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Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats
Neuroscience Letters 513 (2012) 114–118
Contents lists available at SciVerse ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats Ying-Chou Wang a , Bo-Han He b , Chih-Chung Chen c , Andrew Chih Wei Huang b,∗ , Yu-Chi Yeh d a
Department of Clinical Psychology, Fu-Jen Catholic University, New Taipei City, Taiwan Department of Psychology, Fo Guang University, Yilan County 26247, Taiwan Department of Physical Therapy, Chang Gung University, Tao-Yuan 333, Taiwan d Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 6 November 2011 Received in revised form 4 January 2012 Accepted 19 January 2012 Keywords: Gender Dopamine agonist Latent inhibition Sexual dimorphism
a b s t r a c t The present study investigated gender differences in the effects of presynaptic and postsynaptic DA agonists on latent inhibition in the passive avoidance paradigm. During the preexposure phase, 32 male and 32 female Wistar rats were exposed to a passive avoidance box (or a different context) and received drug injections in three trials: the control group received an injection of 10% ascorbic acid in a different context. The experimental groups received injections of 10% ascorbic acid (latent inhibition [LI] group), 1 mg/kg of the postsynaptic DA D1 /D2 agonist apomorphine (APO group), and 1.5 mg/kg of the presynaptic DA agonist methamphetamine (METH group) in a passive avoidance box. All experimental groups were placed in the light compartment of the passive avoidance box and were allowed to enter into the dark compartment to receive a footshock (1 mA, 2 s) in five trials over 5 days. The latency to enter into the dark compartment was recorded in these five trials. The latent inhibition occurred in the female LI group but not in the male LI group. Regardless of gender, the APO group exhibited an increase in latent inhibition. Male rats in the METH group exhibited a decrease in latent inhibition, but female rats in the METH group exhibited an increase in latent inhibition, indicating that the METH group exhibited sexual dimorphism. The gender factor interacted only with the METH group and not the LI or APO group. The present paper discusses whether gender, the postsynaptic DA D1 /D2 agonist APO, and presynaptic DA agonist METH may be related to schizophrenia. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Latent inhibition is defined as preexposure to a conditioned stimulus (CS), after which the CS is less able to be associated with a subsequent unconditioned stimulus (US) [14]. Since the 1990s, many studies have investigated latent inhibition in human and animal models, and diverse hypotheses have been proposed, including attentional theory [15], switching theory [27], occasion setting [17,21], and associative theory [4,8], to explain why previous CS preexposure later disrupts CS–US conditioning. According to associative theory, latent inhibition may reflect the disruptions of the CS–US association learning before pre-exposing the CS-context association. Healthy participants learn the CS-context association to interfere with the later CS–US association learning. Schizophrenia patients are unable to learn the CS-context association, and then
∗ Corresponding author at: Department of Psychology, Fo Guang University, No. 160, Linwei Road, Jiaosi Shiang, Yilan County 26247, Taiwan. Tel.: +886 3 9871000x27114; fax: +886 3 9875530. E-mail address: [email protected] (A.C.W. Huang). 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2012.01.047
do not exhibit a disruption of the CS–US association. Therefore, schizophrenia patients are often suggested to have disturbances in latent inhibition [9,12,15]. Numerous neurocircuitry investigations of latent inhibition have focused on the involvement of the mesocorticolimbic dopamine (DA) system [7,11]. A previous microdialysis study manipulated a tone and light conditioned to an aversive footshock to examine DA release in the nucleus accumbens during the conditioning phase. The results showed that enhanced DA release in the nucleus accumbens blunted latent inhibition [30]. Pharmacological studies showed that latent inhibition was attenuated following consecutive amphetamine injections over several days. This attenuation of latent inhibition was reversed by concomitant administration of the DA D2 receptor antagonist chlorpromazine [25]. Latent inhibition was blocked and enhanced by increasing and decreasing DA signal transduction, respectively [27]. However, Feldon et al. [5] demonstrated that the D1 -selective agonist SKF38393 and D2 -selective agonist quinpirole did not affect latent inhibition. A low dose of apomorphine (APO; 0.3 mg/kg), which activates D2 autoreceptors as a functional DA antagonist, and a high dose of APO (1.5 mg/kg), which activates postsynaptic D1 /D2
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receptors as a functional DA agonist, also did not affect latent inhibition [5]. In summary, the present study investigated whether presynaptic and postsynaptic DA agonists treatments were respectively given prior to the CS preexposure condition, and thereby influenced the later CS–US association. Thus, it was thought to test the effect of latent inhibition. Moreover, previous studies predominantly utilized male animals. To our knowledge, no study has investigated the possible differential effects of gender on latent inhibition. Therefore, gender differences were also examined in the present study. Altogether, the present study systematically investigated gender differences in (1) latent inhibition and (2) the effects of the postsynaptic D1 /D2 agonist APO and presynaptic DA agonist methamphetamine (METH) during the CS preexposure condition could affect the later CS–US association.
