European Journal of Pharmacology, 220 (1992) 43-48
43
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 52628
Effect of excitatory amino acid receptor antagonists on apomorphine-, oxytocin- and ACTH-induced penile erection and yawning in male rats M a r i a R o s a r i a Melis, R o b e r t o S t a n c a m p i a n o a n d A n t o n i o A r g i o | a s 'Bernard B. Brodie' Department of Neuroscience, Unit ersity of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
Received 23 January 1992, revised MS received 11 May 1992, accepted 16 June 1992
The effect of excitatory amino acid receptor antagonists, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten5,10-imine hydrogen maleate ((+)-MK-801), (+_)-3-(2-carboxy-piperazin-4-yl)-propyl-l-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (_+)-2-amino-4-phosphonobutanoic acid (AP-4), on penile erection and yawning induced by subcutaneous apomorphine (80 txg/kg), intracerebroventricular (i.c.v.) oxytocin (30 ng) and adrenocorticotropin (ACTH)-(1-24) (10 Ixg) was studied in male rats. Intraperitoneal (0.1-0.4 mg/kg) and i.c.v. (10-50 txg) (+)-MK-801 prevented dose dependently the penile erection and yawning induced by the three drugs. The (+)-MK-801 effect coincided with the appearance of head weaving, body rolling, hyperlocomotion and ataxia. Haloperidol (0.5 mg/kg i.p.) antagonized the prevention by (+)-MK-801 of oxytocin responses. Penile erection but not yawning was also prevented by high, but not low doses of CPP and CNQX, which impaired motor performance, AP-4 was ineffective at all doses tested. The above compounds were ineffective when injected into the paraventricular nucleus of the hypothalamus, the brain area where apomorphine and oxytocin act to induce penile erection and yawning. The results suggest that excitatory amino acid transmission is not involved in the expression of penile erection and yawning induced by the above compounds. Penile erection; Yawning; Apomorphine; Oxytocin; ACTH (adrenocorticotropin); Excitatory amino acid receptor antagonists
1. Introduction
Penile erection and yawning are two distinct behavioral patterns that often occur concomitantly under certain physiological and experimental conditions (Holmgren et al., 1985). In addition to the importance of penile erection in the reproduction of mammals yawning, alone or associated with stretching, is considered a vestige, surviving evolution, that subserves the purpose of arousal (see Bertolini and Gessa, 1981). Among substances that induce both penile erection and yawning, dopamine agonists, oxytocin and adrenocorticotropin (ACTH) are certainly the most widely known. While several lines of experimental evidence suggest that a dopamine-oxytocin link plays a key role in the expression of this behavioral response (see Melis et al., 1989), A C T H and related peptides seem to act at sites located after dopamine and oxytocin receptors with a mechanism(s) not involving central dopamine or oxytocin (Argiolas et al., 1990a). In spite of this differ-
Correspondence to: A. Argiolas, 'Bernard B. Brodie' Department of Neuroscience, University of CagliarL Via Porcell 4, 09124 Cagliari, Italy. Fax 39.70.657237.
ence, Ca 2+ seems to be involved in the expression of the above symptomatology induced by the dopamine agonist apomorphine, oxytocin and ACTH. Accordingly, the intracerebroventricular (i.c.v.) injection of nanogram amounts of w-conotoxin, one of the most potent inhibitors of voltage-dependent Ca 2+ channels in nervous tissue (McCleskey et al., 1987), prevents in a dose-dependent manner the above behavioral responses to apomorphine, oxytocin and A C T H (Argiolas et al., 1990a,b). This finding suggests that the above compounds induce penile erection and yawning by mobilizing Ca 2+ through w-conotoxin-sensitive Ca 2+ channels. However, the three compounds might induce Ca 2+ mobilization by increasing excitatory amino acid neurotransmission, i.e. Ca 2+ influx might be mediated by the stimulation of excitatory amino acid receptors (see Monaghan et al., 1989). Indeed, both oxytocin and vasopressin have been found to be capable of increasing the response of lateral septal neurons to glutamate, a natural agonist of excitatory amino acid receptors (JoEls and Urban, 1982). In order to test such a possibility, we studied the effect of several excitatory amino acid receptor antagonists on spontaneous penile erection and yawning as well as on the above responses induced by apomorphine, oxytocin and ACTH-(1-24) in male rats.
