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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: Schizophr Res. 2017 Mar 14;194:107–114. doi: 10.1016/j.schres.2017.03.024

An analysis of the rewarding and aversive associative properties of nicotine in the neonatal quinpirole model: Effects on glial cell line-derived neurotrophic factor (GDNF)

Russell W Brown 1, Seth L Kirby 2, Adam R Denton 2, John M Dose 3, Elizabeth D Cummins 2, Katherine C Burgess 1
PMCID: PMC5599315  NIHMSID: NIHMS860825  PMID: 28314679

Abstract

This study analyzed the associative properties of nicotine in a conditioned place preference (CPP) paradigm in adolescent rats neonatally treated with quinpirole (NQ) or saline (NS). NQ produces dopamine D2 receptor supersensitivity that persists throughout the animal’s lifetime, and therefore has relevance towards schizophrenia. In two experiments, rats were ip administered quinpirole (1mg/kg) or saline from postnatal day (P)1–21. After an initial preference test at P42–43, animals were conditioned for eight consecutive days with saline or nicotine (0.6 mg/kg free base) in Experiment 1 or saline or nicotine (1.8 mg/kg free base) in Experiment 2. In addition, there were NQ and NS groups in each experiment given the antipsychotic haloperidol (0.05 mg/kg) or clozapine (2.5 mg/kg) before nicotine conditioning. A drug free post-conditioning test was administered at P52. At P53, the nucleus accumbens (NAc) was analyzed for glial cell-line derived neurotrophic factor (GDNF). Results revealed that NQ enhanced nicotine CPP, but blunted the aversive properties of nicotine. Haloperidol was more effective than clozapine at blocking nicotine CPP in Experiment 1, but neither antipsychotic affected nicotine conditioned place aversion in Experiment 2. NQ increased accumbal GDNF which was sensitized in NQ rats conditioned to nicotine in Experiment 1, but the aversive dose of nicotine reduced GDNF in NQ animals in Experiment 2. Both antipsychotics in combination with the aversive dose of nicotine decreased accumbal GDNF. In sum, increased D2 receptor sensitivity influenced the associative properties and GDNF response to nicotine which has implications towards pharmacological targets for smoking cessation in schizophrenia.

Keywords: Dopamine D2 receptor, schizophrenia, adolescence, nicotine, antipsychotics, conditioned place preference

1. Introduction

Tobacco dependence in individuals diagnosed with schizophrenia is 3–4 times higher than that of the general population (Le Foll et al., 2015). Our laboratory and collaborators have published a series of studies over the past 25 years that have demonstrated that rats neonatally treated with quinpirole (NQ), a dopamine D2/D3 agonist during postnatal days (P) 1–11, 1–21, or 11–21, display an increase in sensitivity of the dopamine D2 receptor throughout the animal’s lifetime without an increase in receptor number (Kostrzewa, 1995). Increased activation of the dopamine D2 receptor has been shown to play a major role in the abnormal behaviors observed in schizophrenia (Urs et al., 2017). Using this model, our projects have focused on substance abuse comorbidity that is often observed in human patients diagnosed with schizophrenia, especially nicotine abuse (for review, see Brown et al., 2012). Past work in our laboratory has reported that NQ treatment to rats results in an enhanced behavioral response to nicotine in adolescence and adulthood, and enhances accumbal dopamine and brain-derived neurotrophic factor (BDNF) response to nicotine in adolescence (Perna and Brown, 2013; for review, see Brown et al., 2012).

Conditioned place preference (CPP) is a behavioral test that has been used to analyze the associative properties of reinforcing drugs. Past work has shown robust CPP in rats with a number of psychostimulants, including methamphetamine, d-amphetamine, and cocaine in adult animals (for review, see Bardo and Bevins, 2000), but nicotine CPP has proven difficult to obtain in adults (Clarke and Fibiger, 1987). However, adolescent rats have demonstrated CPP to nicotine (Vastola et al., 2002; Belluzzi, et al., 2004), suggesting an enhanced sensitivity to the rewarding properties of nicotine in adolescence. The CPP behavioral paradigm can also be used to analyze the aversive properties of drugs, including nicotine, if a high, aversive dose of nicotine is paired in time with a particular context (Le Foll and Goldberg, 2005; Sellings et al., 2008). In this case, on the drug-free conditioning test the animal spends more time in the context previously temporally paired with the vehicle. We have shown that NQ treatment enhances the associative properties of a rewarding dose of nicotine in the CPP paradigm in adolescent rats compared to animals neonatally treated with saline (Perna et al., 2011). To date, however, there are no published studies that have compared rewarding versus aversive doses of nicotine in adolescence in normal animals or in an animal model of schizophrenia.