2. Methods and materials 2.1. Subjects Thirty-two male and 32 female Wistar rats were purchased from the Laboratory Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan. All rats weighed 220–250 g at the beginning of the experiment and were individually housed in stainless steel cages under controlled temperature (22 ± 2 ◦ C) and a 12 h/12 h light/dark cycle (lights on 6:00 AM to 6:00 PM) with food and water available ad libitum. This study was performed in compliance with the Animal Scientific Procedures Act of 1986 and received local ethics committee approval.
Fig. 1. (A) Diagram showing the experimental design. (B) Mean (±SEM) total latency time in males and females in the control, LI, APO, and METH groups. *p < 0.05, significant difference between sexes in the control, LI, APO, and METH groups. # p < 0.05, $ p < 0.05, significant difference between the LI group and control, LI, APO, and METH groups in males and females. LI, latent inhibition; APO, apomorphine; METH, methamphetamine.
2.2. Apparatus The passive avoidance apparatus (95 cm length, 54 cm width, 39 cm height) had a one-step-through down alley and consisted of a light/safe compartment (35 cm; a 25 W light bulb illuminated) and dark/shock compartment (60 cm; no light with a footshock). These two compartments were divided by a guillotine door. The latency for the rat to go from the light compartment to the dark compartment was recorded by a timer, reflecting the effect of conditioning [13]. 2.3. Procedure All rats underwent adaptation in their home cages in the colony room for 5–7 days. Exception that the control group was given 10% ascorbic acid injections and was exposed to a different box, the other groups were injected an appropriate drug and freely exposed to the passive avoidance box during three 5 min trials each day without a footshock during the preexposure phase. The control group was exposed to a context box that was configured completely differently from the passive avoidance box. These groups were respectively the control group (10% ascorbic acid injections in a different context; n = 8), latent inhibition (LI) group (10% ascorbic acid injections; n = 8), APO group (1 mg/kg APO injections; n = 8), and METH group (1.5 mg/kg METH injections; n = 8). As considering the gender factor, all rats were equally divided into eight groups: Control/Male, Control/Female, LI/Male, LI/Female, APO/Male, APO/Female, METH/Male, and METH/Female. During the conditioning phase, all groups were placed in the light compartment, and the latency to move into the dark compartment was recorded. When the rats moved into the dark compartment, they received the footshock (1 mA for 2 s). This treatment was performed for 5 days with one trial per day. If the rats spent more than 10 min in the safe compartment, then the data
were recorded as a 10 min latency. The rat was then placed into the dark footshock compartment (Fig. 1A). 2.4. Drugs Apomorphine and its vehicle, ascorbic acid, were obtained from Sigma (Taipei, Taiwan). Methamphetamine was purchased from the Pharmaceutical Plat of Controlled Drugs, Food and Drug Administration, Department of Health, Executive Yuan (Taipei, Taiwan). Ascorbic acid powder was dissolved in distilled water to a final concentration of 10% for the LI and control groups. Apomorphine (1 mg/kg) was prepared in 10% ascorbic acid solution. Methamphetamine (1.5 mg/kg) was prepared in normal saline solution. All of the injections were administered intraperitoneally in a 1 ml/kg volume. 2.5. Statistical analysis The mean (±SEM) latency was obtained for the five conditioning trials. The latencies for trials 1–5 were combined into a total latency time. An independent t-test was conducted to analyze the total latency time to compare the different genders in the control, LI, APO, and METH groups. Moreover, males and females in the LI group were compared with the control, APO, and METH groups using an independent t-test. Furthermore, a 2 × 2 × 5 three-way mixed analysis of variance (ANOVA) with repeated trials in the passive avoidance task was analyzed in the LI, APO, and METH groups, with gender as a factor. 3. Results Gender, APO, and METH may affect latent inhibition. The mean (±SEM) total latencies (i.e., from pooling the data from trials 1 to 5)
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were determined for male and female rats in the control, LI, APO, and METH groups in the conditioning sessions (Fig. 1B). The mean (±SEM) total latencies were tested for gender differences in the control, LI, APO, and METH groups using an independent t-test. The APO group (t = −2.37, p < 0.05) and METH group (t = 3.48, p < 0.05) had significant differences between males and females. The control and LI groups did not have differences between males and females (both p > 0.05). Interestingly, male rats in the APO group had a lower total latency time compared with females in the APO group. Males in the METH group had a higher total latency time than the females in the METH group. Males in the LI group were not significantly different (t = 1.80, p > 0.05) from male controls. Males in the APO group were not significantly different from males in the LI group (t = 1.75, p > 0.05). Males in the METH had significantly higher latencies compared with males in the LI group (t = −2.63, p < 0.05). These results indicate that METH increased total latency time in males to a greater extent compared with males in the