44 2. Materials and methods
2.1. Animals" Male Sprague-Dawley rats (200-250 g, Morini, Bologna, Italy)were used in all experiments. The rats were caged in groups of four to six at 24°C, 60% humidity, with water and standard laboratory food ad libitum.
2.2. Drugs and peptides Apomorphine-HCl was purchased from Sigma (S.Louis, MO, U.S.A.), haloperidol from Janssen, Belgium. (5R,10S)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate ((+)-MK-801), ( _+ )-3-(2-carboxy-piperazin-4-yl)-propyl-l-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (_+)-2-amino-4-phosphonobutanoic acid (AP-4) were purchased from Research Biochemicals Inc. (Natick, MA, U.S.A.). Synthetic oxytocin, ACTH-(1-24) and w-conotoxin-GVIA were purchased from Peninsula Laboratories (Palo Alto, CA, U.S.A.).
2.3. I.c.c. and parat~entricular nucleus (PVN) injections Stainless-steel guide cannulas (22 gauge) aimed at one lateral ventricle (i.c.v.) or unilaterally at the PVN were stereotaxically implanted under chloral hydrate anaesthesia 5 days before the experiments (coordinates: lateral ventricle, 1 mm anterior to bregma, 1.5 mm lateral to midline and 2 mm ventral to dura; PVN, 0.2 mm anterior to bregma, 0.4 mm lateral to midline and 2 mm ventral to dura) (Pellegrino and Cushman, 1971). The animals were allowed 5 days to recover from surgery; each rat was used only once. Substances dissolved in saline, except for CNQX which was dissolved in dimethylsulfoxide (DMSO), or saline (DMSO for CNQX) alone (5 #1 in 15 s) were injected i.c.v, via an internal cannula (28 gauge), which extended 2 mm below the tip of the guide cannula and was connected by polyethylene tubing to a 10-/xl Hamilton syringe driven by a micrometric screw. For PVN microinjections, substances dissolved in saline (DMSO for CNQX) or saline alone (0.3 /xl in 2 min) were injected in the PVN by means of an internal cannula (28 gauge) which extended 5.3 mm below the tip of the guide cannula and was connected to a 10-/xl Hamilton syringe driven by a Stoelting microinfusion pump. After PVN injections the tip of the cannula was left in the injection site for 30 s to allow the injected solution to spread.
2.4. Systemic treatments Apomorphine-HCl was dissolved in saline and injected subcutaneously (s.c.) in a volume of 0.2 ml/200
g body weight. Controls received the same volume of s.c. saline. Haloperidol was dissolved with a drop of acetic acid, diluted with saline (final pH = 5.5) and injected intraperitoneally (i.p.) in a volume of 1 ml/200 g body weight. The controls received the same volume of i.p. vehicle. (+)-MK-801 was injected i.p. in a volume of 1 ml/200 g body weight. The controls received the same volume of i.p. saline.
2.5. Behat,ioral studies Excitatory amino acid antagonists were given i.c.v. or in the PVN 10 min before apomorphine, oxytocin or ACTH-(l-24). In experiments in which haloperidol was used, the drug was given 10 min before ( + ) - M K 801. Shortly after receiving oxytocin, apomorphine or ACTH-(1-24) the animals were placed individually into Plexiglas cages (30 × 30 × 30 cm) and observed for 60 rain after oxytocin or apomorphine, or 120 min after ACTH-(l-24), during which penile erection and yawning episodes were counted. At the end of experiments, the animals were killed by decapitation, the brains were removed and visually inspected to ascertain the correct positioning of the cannula tip in the lateral ventricle. In experiments in which PVN microinjections were performed, at the end of experiments the animals were killed by decapitation, the brains were removed and stored for 12-15 days in saline containing 2% formaldehyde. In order to localize the extension of the lesion a n d / o r injection site, 50-/xm transverse brain sections were prepared by means of a freezing microtome, stained with Neutral Red and inspected with a phase contrast microscope. The injection site was localized by following the internal cannula tract through a series of brain sections. Only animals that were found to have the internal cannula tip positioned correctly in the lateral ventricle or in the PVN were considered for statistical analysis of the results.
2.6. Statistics Statistical evaluation of the results was performed by one-way analysis of variance (ANOVA), followed by Duncan's multiple range test. A P < 0.05 was considered significant.