In addition, there have not been any published studies that analyzed the effects of antipsychotics on the associative properties of nicotine in the CPP behavioral paradigm. Haloperidol is a typical (1st generation) antipsychotic and a potent dopamine D2-like receptor antagonist. Haloperidol has been shown to produce an increase in nicotine consumption among human patients diagnosed with schizophrenia (McEvoy et al., 1995). While there have not been any previous studies to analyze the effects of haloperidol on nicotine CPP in rats, Levin and colleagues have published a series of studies demonstrating that haloperidol blocks enhancement of working memory produced by nicotine (Addy and Levin, 2002; Rezvani and Levin, 2004). In contrast, haloperidol infused into the insular cortex, nucleus accumbens (NAc), anterior cingulate cortex, or parietal association cortex did not affect nicotine self-administration (Kutlu et al., 2013; Hall et al., 2015). Clozapine is an atypical (2nd generation) antipsychotic which antagonizes the dopamine D2 receptor with less affinity than haloperidol, but acts on a variety of other neurotransmitter systems including as an agonist at 5-HT1a receptors (Lieberman, 1993). Studies have demonstrated that clozapine treatment results in a decrease in smoking behavior among schizophrenic patients (George et al., 1995). Clozapine has not been studied relative to nicotine CPP or nicotine self-administration in rats, but has been shown to attenuate the discriminative stimulus properties of nicotine (Brioni et al., 1994) and, similar to haloperidol, blocks working memory improvement produced by nicotine (Addy and Levin, 2002).

A final focus of the present study was to examine the effects of nicotine and the combination of antipsychotics and nicotine in the NQ model on glial cell-line derived neurotrophic factor (GDNF). GDNF is a secreted protein (Lin et al., 1993) and the most prominent feature of GDNF is its ability to support and promote survival of dopaminergic neurons (Granholm et al., 2000; Boger et al., 2006; Pascual et al., 2008). GDNF has primarily been studied relative to its improvement of dopaminergic synaptic plasticity in Parkinson’s Disease (Lindholm et al., 2016). There has been very little work published regarding nicotine and GDNF, but GDNF has been implicated in drug addiction (Pickens et al., 2011; Kotyuk et al., 2016). For example, injections of an adeno-associated viral (AAV) vector containing rat GDNF cDNA into the ventral tegmental area (VTA) on withdrawal day 1 increased cocaine seeking in later tests (Lu et al., 2009). Importantly, interfering with VTA GDNF function by chronic delivery of anti-GDNF monoclonal neutralizing antibodies during withdrawal days 1–14 prevented the time-dependent increases in cocaine seeking on withdrawal days 11 and 31 (Lu et al., 2009). In addition, time-dependent increases in heroin seeking were associated with time-dependent changes in GDNF mRNA expression in the VTA and NAc during the first month of withdrawal from heroin. Moreover, GDNF injection into the VTA immediately after the last drug self-administration session enhanced heroin seeking after withdrawal (Airarvara et al., 2011).

Finally, although the effects of nicotine and GDNF have not been analyzed in a preclinical model of schizophrenia, given the importance of GDNF in dopamine neuronal differentiation and plasticity and the finding that GDNF influences the behavioral response to cocaine (Pickens et al., 2011), GDNF may be an important target for nicotine addiction as well. Consistent with this idea, a recently published study suggested that tobacco smoking may be related to genetic variants of GDNF, although this finding was not tested in a population diagnosed with schizophrenia (Kotyuk et al., 2016).