LI group. Females in the LI group were significantly different from controls (t = 2.44, p < 0.05). Females in the APO group had significantly lower latencies compared with females in the LI group (t = 2.28, p < 0.05). Females in the METH group had significantly lower latencies compared with females in the LI group (t = 2.53, p < 0.05; Fig. 1B). The present results indicate that latent inhibition occurred with females in both the LI and control groups. Females in the APO group exhibited a decrease in total latency time. Females in the METH group also exhibited a decrease in total latency time. Therefore, both APO and METH facilitated latent inhibition compared with the LI group in females. We further analyzed the mean (±SEM) latencies in the Control/Male, Control/Female, LI/Male, LI/Female, APO/Male, APO/Female, METH/Male, and METH/Female groups in the conditioning trials (Fig. 2A–C). The analysis of the mean (±SEM) latencies in male and female rats using a 2 × 2 × 5 three-way mixed ANOVA with repeated trials indicated that the LI group factor was significant (F1,28 = 8.22, p < 0.05), the gender factor was significant (F1,28 = 5.87, p < 0.05), and the trial factor was significant (F4,112 = 67.27, p < 0.05). The LI group × gender interaction was not significant (F1,28 = 0.01, p > 0.05). The trial × LI group interaction was significant (F4,112 = 6.75, p < 0.05). The trial × gender interaction was not significant (F4,112 = 2.00, p > 0.05). The trial × gender × LI group interaction was not significant (F4,112 = 1.21, p > 0.05; Fig. 2A). The present results demonstrated significant effects of LI and gender but no interaction between LI and gender. Additionally, the results showed that the LI/Male group had the strongest latent inhibition, and the LI/Female group had lower latent inhibition compared with the LI/Male group. The APO group factor was significant (F1,28 = 7.74, p < 0.05), the gender factor was significant (F1,28 = 7.79, p < 0.05), and the trial factor was significant (F4,112 = 68.36, p < 0.05). The APO group × gender interaction was not significant (F1,28 = 0.00, p > 0.05). The trial × APO group interaction was not significant (F4,112 = 1.15, p > 0.05). The trial × gender interaction was significant (F4,112 = 5.57, p < 0.05). The trial × gender × APO group interaction was significant (F4,112 = 4.68, p < 0.05; Fig. 2B). The present results showed that the APO/Male group had enhanced latent inhibition compared with the LI/Male group, but the APO/Female group was not different from the LI/Female group. The METH group factor was not significant (F1,28 = 0.04, p > 0.05), the gender factor was not significant (F1,28 = 1.35, p > 0.05), and the trial factor was significant (F4,112 = 69.09, p < 0.05). The METH group × gender interaction was significant (F1,28 = 13.36, p < 0.05). The trial × METH group interaction was not significant (F4,112 = 0.91, p > 0.05). The trial × gender interaction was not significant (F4,112 = 0.76, p > 0.05). The trial × gender × METH group interaction was not significant (F4,112 = 1.73, p > 0.05; Fig. 2C). The
Fig. 2. Mean (±SEM) latency time in Control/Male, Control/Female, LI/Male, LI/Female, APO/Male, APO/Female, METH/Male, and METH/Female groups. (A) Effects of latent inhibition compared with control in males and females. (B) Effects of APO compared with LI in males and females. (C) Effects of METH compared with LI in males and females. LI, latent inhibition; APO, apomorphine; METH, methamphetamine.
METH manipulation, regardless of the male and female groups, did not affect conditioned learning. 4. Discussion The present study showed that latent inhibition occurred in the female LI group but not in the male LI group. Moreover, the postsynaptic D1 /D2 agonist APO in males and females enhanced to interfere with conditioned learning, indicating an increase in latent inhibition. The presynaptic DA agonist METH in males attenuated the interference in conditioned learning, but METH in females potentiated the interference in conditioned learning, demonstrating sexual dimorphism in the METH group (Table 1). 4.1. Latent inhibition and gender differences Compared with studies that investigated the involvement of DA systems in latent inhibition, few studies have investigated the effects of gender on latent inhibition. The issue of whether gender affects latent inhibition needs to be scrutinized. Sexual dimorphism regulates the development of latent inhibition [6]. In a human model, Lubow and De la Casa [16] tested low and high male and female schizophrenia patients in a latent inhibition task. They found that high schizophrenia males and low schizophrenia females exhibited latent inhibition. However, high schizophrenia females and low schizophrenia males did not exhibit latent inhibition [16]. A recent D1 and D2 receptor-deficient mouse study utilized a latent inhibition task to examine gender differences and found that augmented latent inhibition occurred only in female D1
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Table 1 Latent inhibition during the preexposure and conditioning trials and effects of dopamine agonists on latent inhibition in male and female rats. Sex
Control
LI
LI
Postsynaptic DA D1 /D2 agonist APO (1 mg/kg)
Presynaptic DA agonist METH (1.5 mg/kg)
Male Female
– –
– ↑
– –
↑ ↑
↓ ↑
LI: latent inhibition; DA, dopamine; APO, apomorphine; METH, methamphetamine; –: no difference/control group; ↓, decrease; ↑, increase.
