- Email: [email protected]
P-11-28 Blunted response in the citalopram challenge test (CCT) in diabetes
P-11 Basic neuroscience and neurop,~vchopharmacology
413
and 90 days (adult) old rats of the Wtstar strain by ustng the procedures described elsewhere [1]. The training session and the test one were spaced 24 hours. 7 OH DPAT was injected i p. 30 m,n before the training sess~oP in the doses 001 and 0.025 mg/kg This range of the doses was found to be linked to D3 specific effect of 7-OH-DPAT - - inhibitory modu,ation of dopamine release [2]. 7-OH-DPAT did not affect the initial amplitude of the ASR and the latency of the peak amplitude in rats of al! the ages The agon~st s~gnificantly improved SHT of the reflex ~n the preweanling and adult rats and d~d not change it in the young animals, it was shown that 70H-DPAT improved expression of LTH of the ASR dunng the test session only in the adult rats. The freezing behavior during traimng was not affected by the agon~st injections irrespective of rats' ages, although during the test session the drugged preweanling and adult rats froze much less than the controls Interestingly, the amount of freezing t~mes of the drugged young animals and the control group were similar In conclusion, the present data indicate that 7 OH-DPAT had selective ac tions on the different fear-related behawors across postnatal development of rat. These results are discussed in respect of (1) a possible involvement of D3 dopamine receptor ~n the development of fear-like states across the rat's oetogeny, and (2}the practical perspective of considering D3 dopamine autoreceptor as a possible new target {or treatment of psychiatric disorders
References Storozheva ZI Pletnicov M M { 1994) Habituation of acoustic startle In rats A luncttonal ablation study NeuroReport 5. 2065-2068 Gainetdinov R R Sotnikova T D Grekhova TM. RayevskyK S (1994) In wvo evidence of preferential role of D3 dopamlne autoreceptor n Dresynapbc regulatio'7 of dopam~ne release Soc Neuroscl Abstr 20, 1355 r
IP-1 1
i ~2 7
I Time and dose dependent behavioural and
physiological effects of repeated administration of (+)-amphetamine to rats
J R Kelly, A. O'Halloran. B.E Leonard Pharmaco/ogy Department,
Univers/ty Co//ege Ga/way, ~re~and The psychomotor stimulant (+}-amphetamine has oeen extensively stud led in humans as well as experimental animals A behavioura~ conse quence of the increased dopaminerg~c activity following administration of (+)-amphetamine is an increase in locomotor actiwty ,n rats Kaliwas and Stewart, 1991): repeated admlntstration can gwe rise to tolerance and sen sitization responses The purpose of this study was to examine the effect of repeated administration of (+Famphetamine on home cage actwity and colonic temperature responses The advantage of conducting these mea surements in the home cage means that there are no stress related o ~ habituatory responses which would occur if the animals were repeatedly examined in another apparatus, such as the open-field Male Sprague-Dawley rats (mean weight 200 g prior to treatment) were used. They were individually housed in cages to which an infrared photo beam was situated to allow continuous locomotor activity measurement (Nsimba et al., 1994). Rats received an mtraperitoneal miection of 0, 2, 5 or 10 mg/kg (+)-amphetamine sulphate dissolved in saline daffy for 10 days immediately prior to and 30 min. following dosing, the colonic temperature for each rat was recorded. Rats were killed 4 nr after the last Inlect~on, aPd striatal neurotransmitter levels were determined The results show that on day 1 of dosing, there was a clearly defined dose response relationship with {~)-amphetamme However a tolerance t o t h ! s effect was observed in t h e S a n d 10 mg/kg groups In contrastsenslt~zation was found in the 2 mg/kg group with slgni%ant increases in activltyfound on several davs from day 2 onwards Dunng the study, ahypothermicresponse to 10 mg/kg group was found on the first 6 days and days 2, 3 and 6 in the 5 mg/kg group. A significant reductton m weight gain over the dosing period was found in t h e 5 mg/kg(P < 005) and 10 mg/kg (P < 001) groups The only significant change in neurotransmltters was a sign hcant reductior" irl DOPAC in the striatum m the 10 mg/kg group (P < 005) Table 1 The effect of (+}-amphetamine on home cage actwit~ Median values sf ~ animals per dose group are shown Group Control 2 mg/kg 5 mg/kg 10 mg/kg