3. Results
(+)-MK-801 given either i.p. (0.1-0.2 mg/kg) or i.c.v. (10 Ixg) as well as i.c.v. CPP, CNQX and Apo4 (10 Ixg) unlike s.c. apomorphine (80/xg/kg), i.c.v, oxytocin (30 ng) or ACTH-(1-24) (10/xg) did not induce penile erection or yawning (table 1). Nevertheless, systemic (+)-MK-801 (0.1, 0.2 and 0.4 m g / k g i.p.) given 10 min before apomorphine, oxytocin or ACTH-(1-24) pre-
45 TABLE l Effect of (+)-MK-801, CPP, CNQX, AP-4, apomorphine, oxytocin and ACTH-(I-24) on spontaneous penile erection and yawning in male rats.
4
!3 o
2
After treatment, the rats were placed individually into Plexiglas cages and observed for 60 rain (120 rain for ACTH-(1-24)), during which penile erection and yawning episodes were counted. Values are means_+S.E.M, for 10 rats per group. Drug
Dose
Penile erections/rat
Yawns/rat
Saline ( + )-MK-801 (+)-MK-801 Saline (+)-MK-801 CPP CNQX b AP-4 Apomorphine Oxytocin ACTH-(1-24)
1 ml i.p. 0.1 m g / k g i.p. 0.2 m g / k g i.p. 5/xl i.c.v. 10 ~g i.c.v. 10/tg i.c.v. 10 ~g i.c.v. 10/zg i.c.v. 8 0 / x g / k g s.c, 30 ng i.c.v. 10/xg i.c.v.
(1.3 _+0.2 0.4-+0.3 0.3_+0.1 0.5 _+0.2 0.4_+0.2 0.2 _+0.1 0.3 _+0.2 0.4_+0.1 4.1 _+0.3 ~' 4.3+0.5 " 4.5-+0.3 "
1.8 + 0.3 2.1_+0.4 2.0_+0.3 1.8 + 0.4 1.5_+0.2 1.7 _+0.2 2.0 + 0.3 1.8-+0.4 19.6 + 2.2 18.8_+2.0 21.0-+2.1
N
2o
-
-
w
20
)...
o
;
0'.1
0'2
"_a 0.4
(+)-MK-B01 (mg/kg Z.p.)
" P < 0.05 with respect to saline-pretreated rats (one-way A N O V A followed by Duncan's multiple range test), b All drugs were dissolved in saline except for CNQX which was dissolved in DMSO.
vented in a dose-dependent manner the above behavioral responses induced by apomorphine, oxytocin and ACTH-(1-24) (fig. 1). While the 0.1 mg/kg dose was ineffective, more than 50% prevention was observed with 0.2 mg/kg of the drug. Complete prevention of the above effects was found with 0.4 mg/kg, which induced marked hyperlocomotion, body weaving, sniffing and ataxia that lasted about 2 h. Systemic (+)-MK801 also prevented ACTH-induced stretching (not shown). When given i.c.v. 10 rain before apomorphine, oxytocin or ACTH-(1-24), (+)-MK-801 was ineffective on penile erection and yawning at the dose of 10 #g,
Fig. 1, Effect of systemic ( + )-MK-801 on penile erection and yawning induced by apomorphinc (open bars), oxytocin (filled bars) or ACTH-(l-24) (hatched bars): dose-response curve. Saline (1 m l / r a t ) alone or containing (+)-MK-801 was given i.p. 10 rain before apomorphine (80/xg/kg s.c.), oxytocin (30 ng i.c.v.) or ACTH-(I-24) (10 /zg i.c.v.). After the injections, the rats were placed individually into Plexiglas cages and observed for 60 min after apomorphine or oxytocin and 120 min after ACTH-(l-24), respectively, during which penile erection and yawning episodes were counted. The values are means_+S.E.M, for 12 rats per group. * P < 0 . 0 5 with respect to saline-pretreated rats.