knockout mice and not in male mice. D2 knockout mice did not show sexual dimorphism in the enhancement of latent inhibition [1]. A series of studies were conducted in handled and nonhandled rats during the preweanling stage, and the rats were tested in the postweanling period. Female rats exhibited latent inhibition regardless of handling exposure, and only nonhandled male rats failed to exhibit latent inhibition [23,28,29]. Few animal studies of the effects of gender on latent inhibition have manipulated prenatal stress exposure (e.g., restraint, corticosterone administration, and inescapable footshock). One study found that prenatal restraint did not influence latent inhibition in either gender, but footshock and corticosterone injections disrupted latent inhibition in males but not females [24]. A similar study indicated that prenatal stress enhanced latent inhibition only in males [2]. Sexual dimorphism in latent inhibition appears to be supported by this research, but another study suggested that no sexual dimorphism exists in latent inhibition [19]. In this previous study, a tone served as the preexposure stimulus to test tone-footshock conditioning between genders. They found no gender differences in latent inhibition [19]. Using a human visual search paradigm, a schizophrenia study showed that latent inhibition was enhanced in low schizotypy females compared with high schizotypy females, but this effect did not occur in schizotypy males [18]. The present METH manipulation results in the different genders support sexual dimorphism in latent inhibition. The administration of a DA agonist decreased latent inhibition in males but increased latent inhibition in females. However, the APO groups did not show sexual dimorphism.
study utilized in vivo microdialysis to measure DA release in the nucleus accumbens core and shell during CS–US associative learning and found that the shell had decreased DA release associated with a disruption of latent inhibition, but the core did not exhibit this attenuated DA release. Therefore, the core and shell of the nucleus accumbens were suggested to differentially mediate latent inhibition, with the shell playing a crucial role [20]. However, both the nucleus accumbens core and shell have been suggested to play a crucial role in latent inhibition [26]. Therefore, the differential involvement of these subregions of the nucleus accumbens in latent inhibition should be investigated in future studies.
4.2. Latent inhibition and DA system
This research was supported by funding from the National Research Council of the Republic of China (NSC 99-2410-H-431013) to ACW Huang and grant 98CGH-FJU-B-12 from Cathay General Hospital. The authors gratefully acknowledge Dr. W.L. Lin for her helpful comments on this article.
The present data showed that, regardless of gender, 1 mg/kg APO facilitated latent inhibition. Our results, however, do not support a study conducted by Feldon et al. [5], in which 0.3 and 1.5 mg/kg APO did not influence latent inhibition. Moreover, these authors found that the D1 -selective agonist SKF38393 and D2 -selective agonist quinpirole did not affect latent inhibition when they tested a wide range of doses, suggesting that latent inhibition was not influenced by these direct DA agonists. High-dose APO (>0.5 mg/kg) activates postsynaptic DA receptors and functions as a D1 /D2 agonist, whereas low-dose APO (<0.1 mg/kg) preferentially activates D2 autoreceptors, thereby inhibiting DA neurons and serving as a functional DA antagonist [3]. Therefore, the present study tested the effects of 1 mg/kg APO on latent inhibition in male and female rats. Our dose of 1 mg/kg APO enhanced latent inhibition in males, but this effect of APO was inconsistent with the effects of METH, in which an attenuation of latent inhibition was found, although both APO and METH facilitated latent inhibition in female rats. Whether the differential neural mechanisms of APO (i.e., activation of postsynaptic D1 /D2 receptors) and METH (i.e., stimulation of presynaptic neurons) are attributable to opposite effects remains to be scrutinized in future studies. Neurobiological investigations have examined the neural substrates related to latent inhibition, particularly the mesolimbic DA system and retrohippocampal area, which is reciprocally connected to the hippocampus [10]. The hippocampal formation and nucleus accumbens may mediate latent inhibition [7,30]. Disruption of the entorhinal cortex by tetrodotoxin injections disrupted the mediation of latent inhibition by the nucleus accumbens [22]. Another
5. Conclusion The present study showed that latent inhibition occurred in the females LI group but not the male LI group compared with controls. Treatment with the presynaptic DA agonist METH decreased latent inhibition in males. This same treatment increased latent inhibition in females. Therefore, the sexual dimorphism of latent inhibition was only evident in the METH group. However, APO did not show sexual dimorphism. Males and females in the APO group exhibited an increase in latent inhibition. The differences between the presynaptic DA agonist METH and postsynaptic DA D1 /D2 agonist APO with regard to sexual dimorphism should be scrutinized in future studies. Acknowledgments
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Contents lists available at SciVerse ScienceDirect
Neuroscience Letters journal homepage: www.elsevier.com/locate/neulet
Gender differences in the effects of presynaptic and postsynaptic dopamine agonists on latent inhibition in rats Ying-Chou Wang a , Bo-Han He b , Chih-Chung Chen c , Andrew Chih Wei Huang b,∗ , Yu-Chi Yeh d a