Day o1 treatment 7
2
3
4
5
6
7
8
9
10
254 312 816* 1163""
310 746" 743" 479"
277 473 564" 588"
292 548 444 455
232 632" 294 [;17
286 707" 325 665'
213 553 220 347
221 734' 264 679*
189 759" 352 i048""
176 742" 296 709"
"P<005,'*P<001
It can be concluded that repeated administration of (+}-amphetamine has complex effects on home cage locomotor activity in rats which are time- and dose-dependent, in addition, a tolerance to the hypothermic effects of (+)amphetamine The reduced wetght gain in the 5 mg/kg and 10 mg/kg groups would suggest that these doses are toxic when administered repeatedly to rats
References Kalivas, PW and Stewart, J (1991). Dopamine transrniss~on in the initiation and expression of drug and stress induced sensitization of motor activity. Brain Research 16, 223 244 Nsimba SE D Kelly,JR and Leonard, 8 E (1994) Dose-dependent behavioural effects of phencycl~dine(PCP} Medical Science Research 22,207 209
IP-1 1
i 28
i
I Blunted response in the citalopram challenge test (CCT) in diabetes
S.D. Schlndler. T Kapitany. C. Barnas, A. Neumeister, W. Sieghart. S. Kasper. Umversity Hospita/ of Psychiatr)4, Clinical Department of Genera/
Psychiatry Wdhnnger G~)rtel 18-20, A 1090 Vienna, Austria Neuroendocnne reactions to psychopharmacological stimuli are a sensitive clinical method to study neurotransmitter systems. In healthy subjects the acute administration of serotonergic agents leads to increased secretion of orolactin and cortisol A blunted reaction of hormonal response was seen in depressed patients when serotonergically stimulated. Several compoJnds were used for stimulation like L-tryptophan, 5-HT or fenfluramine, but also tricyclic antidepressants (e.g. desipramine and clomipramine). As a new substance for serotonergic challenge citalopram is introduced (Kap~tany et al, 1995. see this abstract publication). This substance combines tqe advantage of a selective serotonergic stimulation with the possibility o; ,ntravenous administration, avoiding interindividual differences through enteral absorbtion A patient (male, 30 a) suffering from type I diabetes took part in this study as a control and showed a blunted response to citalopram in terms of a s~gnificantly reduced hormonal secretion compared to healthy controls. Blood glucose differences excert influences on the secretion of prolactin tVierhapperetal 1983). Since our patient had close to normal blood glucose founts (77-146 rag/d) we do not think that the patients glycaemic state does explain these &fferences in response alone We d~scuss the problems why patients suffering from diabetes mellitus type 1 m~ght have a d~fferent response to serotonerglc stimulation. Furthermore, additional factors which could be influencial for a blunted hormonal pattern to neuroendoeqne challenge paradigms of the serotonergic system will be elaborated.
References ~aakman G. Gugath M, Kuss HJ, Zygan K (1984) Comparison of growth hormone and prolactin stimulation induced by chlorimipramine and deslpramine in man in connecnon w~thchlonmipramlne metabolism Psychopharmacology82:62 67 Kasper S, Vie,ra A Schmidt R, Richter P {1990): Multiple hormone responses to stimuaton with d!-fenfluramine in patients with major depression before and after antidepressant treatment Pharmacopsychiat 23:76-84 Wehapper H, Bratusch Marrain P,WaJdh~usl W, Nowotny R PanzerS, (1982) Impact of euglycaemla and hyperglycaemia on the release of growth hormone and prolactin in type I! diabetics Horm Metab Res 15:24 29
IP-1 1
129
i
I
Are the contrasting effects of GR 127935 and methiothepin on recombinant 5-HT~c receptor systems physiologically relevant?