but prevented both responses at the dose of 50/zg (fig. 2), which also induced a dramatic symptomatology characterized by head weaving, body rolling and hyperlocomotion that lasted at least 2 h. Haloperidol (0.5 mg/kg i.p.) given 10 rain before (+)-MK-801, partially antagonized the prevention of oxytocin-induced penile erection and yawning as well as the behavioral syndrome induced by i.p. (+)-MK-801 (not shown). In contrast, no difference was found after apomorphine
I--
43
© 1992 Elsevier Science Publishers B.V. All rights reserved 0014-2999/92/$05.00
EJP 52628
Effect of excitatory amino acid receptor antagonists on apomorphine-, oxytocin- and ACTH-induced penile erection and yawning in male rats M a r i a R o s a r i a Melis, R o b e r t o S t a n c a m p i a n o a n d A n t o n i o A r g i o | a s 'Bernard B. Brodie' Department of Neuroscience, Unit ersity of Cagliari, Via Porcell 4, 09124 Cagliari, Italy
Received 23 January 1992, revised MS received 11 May 1992, accepted 16 June 1992
The effect of excitatory amino acid receptor antagonists, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten5,10-imine hydrogen maleate ((+)-MK-801), (+_)-3-(2-carboxy-piperazin-4-yl)-propyl-l-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (_+)-2-amino-4-phosphonobutanoic acid (AP-4), on penile erection and yawning induced by subcutaneous apomorphine (80 txg/kg), intracerebroventricular (i.c.v.) oxytocin (30 ng) and adrenocorticotropin (ACTH)-(1-24) (10 Ixg) was studied in male rats. Intraperitoneal (0.1-0.4 mg/kg) and i.c.v. (10-50 txg) (+)-MK-801 prevented dose dependently the penile erection and yawning induced by the three drugs. The (+)-MK-801 effect coincided with the appearance of head weaving, body rolling, hyperlocomotion and ataxia. Haloperidol (0.5 mg/kg i.p.) antagonized the prevention by (+)-MK-801 of oxytocin responses. Penile erection but not yawning was also prevented by high, but not low doses of CPP and CNQX, which impaired motor performance, AP-4 was ineffective at all doses tested. The above compounds were ineffective when injected into the paraventricular nucleus of the hypothalamus, the brain area where apomorphine and oxytocin act to induce penile erection and yawning. The results suggest that excitatory amino acid transmission is not involved in the expression of penile erection and yawning induced by the above compounds. Penile erection; Yawning; Apomorphine; Oxytocin; ACTH (adrenocorticotropin); Excitatory amino acid receptor antagonists
1. Introduction
Penile erection and yawning are two distinct behavioral patterns that often occur concomitantly under certain physiological and experimental conditions (Holmgren et al., 1985). In addition to the importance of penile erection in the reproduction of mammals yawning, alone or associated with stretching, is considered a vestige, surviving evolution, that subserves the purpose of arousal (see Bertolini and Gessa, 1981). Among substances that induce both penile erection and yawning, dopamine agonists, oxytocin and adrenocorticotropin (ACTH) are certainly the most widely known. While several lines of experimental evidence suggest that a dopamine-oxytocin link plays a key role in the expression of this behavioral response (see Melis et al., 1989), A C T H and related peptides seem to act at sites located after dopamine and oxytocin receptors with a mechanism(s) not involving central dopamine or oxytocin (Argiolas et al., 1990a). In spite of this differ-
Correspondence to: A. Argiolas, 'Bernard B. Brodie' Department of Neuroscience, University of CagliarL Via Porcell 4, 09124 Cagliari, Italy. Fax 39.70.657237.
ence, Ca 2+ seems to be involved in the expression of the above symptomatology induced by the dopamine agonist apomorphine, oxytocin and ACTH. Accordingly, the intracerebroventricular (i.c.v.) injection of nanogram amounts of w-conotoxin, one of the most potent inhibitors of voltage-dependent Ca 2+ channels in nervous tissue (McCleskey et al., 1987), prevents in a dose-dependent manner the above behavioral responses to apomorphine, oxytocin and A C T H (Argiolas et al., 1990a,b). This finding suggests that the above compounds induce penile erection and yawning by mobilizing Ca 2+ through w-conotoxin-sensitive Ca 2+ channels. However, the three compounds might induce Ca 2+ mobilization by increasing excitatory amino acid neurotransmission, i.e. Ca 2+ influx might be mediated by the stimulation of excitatory amino acid receptors (see Monaghan et al., 1989). Indeed, both oxytocin and vasopressin have been found to be capable of increasing the response of lateral septal neurons to glutamate, a natural agonist of excitatory amino acid receptors (JoEls and Urban, 1982). In order to test such a possibility, we studied the effect of several excitatory amino acid receptor antagonists on spontaneous penile erection and yawning as well as on the above responses induced by apomorphine, oxytocin and ACTH-(1-24) in male rats.