Department of Clinical Psychology, Fu-Jen Catholic University, New Taipei City, Taiwan Department of Psychology, Fo Guang University, Yilan County 26247, Taiwan Department of Physical Therapy, Chang Gung University, Tao-Yuan 333, Taiwan d Department of Psychiatry, Cathay General Hospital, Taipei, Taiwan b c
a r t i c l e
i n f o
Article history: Received 6 November 2011 Received in revised form 4 January 2012 Accepted 19 January 2012 Keywords: Gender Dopamine agonist Latent inhibition Sexual dimorphism
a b s t r a c t The present study investigated gender differences in the effects of presynaptic and postsynaptic DA agonists on latent inhibition in the passive avoidance paradigm. During the preexposure phase, 32 male and 32 female Wistar rats were exposed to a passive avoidance box (or a different context) and received drug injections in three trials: the control group received an injection of 10% ascorbic acid in a different context. The experimental groups received injections of 10% ascorbic acid (latent inhibition [LI] group), 1 mg/kg of the postsynaptic DA D1 /D2 agonist apomorphine (APO group), and 1.5 mg/kg of the presynaptic DA agonist methamphetamine (METH group) in a passive avoidance box. All experimental groups were placed in the light compartment of the passive avoidance box and were allowed to enter into the dark compartment to receive a footshock (1 mA, 2 s) in five trials over 5 days. The latency to enter into the dark compartment was recorded in these five trials. The latent inhibition occurred in the female LI group but not in the male LI group. Regardless of gender, the APO group exhibited an increase in latent inhibition. Male rats in the METH group exhibited a decrease in latent inhibition, but female rats in the METH group exhibited an increase in latent inhibition, indicating that the METH group exhibited sexual dimorphism. The gender factor interacted only with the METH group and not the LI or APO group. The present paper discusses whether gender, the postsynaptic DA D1 /D2 agonist APO, and presynaptic DA agonist METH may be related to schizophrenia. © 2012 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Latent inhibition is defined as preexposure to a conditioned stimulus (CS), after which the CS is less able to be associated with a subsequent unconditioned stimulus (US) [14]. Since the 1990s, many studies have investigated latent inhibition in human and animal models, and diverse hypotheses have been proposed, including attentional theory [15], switching theory [27], occasion setting [17,21], and associative theory [4,8], to explain why previous CS preexposure later disrupts CS–US conditioning. According to associative theory, latent inhibition may reflect the disruptions of the CS–US association learning before pre-exposing the CS-context association. Healthy participants learn the CS-context association to interfere with the later CS–US association learning. Schizophrenia patients are unable to learn the CS-context association, and then
∗ Corresponding author at: Department of Psychology, Fo Guang University, No. 160, Linwei Road, Jiaosi Shiang, Yilan County 26247, Taiwan. Tel.: +886 3 9871000x27114; fax: +886 3 9875530. E-mail address: [email protected] (A.C.W. Huang). 0304-3940/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2012.01.047
do not exhibit a disruption of the CS–US association. Therefore, schizophrenia patients are often suggested to have disturbances in latent inhibition [9,12,15]. Numerous neurocircuitry investigations of latent inhibition have focused on the involvement of the mesocorticolimbic dopamine (DA) system [7,11]. A previous microdialysis study manipulated a tone and light conditioned to an aversive footshock to examine DA release in the nucleus accumbens during the conditioning phase. The results showed that enhanced DA release in the nucleus accumbens blunted latent inhibition [30]. Pharmacological studies showed that latent inhibition was attenuated following consecutive amphetamine injections over several days. This attenuation of latent inhibition was reversed by concomitant administration of the DA D2 receptor antagonist chlorpromazine [25]. Latent inhibition was blocked and enhanced by increasing and decreasing DA signal transduction, respectively [27]. However, Feldon et al. [5] demonstrated that the D1 -selective agonist SKF38393 and D2 -selective agonist quinpirole did not affect latent inhibition. A low dose of apomorphine (APO; 0.3 mg/kg), which activates D2 autoreceptors as a functional DA antagonist, and a high dose of APO (1.5 mg/kg), which activates postsynaptic D1 /D2
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receptors as a functional DA agonist, also did not affect latent inhibition [5]. In summary, the present study investigated whether presynaptic and postsynaptic DA agonists treatments were respectively given prior to the CS preexposure condition, and thereby influenced the later CS–US association. Thus, it was thought to test the effect of latent inhibition. Moreover, previous studies predominantly utilized male animals. To our knowledge, no study has investigated the possible differential effects of gender on latent inhibition. Therefore, gender differences were also examined in the present study. Altogether, the present study systematically investigated gender differences in (1) latent inhibition and (2) the effects of the postsynaptic D1 /D2 agonist APO and presynaptic DA agonist methamphetamine (METH) during the CS preexposure condition could affect the later CS–US association.