In two experiments, the present study analyzed the associative properties of both the reinforcing and aversive effects nicotine using the CPP behavioral paradigm in the NQ model as well as whether haloperidol and clozapine interfere with these effects. In addition, we analyzed the effects of these drug treatments on GDNF protein levels in the NAc, a brain area that plays a primary role in the rewarding effects of addictive drugs, including nicotine (Pistillo et al., 2015). We have shown in past work that NQ enhanced the BDNF response to nicotine in the NAc, but we have yet to analyze its effects on GDNF which has been shown to play a direct role in dopaminergic neuroplasticity (Granholm et al., 2000).

2. Methods

2.1. Subjects

A total of 12 pregnant female dams were ordered from Envigo, Inc (Indianapolis, IN, USA) and their offspring were used as subjects. The day of birth was referred to as postnatal day (P)0. One male from each litter was assigned to each drug condition to control for within litter variance. We decided to not analyze sex differences in this study for two reasons. First, the research design would be complex with three factors if sex was included as a factor. However, although clinical data has reported no gender differences in the incidence of smoking in the population diagnosed with psychosis, there are gender differences as to the basis of tobacco smoking and smoking cessation (Filia et al., 2014). Future work may analyze sex differences in the associative properties of nicotine in this model. Animals were housed in a AAALAC accredited climate-controlled vivarium on a 12 h on/off light/dark cycle and food and water was available ad libitum. All procedures were approved by the East Tennessee State University Committee on Animal Care.

2.2. Drug treatment

All animals were ip administered quinpirole (1 mg/kg) or saline once daily from P1–21, identical to past work (for review, see Brown et al., 2012). Animals were weaned at P21 and raised to P41 with no further drug treatment. The doses of haloperidol (0.05 mg/kg) and clozapine (2.5 mg/kg) were chosen based on past work that demonstrated these doses block working memory effects of nicotine (Addy and Levin, 2002), and thus, known to be effective in altering the behavioral response to nicotine. The rewarding dose of nicotine (0.6 mg/kg free base) was chosen based on work from our laboratory that has shown this dose was sufficient to produce CPP (Perna et al., 2011). The aversive dose of nicotine (1.8 mg/kg) was based on past work that demonstrated a 2.0 mg/kg free base dose of nicotine resulted in a conditioned place aversion (CPA; LeFoll and Goldberg, 2005) and on our own observations that a slightly lower dose was sufficient to produce CPA.

2.3. CPP apparatus

A three-chambered CPP box was employed. All chambers within the box were equal in size (90 cm on each side), separated by removable doors that were lined with Plexiglas and distinct in terms of visual and tactile stimuli. The middle chamber of the CPP box was painted solid gray, whereas each chamber was painted with either black or white vertical or horizontal stripes. In addition, each CPP context also had different tactile surfaces along the floors of the context to make each context distinct. The vertical-striped context had a wire-mesh floor, the horizontal-striped context had a metal dowel rod floor, and the gray chamber had a Plexiglas floor.

2.3.1. CPP pre-conditioning preference test

Beginning on P42 and P43, all animals were given an initial preference test on each day for a period of 10 min each. For initial preference testing, all animals were administered an ip injection of saline 10 min prior to being placed into the CPP apparatus with dividers removed and animals were allowed to freely explore the apparatus. The time spent in all three contexts was recording using Any Maze software (Stoelting Co., Wood Dale, IL, USA).

2.3.2 CPP conditioning

Conditioning began the day after the initial preference tests on P44, and removable dividers were placed into the apparatus. The assignment of each context to be temporally paired with saline or nicotine was based on mean performance of the initial preference test such that there were no significant differences in initial context preference across groups, and the paired context was randomly chosen. Controls were always given saline in both contexts. In the morning session on conditioning days, all animals were given an ip injection of saline, and 10 min later placed into their assigned context for a 10 min conditioning session. In the afternoon session (4 h later), animals were administered saline, haloperidol (0.05 mg/kg) or clozapine (2.5 mg/kg) followed 15–20 min later an ip injection of nicotine (0.6 mg/kg free base). Ten min later, rats were placed into the paired context for a 10 min conditioning trial. Conditioning occurred every consecutive day for eight days from P44–P51. We have shown this conditioning protocol to be sufficient to result in nicotine CPPin adolescent rats using a 0.6 mg/kg (free base) dose (Perna, et al., 2011).