44 2. Materials and methods
2.1. Animals" Male Sprague-Dawley rats (200-250 g, Morini, Bologna, Italy)were used in all experiments. The rats were caged in groups of four to six at 24°C, 60% humidity, with water and standard laboratory food ad libitum.
2.2. Drugs and peptides Apomorphine-HCl was purchased from Sigma (S.Louis, MO, U.S.A.), haloperidol from Janssen, Belgium. (5R,10S)-( + )-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen maleate ((+)-MK-801), ( _+ )-3-(2-carboxy-piperazin-4-yl)-propyl-l-phosphonic acid (CPP), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and (_+)-2-amino-4-phosphonobutanoic acid (AP-4) were purchased from Research Biochemicals Inc. (Natick, MA, U.S.A.). Synthetic oxytocin, ACTH-(1-24) and w-conotoxin-GVIA were purchased from Peninsula Laboratories (Palo Alto, CA, U.S.A.).
2.3. I.c.c. and parat~entricular nucleus (PVN) injections Stainless-steel guide cannulas (22 gauge) aimed at one lateral ventricle (i.c.v.) or unilaterally at the PVN were stereotaxically implanted under chloral hydrate anaesthesia 5 days before the experiments (coordinates: lateral ventricle, 1 mm anterior to bregma, 1.5 mm lateral to midline and 2 mm ventral to dura; PVN, 0.2 mm anterior to bregma, 0.4 mm lateral to midline and 2 mm ventral to dura) (Pellegrino and Cushman, 1971). The animals were allowed 5 days to recover from surgery; each rat was used only once. Substances dissolved in saline, except for CNQX which was dissolved in dimethylsulfoxide (DMSO), or saline (DMSO for CNQX) alone (5 #1 in 15 s) were injected i.c.v, via an internal cannula (28 gauge), which extended 2 mm below the tip of the guide cannula and was connected by polyethylene tubing to a 10-/xl Hamilton syringe driven by a micrometric screw. For PVN microinjections, substances dissolved in saline (DMSO for CNQX) or saline alone (0.3 /xl in 2 min) were injected in the PVN by means of an internal cannula (28 gauge) which extended 5.3 mm below the tip of the guide cannula and was connected to a 10-/xl Hamilton syringe driven by a Stoelting microinfusion pump. After PVN injections the tip of the cannula was left in the injection site for 30 s to allow the injected solution to spread.
2.4. Systemic treatments Apomorphine-HCl was dissolved in saline and injected subcutaneously (s.c.) in a volume of 0.2 ml/200
g body weight. Controls received the same volume of s.c. saline. Haloperidol was dissolved with a drop of acetic acid, diluted with saline (final pH = 5.5) and injected intraperitoneally (i.p.) in a volume of 1 ml/200 g body weight. The controls received the same volume of i.p. vehicle. (+)-MK-801 was injected i.p. in a volume of 1 ml/200 g body weight. The controls received the same volume of i.p. saline.
2.5. Behat,ioral studies Excitatory amino acid antagonists were given i.c.v. or in the PVN 10 min before apomorphine, oxytocin or ACTH-(l-24). In experiments in which haloperidol was used, the drug was given 10 min before ( + ) - M K 801. Shortly after receiving oxytocin, apomorphine or ACTH-(1-24) the animals were placed individually into Plexiglas cages (30 × 30 × 30 cm) and observed for 60 rain after oxytocin or apomorphine, or 120 min after ACTH-(l-24), during which penile erection and yawning episodes were counted. At the end of experiments, the animals were killed by decapitation, the brains were removed and visually inspected to ascertain the correct positioning of the cannula tip in the lateral ventricle. In experiments in which PVN microinjections were performed, at the end of experiments the animals were killed by decapitation, the brains were removed and stored for 12-15 days in saline containing 2% formaldehyde. In order to localize the extension of the lesion a n d / o r injection site, 50-/xm transverse brain sections were prepared by means of a freezing microtome, stained with Neutral Red and inspected with a phase contrast microscope. The injection site was localized by following the internal cannula tract through a series of brain sections. Only animals that were found to have the internal cannula tip positioned correctly in the lateral ventricle or in the PVN were considered for statistical analysis of the results.
2.6. Statistics Statistical evaluation of the results was performed by one-way analysis of variance (ANOVA), followed by Duncan's multiple range test. A P < 0.05 was considered significant.