2. Methods and materials 2.1. Subjects Thirty-two male and 32 female Wistar rats were purchased from the Laboratory Animal Center, National Taiwan University College of Medicine, Taipei, Taiwan. All rats weighed 220–250 g at the beginning of the experiment and were individually housed in stainless steel cages under controlled temperature (22 ± 2 ◦ C) and a 12 h/12 h light/dark cycle (lights on 6:00 AM to 6:00 PM) with food and water available ad libitum. This study was performed in compliance with the Animal Scientific Procedures Act of 1986 and received local ethics committee approval.
Fig. 1. (A) Diagram showing the experimental design. (B) Mean (±SEM) total latency time in males and females in the control, LI, APO, and METH groups. *p < 0.05, significant difference between sexes in the control, LI, APO, and METH groups. # p < 0.05, $ p < 0.05, significant difference between the LI group and control, LI, APO, and METH groups in males and females. LI, latent inhibition; APO, apomorphine; METH, methamphetamine.
2.2. Apparatus The passive avoidance apparatus (95 cm length, 54 cm width, 39 cm height) had a one-step-through down alley and consisted of a light/safe compartment (35 cm; a 25 W light bulb illuminated) and dark/shock compartment (60 cm; no light with a footshock). These two compartments were divided by a guillotine door. The latency for the rat to go from the light compartment to the dark compartment was recorded by a timer, reflecting the effect of conditioning [13]. 2.3. Procedure All rats underwent adaptation in their home cages in the colony room for 5–7 days. Exception that the control group was given 10% ascorbic acid injections and was exposed to a different box, the other groups were injected an appropriate drug and freely exposed to the passive avoidance box during three 5 min trials each day without a footshock during the preexposure phase. The control group was exposed to a context box that was configured completely differently from the passive avoidance box. These groups were respectively the control group (10% ascorbic acid injections in a different context; n = 8), latent inhibition (LI) group (10% ascorbic acid injections; n = 8), APO group (1 mg/kg APO injections; n = 8), and METH group (1.5 mg/kg METH injections; n = 8). As considering the gender factor, all rats were equally divided into eight groups: Control/Male, Control/Female, LI/Male, LI/Female, APO/Male, APO/Female, METH/Male, and METH/Female. During the conditioning phase, all groups were placed in the light compartment, and the latency to move into the dark compartment was recorded. When the rats moved into the dark compartment, they received the footshock (1 mA for 2 s). This treatment was performed for 5 days with one trial per day. If the rats spent more than 10 min in the safe compartment, then the data
were recorded as a 10 min latency. The rat was then placed into the dark footshock compartment (Fig. 1A). 2.4. Drugs Apomorphine and its vehicle, ascorbic acid, were obtained from Sigma (Taipei, Taiwan). Methamphetamine was purchased from the Pharmaceutical Plat of Controlled Drugs, Food and Drug Administration, Department of Health, Executive Yuan (Taipei, Taiwan). Ascorbic acid powder was dissolved in distilled water to a final concentration of 10% for the LI and control groups. Apomorphine (1 mg/kg) was prepared in 10% ascorbic acid solution. Methamphetamine (1.5 mg/kg) was prepared in normal saline solution. All of the injections were administered intraperitoneally in a 1 ml/kg volume. 2.5. Statistical analysis The mean (±SEM) latency was obtained for the five conditioning trials. The latencies for trials 1–5 were combined into a total latency time. An independent t-test was conducted to analyze the total latency time to compare the different genders in the control, LI, APO, and METH groups. Moreover, males and females in the LI group were compared with the control, APO, and METH groups using an independent t-test. Furthermore, a 2 × 2 × 5 three-way mixed analysis of variance (ANOVA) with repeated trials in the passive avoidance task was analyzed in the LI, APO, and METH groups, with gender as a factor. 3. Results Gender, APO, and METH may affect latent inhibition. The mean (±SEM) total latencies (i.e., from pooling the data from trials 1 to 5)
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were determined for male and female rats in the control, LI, APO, and METH groups in the conditioning sessions (Fig. 1B). The mean (±SEM) total latencies were tested for gender differences in the control, LI, APO, and METH groups using an independent t-test. The APO group (t = −2.37, p < 0.05) and METH group (t = 3.48, p < 0.05) had significant differences between males and females. The control and LI groups did not have differences between males and females (both p > 0.05). Interestingly, male rats in the APO group had a lower total latency time compared with females in the APO group. Males in the METH group had a higher total latency time than the females in the METH group. Males in the LI group were not significantly different (t = 1.80, p > 0.05) from male controls. Males in the APO group were not significantly different from males in the LI group (t = 1.75, p > 0.05). Males in the METH had significantly higher latencies compared with males in the LI group (t = −2.63, p < 0.05). These results indicate that METH increased total latency time in males to a greater extent compared with