2.3.3. CPP post-conditioning preference test

The post-conditioning test was conducted the day after conditioning was complete on P52. This test was identical to the initial preference test: all animals were administered two saline ip injections spaced apart in time identical to the injections all animals received during conditioning to control for the stress of the injections, and allowed to freely explore the apparatus with the dividers removed. For the post-conditioning preference test, the dependent measure was the mean percentage time spent in the paired context on the pre-conditioning preference test subtracted from the percentage time spent in the paired context on the post-conditioning preference test. The percentage time was calculated using the total time spent in the horizontal- and vertical striped-context on each of the pre- and post-conditioning tests, and the gray context was not used in this calculation. The rationale for not using the time spent in the gray context is because it is not behaviorally equivalent to the other two contexts; animals only experienced the gray context on the pre- and post-conditioning tests.

2.4. GDNF ELISA

For both the GDNF ELISA, the NAc was dissected from the rest of the brain tissue and analyzed using the Emax immunoassay system (Promega, Madison, WI). The antibodies used in this system have typically less than 3% cross-reactivity with other neurotrophic factors at 10ng/ml (Hornbeck, 1994). All brain tissue samples were weighed and homogenized using a Fisher scientific sonic dismembrator 500 in 250 ul of a RIPA cell lysis buffer (150 mM NaCl, 50 mM Tris—HCl, 1.0% NP-40, 0.5% Sodium deoxycholate and 0.1% SDS), which included protease and phosphatase inhibitors (P5726, P8340, P0044, Sigma-Aldrich, St. Louis, MO). The brain region was centrifuged at 20,000 × g for 25 min at 4°C. A NUNC 96-well plate was coated using an anti-GDNF polyclonal antibody (pAb) mixed into a carbonate coating buffer (pH = 8.2) and incubated for 24 h. The following day, the nonspecific binding was blocked using a block and sample buffer and 1 h later samples were applied to the plate followed 6 h later by an anti-human GDNF monoclonal antibody (mAb) and incubated for 24 h. The following day the anti-chicken IgY HRP conjugate was added followed by 1 h later by the TMB one solution. The reaction was stopped using 1N hydrochloric acid. Optical density was measured using a Bio-Tek ELx 800 microplate reader (Winooski, VT).

2.5. Research Design

In Experiment 1, the dose of nicotine administered during conditioning was 0.6 mg/kg (free base). Factors in Experiment 1 included neonatal drug treatment (saline, quinpirole) and adolescent drug treatment (saline/saline, saline/nicotine, clozapine/nicotine, haloperidol/nicotine). In Experiment 2, the factors were the same with the exception the dose of nicotine used during conditioning was 1.8 mg/kg (free base). The rationale for not including a group that only received clozapine or haloperidol was that the focus of the study was to analyze the role of these antipsychotics on the associative effects of both the rewarding and aversive dose of nicotine, and not their effects alone. Group codes for Experiment 1 were neonatal drug treatment: NQ (neonatal quinpirole treatment) or NS (neonatal saline treatment) followed by adolescent drug treatment, which included SS (two saline injections separated by 15–20 min to mimic all treatment groups), SN (saline followed 15–20 min later by the rewarding 0.6 mg/kg free base nicotine), HN (haloperidol followed 15 min later by the rewarding 0.6 mg/kg free base nicotine), and CN (clozapine followed 20 min later by the rewarding 0.6 mg/kg free base nicotine). Group codes for Experiment 2 were the same for neonatal drug treatment, and adolescent drug treatment that included SS (two saline injections separated by 15–20 min to mimic the time period of separation for the delivery of drug treatments for all other groups), SA (saline followed 15–20 min later by the aversive 1.8 mg/kg free base nicotine), HA (haloperidol followed 15 min later by the aversive 1.8 mg/kg free base nicotine), and CA (clozapine followed 20 min later by the aversive 1.8 mg/kg free base nicotine). There was a total of 7–10 animals per drug treatment group.