B.~ Jones, M. Burton, DN. Middlemiss, G.W. Price, C. Roberts. SmithK//ne Beecham Pharmaceuticals, New Frontiers Sc/enee Park, Third Avenue, Han'ow, Essex, CM19 5AW, UK The discovery of GR 127935 (2'-methyl-4'-(5-methyl-[1,2,4]oxadiazole-3vl)-b4ph enyl-4-ca rboxylic acid [4-m ethoxy-3-(4-m ethyl-piperazin- 1-yl)phenyl]amice), a compound selective for 5-HT1D receptors, has provided the opportunity to confirm the widely-held belief that the 5-HT terminal autoreceptor in non-rodent species is of the 5-HT1D receptor subtype. However, we demonstrated recently that GR 127935 is a partial agonist at human 5HT1D receptors expressed in Chinese Hamster Ovary (CHO) cells (Watson et al, 1995) To establish whether this property was also manifest in a physological system, we tested GR 127935 for its abihty to modify 5-HT terminal autcreceptor function in guinea pig brain slices, using methiothepin as a eoml3arator Both compounds were tested on h u m a n 5 H T 1 D ~andS-HT1D #
413
and 90 days (adult) old rats of the Wtstar strain by ustng the procedures described elsewhere [1]. The training session and the test one were spaced 24 hours. 7 OH DPAT was injected i p. 30 m,n before the training sess~oP in the doses 001 and 0.025 mg/kg This range of the doses was found to be linked to D3 specific effect of 7-OH-DPAT - - inhibitory modu,ation of dopamine release [2]. 7-OH-DPAT did not affect the initial amplitude of the ASR and the latency of the peak amplitude in rats of al! the ages The agon~st s~gnificantly improved SHT of the reflex ~n the preweanling and adult rats and d~d not change it in the young animals, it was shown that 70H-DPAT improved expression of LTH of the ASR dunng the test session only in the adult rats. The freezing behavior during traimng was not affected by the agon~st injections irrespective of rats' ages, although during the test session the drugged preweanling and adult rats froze much less than the controls Interestingly, the amount of freezing t~mes of the drugged young animals and the control group were similar In conclusion, the present data indicate that 7 OH-DPAT had selective ac tions on the different fear-related behawors across postnatal development of rat. These results are discussed in respect of (1) a possible involvement of D3 dopamine receptor ~n the development of fear-like states across the rat's oetogeny, and (2}the practical perspective of considering D3 dopamine autoreceptor as a possible new target {or treatment of psychiatric disorders
References Storozheva ZI Pletnicov M M { 1994) Habituation of acoustic startle In rats A luncttonal ablation study NeuroReport 5. 2065-2068 Gainetdinov R R Sotnikova T D Grekhova TM. RayevskyK S (1994) In wvo evidence of preferential role of D3 dopamlne autoreceptor n Dresynapbc regulatio'7 of dopam~ne release Soc Neuroscl Abstr 20, 1355 r
IP-1 1
i ~2 7
I Time and dose dependent behavioural and
physiological effects of repeated administration of (+)-amphetamine to rats
J R Kelly, A. O'Halloran. B.E Leonard Pharmaco/ogy Department,
Univers/ty Co//ege Ga/way, ~re~and The psychomotor stimulant (+}-amphetamine has oeen extensively stud led in humans as well as experimental animals A behavioura~ conse quence of the increased dopaminerg~c activity following administration of (+)-amphetamine is an increase in locomotor actiwty ,n rats Kaliwas and Stewart, 1991): repeated admlntstration can gwe rise to tolerance and sen sitization responses The purpose of this study was to examine the effect of repeated administration of (+Famphetamine on home cage actwity and colonic temperature responses The advantage of conducting these mea surements in the home cage means that there are no stress related o ~ habituatory responses which would occur if the animals were repeatedly examined in another apparatus, such as the open-field Male Sprague-Dawley rats (mean weight 200 g prior to treatment) were used. They were individually housed in cages to which an infrared photo beam was situated to allow continuous locomotor activity measurement (Nsimba et al., 1994). Rats received an mtraperitoneal miection of 0, 2, 5 or 10 mg/kg (+)-amphetamine sulphate dissolved in saline daffy for 10 days immediately prior to and 30 min. following dosing, the colonic temperature for each rat was recorded. Rats were killed 4 nr after the last Inlect~on, aPd striatal neurotransmitter levels were determined The results show that on day 1 of dosing, there was a clearly defined dose response relationship with {~)-amphetamme However a tolerance t o t h ! s effect was observed in t h e S a n d 10 mg/kg groups In contrastsenslt~zation was found in the 2 mg/kg group with slgni%ant increases in activltyfound on several davs from day 2 onwards Dunng the study, ahypothermicresponse to 10 mg/kg group was found on the first 6 days and days 2, 3 and 6 in the 5 mg/kg group. A significant reductton m weight gain over the dosing period was found in t h e 5 mg/kg(P < 005) and 10 mg/kg (P < 001) groups The only significant change in neurotransmltters was a sign hcant reductior" irl DOPAC in the striatum m the 10 mg/kg group (P < 005) Table 1 The effect of (+}-amphetamine on home cage actwit~ Median values sf ~ animals per dose group are shown Group Control 2 mg/kg 5 mg/kg 10 mg/kg