males in the LI group. Females in the LI group were significantly different from controls (t = 2.44, p < 0.05). Females in the APO group had significantly lower latencies compared with females in the LI group (t = 2.28, p < 0.05). Females in the METH group had significantly lower latencies compared with females in the LI group (t = 2.53, p < 0.05; Fig. 1B). The present results indicate that latent inhibition occurred with females in both the LI and control groups. Females in the APO group exhibited a decrease in total latency time. Females in the METH group also exhibited a decrease in total latency time. Therefore, both APO and METH facilitated latent inhibition compared with the LI group in females. We further analyzed the mean (±SEM) latencies in the Control/Male, Control/Female, LI/Male, LI/Female, APO/Male, APO/Female, METH/Male, and METH/Female groups in the conditioning trials (Fig. 2A–C). The analysis of the mean (±SEM) latencies in male and female rats using a 2 × 2 × 5 three-way mixed ANOVA with repeated trials indicated that the LI group factor was significant (F1,28 = 8.22, p < 0.05), the gender factor was significant (F1,28 = 5.87, p < 0.05), and the trial factor was significant (F4,112 = 67.27, p < 0.05). The LI group × gender interaction was not significant (F1,28 = 0.01, p > 0.05). The trial × LI group interaction was significant (F4,112 = 6.75, p < 0.05). The trial × gender interaction was not significant (F4,112 = 2.00, p > 0.05). The trial × gender × LI group interaction was not significant (F4,112 = 1.21, p > 0.05; Fig. 2A). The present results demonstrated significant effects of LI and gender but no interaction between LI and gender. Additionally, the results showed that the LI/Male group had the strongest latent inhibition, and the LI/Female group had lower latent inhibition compared with the LI/Male group. The APO group factor was significant (F1,28 = 7.74, p < 0.05), the gender factor was significant (F1,28 = 7.79, p < 0.05), and the trial factor was significant (F4,112 = 68.36, p < 0.05). The APO group × gender interaction was not significant (F1,28 = 0.00, p > 0.05). The trial × APO group interaction was not significant (F4,112 = 1.15, p > 0.05). The trial × gender interaction was significant (F4,112 = 5.57, p < 0.05). The trial × gender × APO group interaction was significant (F4,112 = 4.68, p < 0.05; Fig. 2B). The present results showed that the APO/Male group had enhanced latent inhibition compared with the LI/Male group, but the APO/Female group was not different from the LI/Female group. The METH group factor was not significant (F1,28 = 0.04, p > 0.05), the gender factor was not significant (F1,28 = 1.35, p > 0.05), and the trial factor was significant (F4,112 = 69.09, p < 0.05). The METH group × gender interaction was significant (F1,28 = 13.36, p < 0.05). The trial × METH group interaction was not significant (F4,112 = 0.91, p > 0.05). The trial × gender interaction was not significant (F4,112 = 0.76, p > 0.05). The trial × gender × METH group interaction was not significant (F4,112 = 1.73, p > 0.05; Fig. 2C). The
Fig. 2. Mean (±SEM) latency time in Control/Male, Control/Female, LI/Male, LI/Female, APO/Male, APO/Female, METH/Male, and METH/Female groups. (A) Effects of latent inhibition compared with control in males and females. (B) Effects of APO compared with LI in males and females. (C) Effects of METH compared with LI in males and females. LI, latent inhibition; APO, apomorphine; METH, methamphetamine.
METH manipulation, regardless of the male and female groups, did not affect conditioned learning. 4. Discussion The present study showed that latent inhibition occurred in the female LI group but not in the male LI group. Moreover, the postsynaptic D1 /D2 agonist APO in males and females enhanced to interfere with conditioned learning, indicating an increase in latent inhibition. The presynaptic DA agonist METH in males attenuated the interference in conditioned learning, but METH in females potentiated the interference in conditioned learning, demonstrating sexual dimorphism in the METH group (Table 1). 4.1. Latent inhibition and gender differences Compared with studies that investigated the involvement of DA systems in latent inhibition, few studies have investigated the effects of gender on latent inhibition. The issue of whether gender affects latent inhibition needs to be scrutinized. Sexual dimorphism regulates the development of latent inhibition [6]. In a human model, Lubow and De la Casa [16] tested low and high male and female schizophrenia patients in a latent inhibition task. They found that high schizophrenia males and low schizophrenia females exhibited latent inhibition. However, high schizophrenia females and low schizophrenia males did not exhibit latent inhibition [16]. A recent D1 and D2 receptor-deficient mouse study utilized a latent inhibition task to examine gender differences and found that augmented latent inhibition occurred only in female D1
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Table 1 Latent inhibition during the preexposure and conditioning trials and effects of dopamine agonists on latent inhibition in male and female rats. Sex
Control
LI
LI
Postsynaptic DA D1 /D2 agonist APO (1 mg/kg)
Presynaptic DA agonist METH (1.5 mg/kg)
Male Female
– –
– ↑
– –
↑ ↑
↓ ↑
LI: latent inhibition; DA, dopamine; APO, apomorphine; METH, methamphetamine; –: no difference/control group; ↓, decrease; ↑, increase.