2.6. Statistical Analyses

The primary statistic used was analysis of the variance (ANOVA). All ANOVAs were supplemented, when appropriate, by simple effects analyses on any significant interactions. The simple effect analyses were used to explore the nature of the interaction by examining the effect of one factor at one level of the other factor (see Keppel, 1991 for a review). For example, when the results revealed a significant neonatal drug treatment (saline, quinpirole) × adolescent drug treatment (S/S, S/N, H/N, C/N) interaction, separate one-way ANOVAs to test for cell mean differences of adolescent drug treatment was conducted for the neonatal drug treatment animals treated with saline and with quinpirole.

A Newman-Keuls test was used to analyze whether there were significant differences across multiple groups based on the simple effects analysis. An independent groups t-test was used to compute a priori differences between two groups that we hypothesized would be significantly different. Specifically, an independent groups t-test was used to analyze whether neonatal quinpirole (NQ) treatment changed the behavioral and/or GDNF response to nicotine compared to animals neonatally treated with saline (NS) and conditioned with nicotine.

3. Results

3.1. Experiment 1

3.1.1. Conditioned place preference

The difference in percent time spent in the paired context on the pre- and post-conditioning test using a rewarding dose of nicotine (0.6 mg/kg free base) as a function of group is presented in Figure 1(a). As can be observed, NQ enhanced the rewarding associative properties of nicotine, and NS-treated rats demonstrated nicotine CPP. Both antipsychotics reduced these effects, although differentially across the neonatal drug treatment conditions. These observations were confirmed by a two-way ANOVA which revealed a significant main effect of adolescent drug treatment, F(3,72)=20.02, p<.001 and a significant interaction of neonatal drug treatment × adolescent drug treatment, F(3,72) = 3.69, p<.01. Simple effects analyses were used to analyze the neonatal drug treatment × adolescent drug treatment interaction using two separate one-way ANOVAs (adolescent drug treatment) for the NS and NQ groups. For NS groups, the ANOVA revealed a significant main effect of adolescent drug treatment, F(3,34)=8.11, p<.001. Newman-Keuls post hoc analyses revealed NS-SN was equivalent to NS-CN and both were significantly greater NS-HN and NS-SS, which did not significantly differ from each other. Therefore, nicotine produced a CPP in controls that was blocked by haloperidol, but not clozapine. With respect to the NQ groups, the ANOVA also revealed a significant main effect of adolescent drug treatment, F(3,38)=19.35, p<.001. Post hoc analyses revealed NQ-SN was significantly greater than all other groups. Group NQ-CN was also significantly greater than NQ-SS. There was no significant difference between the NQ-SS and NQ-HN groups. A final comparison was performed to compare NQ-SN to NS-SN to analyze whether NQ treatment enhanced the associative properties of nicotine. An independent groups t-test revealed a significant effect of group, t(18) = 2.99, p<.008. NQ-SN was significantly greater than NS-SN, demonstrating that NQ enhanced the rewarding associative properties of nicotine.

Figure 1.

Figure 1

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Group codes: NQ=neonatal quinpirole; NS=neonatal saline; SS=adolescent saline/saline; SN=adolescent saline/nicotine; CN=adolescent clozapine/nicotine; HN=adolescent haloperidol/nicotine. Dose of nicotine administered = 0.6 mg/kg (base). (a). The difference in time spent in the paired context on the pre- and post-conditioning preference test is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) in Experiment 1. NQ-SN demonstrated a significant increased preference for the paired context on the post-conditioning test (CPP) compared to all other groups (indicated by **, p<.05). Groups NS-SN and NS-CN were statistically equivalent and demonstrated a significant increase preference for the paired context on the post-conditioning test compared to NS-SS (indicated by *, p<.05). (b) Accumbal GDNF (pg/ml) is presented as a function of neonatal drug treatment and adolescent drug treatment. NQ-SN demonstrated a significant increase of accumbal GDNF compared to all other groups (indicated by **, p<.05). NQ-SS demonstrated significantly greater GDNF than NS-SS (indicated by #, p<.05; as analyzed by independent groups t-test comparison). NQ-SS and NQ-HN were statistically equivalent and significantly greater than NQ-CN (indicated by *, p<.05). Likewise, Groups NS-SS, NS-SN, and NS-HN were all statistically equivalent and significantly greater NS-CN (indicated by *, p<.05).

