine, have long been known to induce hyperphagia both in animals (9-12) and in schizophrenic patients (13-15) . Although the mechanisms by
Vol . 21, No . 12, 1977
Clozapine Inducae Hyperphagia
1749
which either clozapine or the phenothiazines induce food intake are unknown, and need not be similar, it 1s nevertheless interesting to note that both have paaerful adrenolytic effects (16,17) in addition to their dopamine-receptor blocking properties . Neuroleptice which are more specific in their antagonism of dopamine receptors, such as the butyrophenones, fail to stimulate feeding and may actually cause a slight anorexia (15) . These findings could suggest that the antiadrenergic properties of both clozapine and the phenothiazines play a key role in their ability to induce feeding . At any rate our results pose a problem for a purely adrenergic theory of feeding (18) . AcknowledSemen t We thank D . Shirk and C . Kraft for typing the manuscript . supported by USPHS grant MH-24114 to S .H,A .
This work was
References 1. 2. 3, 4. 5. 6. 7. 8. 9. lO . 11 . 12 . 13 . 14 . 15 . 16, 17 . 18 .
S .H . SNYDER, D . GREENBERG and H .I, YAMAMURA, Arch . Gen . Psychiat 31 58-61, (1974) . A .C . SAYERS, Psychopharmacology , 51, 15-22, (1976) . N .E . ANDEN and G . STOCK, J . P~arm . Pharmacol ., _25, 346-348, (1973) . B . ZIVROVIC, A . GUIDOTTI, A . REVUELTA aad E . COSTA, J, Pharmacol . Eap . Ther ., 194, 37-46, (1975) . B .H . WESTERINR and J . RORF, Eur . J . Pharmacol ., 33, 31-40, (1975) . P .A . WIESEL and G . SEDVALL, Eur . J . Pharmacol ., 30, 364-367, (1975) . H .Y . MELTZER, S . DANIELS and V .S . FANG, Life Sci ., _17, 339-342, (1975) . H .R . BURRI, E . EICflBZTBERGER, A .C . SAYERS, and T .G . WHITE, Pharmakopsychiatrie , 8, 115-121, (1975) . R .W, REYNOLDS and H,J, CARLISLE, J . Comp . Phyeiol, Psychol ., 54, 354-356, (1961) . S .F . LEIBOWITZ and N,E . MILLER, Science , 165, 609-611, (1969) . I,P . STOLERMAN, Neuropharmacology , _9, 405-417, (1970) . R .G . ROBINSON, P .R . McHUGH, and F .E, BLOOM, Psychopharmacol . Comm ., _1, 37-50, (1975) . E .M . CAFF1iEY, Amer . J . Paychiat ., 117, 713-719, (1961) . H .L . GORDON and C . CROTH, Arch . Gen .Psychiat ., _10, 187-191, (1964) . S . MERLIS and P .A . CARONE, in Psychopharmacological Treatment , H .D . Derber, ed ., Marcel Dekker, New York, 81-96, (1975) . J . HYTTSL, Acta Pharmacol, Toaicol ., 38, 35ö-365, (1976) . N .E . ANDEN, S,G . BUTCHER, H, CORRODI, R . FURS and U, UNGERSTEDT, Eur . J . Pharmacol _11, 303-314, (1970) . S . RITTER, C .D . WISE and L . STEIN, J . Comp . Phyeiol . Psychol ., _88, 778-784, (1975) .
Pnrgamon Preen
CLOZAPINE INDIICES HYPERPBAGIA IN IINDEPßIVED RATS Seymour M. Antalman~, Cynthia A. Black,
and Neil $ . Raalaad+
*Department of Psychiatry IIniversity of Pittsburgh, School of Medicine, Western Psychiatric Institute and Clinic and +Psychobiology Program, Department of Psychology, 15260 Pittsburgh, PA (Eacaived in final form October 14, 1977) Summary Rats given hither intragastric or iatraventricular injections of clozapine showed a dosa"-dependent increase in food intake . Of all the neurolnptica currently under study in the clinic and the laboratory the dibenzodiaznpine clozapine is easily the moat puzzling . Although it is generally agreed that this agent is largely devoid of extra pyramidal effects (1) there ie little agreement regarding its biochemical actions . For inataace, .although the lack of eatrapyramidal effects of clozapine have bees attributed to its' aaticholisergic properties (17, this Even when these properties have contention has been refuted by others (2) . been controlled for, it still fails to azhibit the profile of the more classical neuroleptic agents (2), Further, while some results suggest that clozapine has a marked and preferential influence oa mesolimbic dopamine (3,4) other data (5,6) contradict these conclusions, The action of clozapine in the tubaroinfundibular dopamine system ie likewise an enigma since it has bean shown to have inconsistant effects~oa prolactin secretion (7,8), Most of the existing behavioral data on clozapine relate to its inability to iaduca catalepsy or to eatagonisn the effects of amphetamine and apomorphine (1,2) as the more traditional nnuroleptics are able tc do . We would aoa like The to report that clozapine can induce hyperphagia is undeprived rate . present study originated in the observation made several years ago (Antelman and Szachtman, unpublished observations) that clozapine, in contrast to other neurolnptica tested, enhanced rather than attenuated tail-pinch-induced eating . Methods Male albino rate (Zivic-Miller, Pittsburgh) weighing 250-350 gms ware used in these studies . Animals were individually housed in wire mesh cages with Colony room lights were food (Purina pellets) and water available ad libitum. oa from 0700-1900 hrs and feeding tests warn conducted is the how cages between 1300 and 1600 hra . Rate are usually quiet at this time and show little Fending teats were two hours in duration and began spontaneous feeding. immediately following injection. Food intake was aeasured by weighing food before and after testing . Weight of food after testing included spillage of crumbs collected oa paper placed under the animals' cages .