3. Results
(+)-MK-801 given either i.p. (0.1-0.2 mg/kg) or i.c.v. (10 Ixg) as well as i.c.v. CPP, CNQX and Apo4 (10 Ixg) unlike s.c. apomorphine (80/xg/kg), i.c.v, oxytocin (30 ng) or ACTH-(1-24) (10/xg) did not induce penile erection or yawning (table 1). Nevertheless, systemic (+)-MK-801 (0.1, 0.2 and 0.4 m g / k g i.p.) given 10 min before apomorphine, oxytocin or ACTH-(1-24) pre-
45 TABLE l Effect of (+)-MK-801, CPP, CNQX, AP-4, apomorphine, oxytocin and ACTH-(I-24) on spontaneous penile erection and yawning in male rats.
4
!3 o
2
After treatment, the rats were placed individually into Plexiglas cages and observed for 60 rain (120 rain for ACTH-(1-24)), during which penile erection and yawning episodes were counted. Values are means_+S.E.M, for 10 rats per group. Drug
Dose
Penile erections/rat
Yawns/rat
Saline ( + )-MK-801 (+)-MK-801 Saline (+)-MK-801 CPP CNQX b AP-4 Apomorphine Oxytocin ACTH-(1-24)
1 ml i.p. 0.1 m g / k g i.p. 0.2 m g / k g i.p. 5/xl i.c.v. 10 ~g i.c.v. 10/tg i.c.v. 10 ~g i.c.v. 10/zg i.c.v. 8 0 / x g / k g s.c, 30 ng i.c.v. 10/xg i.c.v.
(1.3 _+0.2 0.4-+0.3 0.3_+0.1 0.5 _+0.2 0.4_+0.2 0.2 _+0.1 0.3 _+0.2 0.4_+0.1 4.1 _+0.3 ~' 4.3+0.5 " 4.5-+0.3 "
1.8 + 0.3 2.1_+0.4 2.0_+0.3 1.8 + 0.4 1.5_+0.2 1.7 _+0.2 2.0 + 0.3 1.8-+0.4 19.6 + 2.2 18.8_+2.0 21.0-+2.1
N
2o
-
-
w
20
)...
o
;
0'.1
0'2
"_a 0.4
(+)-MK-B01 (mg/kg Z.p.)
" P < 0.05 with respect to saline-pretreated rats (one-way A N O V A followed by Duncan's multiple range test), b All drugs were dissolved in saline except for CNQX which was dissolved in DMSO.
vented in a dose-dependent manner the above behavioral responses induced by apomorphine, oxytocin and ACTH-(1-24) (fig. 1). While the 0.1 mg/kg dose was ineffective, more than 50% prevention was observed with 0.2 mg/kg of the drug. Complete prevention of the above effects was found with 0.4 mg/kg, which induced marked hyperlocomotion, body weaving, sniffing and ataxia that lasted about 2 h. Systemic (+)-MK801 also prevented ACTH-induced stretching (not shown). When given i.c.v. 10 rain before apomorphine, oxytocin or ACTH-(1-24), (+)-MK-801 was ineffective on penile erection and yawning at the dose of 10 #g,
Fig. 1, Effect of systemic ( + )-MK-801 on penile erection and yawning induced by apomorphinc (open bars), oxytocin (filled bars) or ACTH-(l-24) (hatched bars): dose-response curve. Saline (1 m l / r a t ) alone or containing (+)-MK-801 was given i.p. 10 rain before apomorphine (80/xg/kg s.c.), oxytocin (30 ng i.c.v.) or ACTH-(I-24) (10 /zg i.c.v.). After the injections, the rats were placed individually into Plexiglas cages and observed for 60 min after apomorphine or oxytocin and 120 min after ACTH-(l-24), respectively, during which penile erection and yawning episodes were counted. The values are means_+S.E.M, for 12 rats per group. * P < 0 . 0 5 with respect to saline-pretreated rats.
but prevented both responses at the dose of 50/zg (fig. 2), which also induced a dramatic symptomatology characterized by head weaving, body rolling and hyperlocomotion that lasted at least 2 h. Haloperidol (0.5 mg/kg i.p.) given 10 rain before (+)-MK-801, partially antagonized the prevention of oxytocin-induced penile erection and yawning as well as the behavioral syndrome induced by i.p. (+)-MK-801 (not shown). In contrast, no difference was found after apomorphine
I--