3.1.2. Experiment 1 GDNF analysis

GDNF (pg/ml) is presented as a function of group in Figure 1(b). As can be observed, NQ enhanced the accumbal GDNF response to nicotine, and NQ administered to control animals conditioned with saline also resulted in an increase in accumbal GDNF. Both antipsychotics appear to block these effects. These observations were confirmed by the results of a two-way ANOVA which revealed a significant main effect of neonatal drug treatment, F(1,61)=35.44, p<.001, adolescent drug treatment, F(3,61)=28.73, p<.001 and a significant interaction of neonatal drug treatment × adolescent drug treatment, F(3,61)=6.11, p<.001. Simple effects analyses were used to analyze the interaction, using two separate one-way ANOVAs (adolescent drug treatment) for the NS and NQ groups. The NS groups revealed a significant main effect of adolescent drug treatment, F(3,31)=17.78, p<.001. Post hoc analyses revealed that Group NS-SN was equivalent to NS-HN and NS-SS and all three groups demonstrated significantly greater accumbal GDNF protein than Group NS-CN. The NQ groups also revealed a significant main effect of adolescent drug treatment, F(3,29)=16.85, p<.001. Newman-Keuls post hoc analyses revealed Group NQ-SN was significantly greater than all other groups, and Group NQ-SS was equivalent to NQ-HN and both were significantly greater than NQ-CN. An independent groups t-test was used to analyze whether NQ enhanced the accumbal GDNF response to nicotine and revealed a significant effect of group, t(17)= 5.07, p<.001. Indeed, NQ produced a significant increase of accumbal GDNF protein response to nicotine, whereas nicotine failed to produce any change in accumbal GDNF protein. Also, an independent groups t-test comparison of NQ-SS and NS-SS was used to analyze whether NQ by itself was sufficient to produce a significant increase in accumbal GDNF. An independent groups t-test revealed a significant effect of group, t(16)=2.27, p<.03. NQ produced a significant increase in accumbal GDNF versus saline-treated controls, demonstrating that NQ treatment was sufficient to enhance GDNF.

3.2. Experiment 2

3.2.1. Conditioned place preference

The difference in percent time spent in the paired context on the pre- and post-conditioning test using an aversive dose of nicotine (1.8 mg/kg free base) as a function of group is presented in Figure 2(a). As can be observed, an aversive dose of nicotine produced a conditioned place aversion (CPA) in NS-treated rats, but NQ-treated rats appear to be equivalent to saline controls. In addition, both antipsychotics appear to produce a CPA which was not differentially affected between both neonatal drug treatment conditions.

Figure 2.

Figure 2

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Group codes: NQ=neonatal quinpirole; NS=neonatal saline; SS=adolescent saline/saline; SN=adolescent saline/nicotine; CN=adolescent clozapine/nicotine; HN=adolescent haloperidol/nicotine. Dose of nicotine administered = 1.8 mg/kg (base). (a). The difference in time spent in the paired context on the pre- and post-conditioning preference test is presented as a function of neonatal drug treatment (x-axis) and adolescent drug treatment (legend) in Experiment 2. NS-SS, NQ-SS and NQ-SA were all statistically equivalent and demonstrated a significant increased preference for the paired context than all other groups (indicated by *, p<.05). (b). Accumbal GDNF (pg/ml) is presented as a function of neonatal drug treatment and adolescent drug treatment. NQ-SS demonstrated significantly greater accumbal GDNF than all other groups (indicated by **, p<.05). Groups NS-SS and NS-SA were statistically equivalent and significantly greater than NS-HA and NS-CA (indicated by *, p<.05). In addition, NQ-SA and NQ-CA were statistically equivalent and significantly greater than NQ-HA.