1747
1748
Clozapine Induces Hyperphagia
Vol . 21, No . 12, 1977
Clozapine was dissolved in .2N HC1 and pH was adjusted to 5 .5-6 .5 by the addition of 1 N NaOH . Feeding tests were carried out following both peripheral and central injections of the drug . Intragastric injections in a volume of lcc/kg were given through a curved metal tube inserted into the throat . Central injections all of a 5y1 volume were made through an indwelling lateral ventricular steel cannula (steraotaxic coordinates : 1 .5 mm lateral to bregma directly on the coronal suture, and 4 .25 mm from the top of the skull) . Statistical significance was assessed using a 2-tailed t-test . Results and-Discuesion The results (shown in Table 1) indicate that both peripheral and central injections of Clozapine produced dose-dependent increases in food intake compared to vehicle~tre8ted animals, Rate typically took a single meal . No differences in water intake were noted . TABLE 1 Effect of Peripheral and Central Injections of Clozapine on Food Intake In The Rat Treatment
Peripheral
Central
Dose
N
Food Intake+ (grams)
Statistical Significance
Vehicle
8
0 .78 + 0.23
lOmg/kg
8
4 .97 + 0.61
P < 0 .001
15mg/kg
8
5 .18 + 1 .06
P t 0 .002
20mg/kg
8
6 .59 + 0.76
P < 0 .001
Vehicle
6
0,81 + 0.30
0.04y:g/5~1
6
1,58 + 0 .53
*N .S .
0 .20pg/5p1
6
1 .82 + 0.49
N .S .
l~g/5~1
6
2 .06 + 0 .17
P < 0.01
5~g/5p1
6
2 .15 + 0 .50
P < 0 .02
25pg/5}il
6
2 .50 + 0 .41
P ~ 0 .01
50y:g/Spl
6
3 .24 + 0 .70
P < 0 .01
+Mean + S .E . *Not significantly different from vehicle-treated controls . So far as we are aware this is the first report indicating that Clozapine can increase food intake . However, pheaothiazine neuroleptics such as chlorpromazine, have long been known to induce hyperphagia both in animals (9-12) and in schizophrenic patients (13-15) . Although the mechanisms by
Vol . 21, No . 12, 1977
Clozapine Inducae Hyperphagia
1749
which either clozapine or the phenothiazines induce food intake are unknown, and need not be similar, it 1s nevertheless interesting to note that both have paaerful adrenolytic effects (16,17) in addition to their dopamine-receptor blocking properties . Neuroleptice which are more specific in their antagonism of dopamine receptors, such as the butyrophenones, fail to stimulate feeding and may actually cause a slight anorexia (15) . These findings could suggest that the antiadrenergic properties of both clozapine and the phenothiazines play a key role in their ability to induce feeding . At any rate our results pose a problem for a purely adrenergic theory of feeding (18) . AcknowledSemen t We thank D . Shirk and C . Kraft for typing the manuscript . supported by USPHS grant MH-24114 to S .H,A .
This work was
References 1. 2. 3, 4. 5. 6. 7. 8. 9. lO . 11 . 12 . 13 . 14 . 15 . 16, 17 . 18 .
S .H . SNYDER, D . GREENBERG and H .I, YAMAMURA, Arch . Gen . Psychiat 31 58-61, (1974) . A .C . SAYERS, Psychopharmacology , 51, 15-22, (1976) . N .E . ANDEN and G . STOCK, J . P~arm . Pharmacol ., _25, 346-348, (1973) . B . ZIVROVIC, A . GUIDOTTI, A . REVUELTA aad E . COSTA, J, Pharmacol . Eap . Ther ., 194, 37-46, (1975) . B .H . WESTERINR and J . RORF, Eur . J . Pharmacol ., 33, 31-40, (1975) . P .A . WIESEL and G . SEDVALL, Eur . J . Pharmacol ., 30, 364-367, (1975) . H .Y . MELTZER, S . DANIELS and V .S . FANG, Life Sci ., _17, 339-342, (1975) . H .R . BURRI, E . EICflBZTBERGER, A .C . SAYERS, and T .G . WHITE, Pharmakopsychiatrie , 8, 115-121, (1975) . R .W, REYNOLDS and H,J, CARLISLE, J . Comp . Phyeiol, Psychol ., 54, 354-356, (1961) . S .F . LEIBOWITZ and N,E . MILLER, Science , 165, 609-611, (1969) . I,P . STOLERMAN, Neuropharmacology , _9, 405-417, (1970) . R .G . ROBINSON, P .R . McHUGH, and F .E, BLOOM, Psychopharmacol . Comm ., _1, 37-50, (1975) . E .M . CAFF1iEY, Amer . J . Paychiat ., 117, 713-719, (1961) . H .L . GORDON and C . CROTH, Arch . Gen .Psychiat ., _10, 187-191, (1964) . S . MERLIS and P .A . CARONE, in Psychopharmacological Treatment , H .D . Derber, ed ., Marcel Dekker, New York, 81-96, (1975) . J . HYTTSL, Acta Pharmacol, Toaicol ., 38, 35ö-365, (1976) . N .E . ANDEN, S,G . BUTCHER, H, CORRODI, R . FURS and U, UNGERSTEDT, Eur . J . Pharmacol _11, 303-314, (1970) . S . RITTER, C .D . WISE and L . STEIN, J . Comp . Phyeiol . Psychol ., _88, 778-784, (1975) .