knockout mice and not in male mice. D2 knockout mice did not show sexual dimorphism in the enhancement of latent inhibition [1]. A series of studies were conducted in handled and nonhandled rats during the preweanling stage, and the rats were tested in the postweanling period. Female rats exhibited latent inhibition regardless of handling exposure, and only nonhandled male rats failed to exhibit latent inhibition [23,28,29]. Few animal studies of the effects of gender on latent inhibition have manipulated prenatal stress exposure (e.g., restraint, corticosterone administration, and inescapable footshock). One study found that prenatal restraint did not influence latent inhibition in either gender, but footshock and corticosterone injections disrupted latent inhibition in males but not females [24]. A similar study indicated that prenatal stress enhanced latent inhibition only in males [2]. Sexual dimorphism in latent inhibition appears to be supported by this research, but another study suggested that no sexual dimorphism exists in latent inhibition [19]. In this previous study, a tone served as the preexposure stimulus to test tone-footshock conditioning between genders. They found no gender differences in latent inhibition [19]. Using a human visual search paradigm, a schizophrenia study showed that latent inhibition was enhanced in low schizotypy females compared with high schizotypy females, but this effect did not occur in schizotypy males [18]. The present METH manipulation results in the different genders support sexual dimorphism in latent inhibition. The administration of a DA agonist decreased latent inhibition in males but increased latent inhibition in females. However, the APO groups did not show sexual dimorphism.
study utilized in vivo microdialysis to measure DA release in the nucleus accumbens core and shell during CS–US associative learning and found that the shell had decreased DA release associated with a disruption of latent inhibition, but the core did not exhibit this attenuated DA release. Therefore, the core and shell of the nucleus accumbens were suggested to differentially mediate latent inhibition, with the shell playing a crucial role [20]. However, both the nucleus accumbens core and shell have been suggested to play a crucial role in latent inhibition [26]. Therefore, the differential involvement of these subregions of the nucleus accumbens in latent inhibition should be investigated in future studies.
4.2. Latent inhibition and DA system
This research was supported by funding from the National Research Council of the Republic of China (NSC 99-2410-H-431013) to ACW Huang and grant 98CGH-FJU-B-12 from Cathay General Hospital. The authors gratefully acknowledge Dr. W.L. Lin for her helpful comments on this article.
The present data showed that, regardless of gender, 1 mg/kg APO facilitated latent inhibition. Our results, however, do not support a study conducted by Feldon et al. [5], in which 0.3 and 1.5 mg/kg APO did not influence latent inhibition. Moreover, these authors found that the D1 -selective agonist SKF38393 and D2 -selective agonist quinpirole did not affect latent inhibition when they tested a wide range of doses, suggesting that latent inhibition was not influenced by these direct DA agonists. High-dose APO (>0.5 mg/kg) activates postsynaptic DA receptors and functions as a D1 /D2 agonist, whereas low-dose APO (<0.1 mg/kg) preferentially activates D2 autoreceptors, thereby inhibiting DA neurons and serving as a functional DA antagonist [3]. Therefore, the present study tested the effects of 1 mg/kg APO on latent inhibition in male and female rats. Our dose of 1 mg/kg APO enhanced latent inhibition in males, but this effect of APO was inconsistent with the effects of METH, in which an attenuation of latent inhibition was found, although both APO and METH facilitated latent inhibition in female rats. Whether the differential neural mechanisms of APO (i.e., activation of postsynaptic D1 /D2 receptors) and METH (i.e., stimulation of presynaptic neurons) are attributable to opposite effects remains to be scrutinized in future studies. Neurobiological investigations have examined the neural substrates related to latent inhibition, particularly the mesolimbic DA system and retrohippocampal area, which is reciprocally connected to the hippocampus [10]. The hippocampal formation and nucleus accumbens may mediate latent inhibition [7,30]. Disruption of the entorhinal cortex by tetrodotoxin injections disrupted the mediation of latent inhibition by the nucleus accumbens [22]. Another
5. Conclusion The present study showed that latent inhibition occurred in the females LI group but not the male LI group compared with controls. Treatment with the presynaptic DA agonist METH decreased latent inhibition in males. This same treatment increased latent inhibition in females. Therefore, the sexual dimorphism of latent inhibition was only evident in the METH group. However, APO did not show sexual dimorphism. Males and females in the APO group exhibited an increase in latent inhibition. The differences between the presynaptic DA agonist METH and postsynaptic DA D1 /D2 agonist APO with regard to sexual dimorphism should be scrutinized in future studies. Acknowledgments
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