These observations were confirmed by the results of a two-way ANOVA which revealed a significant main effect of adolescent drug treatment, F(3,65)=9.50, p<.001 and a significant two-way interaction of neonatal drug treatment × adolescent drug treatment, F(3,65)=5.20, p<.003. Simple effects analyses were used to analyze each neonatal drug treatment condition separately to pinpoint specific group differences. Simple effects analysis of the NS groups revealed a significant main effect of adolescent drug treatment, F(3,30)=8.06, p<.001. Group NS-SS was significantly greater than all other groups, and Groups NS-SA, NS-CA, and NS-HA were all statistically equivalent. Simple effects analysis of the NQ groups also revealed a significant main effect of adolescent drug treatment, F(3,34) = 7.14, p<.001. NQ-SS was equivalent to NQ-SA which were both significantly greater than NQ-CA and NQ-HA, and the latter groups were equivalent. An independent groups t-test was used to verify that NQ blocked the aversive associative properties of nicotine. Indeed, a comparison of groups NS-SA and NQ-SA revealed a significant effect of group, t(18)=3.63, p<.01. NQ-SA was significantly greater than NS-SA, demonstrating the same dose of nicotine did not produce a conditioned place aversion in NQ-treated rats.

3.2.2. Experiment 2 GDNF analysis

GDNF (pg/ml) is represented as a function of group in Figure 2(b). As can be observed, the aversive dose of nicotine appeared to produce a decrease in GDNF in NQ and not NS-treated animals. Further, both antipsychotics failed to block the decrease in accumbal GDNF produced by the aversive dose of nicotine. These observations were confirmed by a two-way ANOVA which revealed a significant main effect of adolescent drug treatment, F(3,60)=23.45, p<.001 and a significant interaction of neonatal drug treatment × adolescent drug treatment, F(3,60)=7.01, p<.001. Simple effects analysis of NS groups revealed a significant main effect of adolescent drug treatment, F(3,27)=12.11, p<.001. Group NS-SS was equivalent to NS-SA and both were significantly greater than both NS-CA and NS-HA, which did not significantly differ from each other. Simple effects analysis of the NQ groups also revealed a significant main effect of adolescent drug treatment, F(3,32)=21.22, p<.001. Group NQ-SS was greater than all other groups. Group NQ-SA was equivalent NQ-CA, and both were greater than NQ-HA. Finally, an independent groups t-test compared groups NS-SA and NQ-SA revealed a significant effect, t(18)=3.88, p<.01. NQ resulted in a significant decrease of GDNF in combination with aversive nicotine compared to controls.

4. Discussion

The present study revealed that NQ enhanced the rewarding associative effects of nicotine in adolescence compared to controls conditioned with nicotine, which is similar to previous work (Perna et al., 2011). Haloperidol completely blocked this effect, whereas clozapine only blocked the enhancing effect of NQ on nicotine CPP. However, clozapine did not block nicotine CPP in NS-treated controls. The fact that haloperidol blocked nicotine CPP in both NQ and NS-treated animals, but clozapine failed to block CPP in controls, is consistent with the pharmacological mechanism of each drug. Haloperidol is a relatively potent dopamine D2-like antagonist, whereas clozapine has a reduced affinity for antagonism of the dopamine D2 receptor. Unlike haloperidol, however, clozapine increases glutamatergic activity (Tanahashi et al., 2012). Haloperidol has not been tested against nicotine CPP, but it has been shown to block CPP with other psychostimulants, including amphetamine and cocaine (Mackey & van der Kooy, 1985; Adams et al., 2001; Banasikowski et al., 2012). There has been limited research using clozapine in CPP. One study showed that clozapine attenuated cocaine CPP, but the dose of clozapine used (10 mg/kg) in that study was substantially higher than the dose used in the present study (Kosten & Nestler, 1994). With respect to the aversive dose of nicotine, NS-treated animals demonstrated a conditioned place aversion, whereas NQ-treated animals did not demonstrate an aversion to the high dose of nicotine. The fact that NQ, which results in a significant increase of dopamine D2 receptor sensitivity, reduced the aversive associative properties of nicotine would seem to be consistent with increased tobacco smoking in schizophrenia, although this has not been directly tested. However, changes in dopamine D2 receptor activation does have the ability to change the motivational valence of nicotine in brain areas related to drug reward (see below, LaViolette et al., 2008). Interestingly, both haloperidol and clozapine failed to block the aversive properties of this dose of nicotine regardless of neonatal drug treatment.