Day o1 treatment 7
2
3
4
5
6
7
8
9
10
254 312 816* 1163""
310 746" 743" 479"
277 473 564" 588"
292 548 444 455
232 632" 294 [;17
286 707" 325 665'
213 553 220 347
221 734' 264 679*
189 759" 352 i048""
176 742" 296 709"
"P<005,'*P<001
It can be concluded that repeated administration of (+}-amphetamine has complex effects on home cage locomotor activity in rats which are time- and dose-dependent, in addition, a tolerance to the hypothermic effects of (+)amphetamine The reduced wetght gain in the 5 mg/kg and 10 mg/kg groups would suggest that these doses are toxic when administered repeatedly to rats
References Kalivas, PW and Stewart, J (1991). Dopamine transrniss~on in the initiation and expression of drug and stress induced sensitization of motor activity. Brain Research 16, 223 244 Nsimba SE D Kelly,JR and Leonard, 8 E (1994) Dose-dependent behavioural effects of phencycl~dine(PCP} Medical Science Research 22,207 209
IP-1 1
i 28
i
I Blunted response in the citalopram challenge test (CCT) in diabetes
S.D. Schlndler. T Kapitany. C. Barnas, A. Neumeister, W. Sieghart. S. Kasper. Umversity Hospita/ of Psychiatr)4, Clinical Department of Genera/
Psychiatry Wdhnnger G~)rtel 18-20, A 1090 Vienna, Austria Neuroendocnne reactions to psychopharmacological stimuli are a sensitive clinical method to study neurotransmitter systems. In healthy subjects the acute administration of serotonergic agents leads to increased secretion of orolactin and cortisol A blunted reaction of hormonal response was seen in depressed patients when serotonergically stimulated. Several compoJnds were used for stimulation like L-tryptophan, 5-HT or fenfluramine, but also tricyclic antidepressants (e.g. desipramine and clomipramine). As a new substance for serotonergic challenge citalopram is introduced (Kap~tany et al, 1995. see this abstract publication). This substance combines tqe advantage of a selective serotonergic stimulation with the possibility o; ,ntravenous administration, avoiding interindividual differences through enteral absorbtion A patient (male, 30 a) suffering from type I diabetes took part in this study as a control and showed a blunted response to citalopram in terms of a s~gnificantly reduced hormonal secretion compared to healthy controls. Blood glucose differences excert influences on the secretion of prolactin tVierhapperetal 1983). Since our patient had close to normal blood glucose founts (77-146 rag/d) we do not think that the patients glycaemic state does explain these &fferences in response alone We d~scuss the problems why patients suffering from diabetes mellitus type 1 m~ght have a d~fferent response to serotonerglc stimulation. Furthermore, additional factors which could be influencial for a blunted hormonal pattern to neuroendoeqne challenge paradigms of the serotonergic system will be elaborated.
References ~aakman G. Gugath M, Kuss HJ, Zygan K (1984) Comparison of growth hormone and prolactin stimulation induced by chlorimipramine and deslpramine in man in connecnon w~thchlonmipramlne metabolism Psychopharmacology82:62 67 Kasper S, Vie,ra A Schmidt R, Richter P {1990): Multiple hormone responses to stimuaton with d!-fenfluramine in patients with major depression before and after antidepressant treatment Pharmacopsychiat 23:76-84 Wehapper H, Bratusch Marrain P,WaJdh~usl W, Nowotny R PanzerS, (1982) Impact of euglycaemla and hyperglycaemia on the release of growth hormone and prolactin in type I! diabetics Horm Metab Res 15:24 29
IP-1 1
129
i
I
Are the contrasting effects of GR 127935 and methiothepin on recombinant 5-HT~c receptor systems physiologically relevant?
B.~ Jones, M. Burton, DN. Middlemiss, G.W. Price, C. Roberts. SmithK//ne Beecham Pharmaceuticals, New Frontiers Sc/enee Park, Third Avenue, Han'ow, Essex, CM19 5AW, UK The discovery of GR 127935 (2'-methyl-4'-(5-methyl-[1,2,4]oxadiazole-3vl)-b4ph enyl-4-ca rboxylic acid [4-m ethoxy-3-(4-m ethyl-piperazin- 1-yl)phenyl]amice), a compound selective for 5-HT1D receptors, has provided the opportunity to confirm the widely-held belief that the 5-HT terminal autoreceptor in non-rodent species is of the 5-HT1D receptor subtype. However, we demonstrated recently that GR 127935 is a partial agonist at human 5HT1D receptors expressed in Chinese Hamster Ovary (CHO) cells (Watson et al, 1995) To establish whether this property was also manifest in a physological system, we tested GR 127935 for its abihty to modify 5-HT terminal autcreceptor function in guinea pig brain slices, using methiothepin as a eoml3arator Both compounds were tested on h u m a n 5 H T 1 D ~andS-HT1D #