Regarding GDNF, somewhat consistent with the CPP behavioral results in Experiment 1, NQ treatment dramatically increased the GDNF response to nicotine in the NAc. The observed increase in GDNF was blocked to control levels by haloperidol and to below control levels by clozapine. The effects of antipsychotics on the GDNF response to a rewarding dose of nicotine is consistent with the ability of both drugs to antagonize the D2 receptor. However, clozapine appears to be more effective at blocking the effects of accumbal GDNF compared to haloperidol, despite being a less potent D2 antagonist. In NS-treated animals, nicotine did not increase GDNF protein levels, but both antipsychotics reduced GDNF levels to below controls. The finding that nicotine did not increase GDNF in NS-treated controls is inconsistent with other reports showing that dopamine agonists usually produce an increase in GDNF (e.g., Li, et al., 2010). It should be noted, however, that the effects of psychostimulants on GDNF has not been thoroughly tested. Interestingly, NQ combined with the aversive dose of nicotine produced a decrease in GDNF compared to NQ-treated animals conditioned with saline. In addition, this same group was equivalent to animals conditioned with clozapine and the aversive dose of nicotine, whereas haloperidol co-administered with the aversive dose of nicotine in NQ-treated animals were significantly below all other groups. In other words, clozapine was less effective at decreasing GDNF in NQ-treated rats compared to haloperidol when the aversive dose of nicotine was administered. Further, in both experiments, GDNF appears to be sensitive to the effects on dopamine, especially in NQ rats, a finding that is consistent with increased dopamine D2 receptor sensitivity in these animals and the known role of GDNF in dopamine plasticity.

In addition, the effects of each antipsychotic in Experiment 1 may also be directly related to the pharmacological mechanisms of each antipsychotic. Haloperidol is primarily a potent dopamine D2-like receptor antagonist (Seeman and Tallerico, 1998), although it does have some antagonistic action at serotonin 5-HT1a receptor subtypes as well as histamine and muscarinic receptors (Kroeze et al., 2003). Although dopamine D2 antagonism has not been directly analyzed to block nicotine CPP, we have shown that eticlopride, a D2-like receptor antagonist, and nafatotride, a relatively specific D3 antagonist were effective at blocking the associative effects of nicotine in the NQ model using a conditioned hyperactivity paradigm (Sheppard et al., 2009). In addition, D2 antagonists have been shown to reduce cue-induced nicotine reinstatement in a self-administration paradigm whether nicotine was administered systemically (Liu et al., 2010) or infused directly into the amygdala or lateral habenula (Khaled et al., 2014). However, infusion of haloperidol into the insular cortex was shown to no effect on nicotine self-administration (Kutlu et al., 2013). Bruijnzeel and Markou (2005) have shown that infusion of the D2-like antagonist eticlopride into the posterior hypothalamus/anterior ventral tegmental area (VTA) region increased reward threshold in an intracranial self-stimulation during chronic nicotine exposure (Ivanova and Greenshaw, 1997). Certainly, there is enough evidence to suggest that the potent D2-like antagonism of haloperidol blocks or attenuates the behavioral effects of nicotine, and that is consistent with the present set of results.

Clozapine has a different mechanism than haloperidol. Although clozapine does work to antagonize D2-like receptors, it is less potent than haloperidol, and it also works as an antagonist at 5-HT1a, histaminergic, muscarinic, and adrenergic receptors (Lieberman, 1993) and possibly more importantly, enhances glutamatergic activity (Tanahashi et al., 2012). There have not been any studies to analyze the effects of clozapine on nicotine CPP, and the vast majority of work with clozapine on the behavioral effects of nicotine has primarily focused on attentional performance (Addy and Levin, 2002; Levin and Rezvani, 2007) rather than behavioral paradigms related to addiction. However, a 2.5 mg/kg dose of clozapine, identical to the one used in the present study, was effective at blocking nicotine sensitization in rats (Kayir et al., 2009). Although behavioral sensitization is not a direct behavioral test of the associative properties of nicotine as is the CPP behavioral paradigm, it has been shown to be directly mediated by the dopaminergic system of the VTA-NAc pathway (Vanderschuren & Kalivas, 2000). Therefore, clozapine has been shown to antagonize dopaminergic effects related to nicotine, and the results here are consistent with this finding.

The increased accumbal GDNF response to nicotine in NQ-treated as compared to NS- treated rats was similar to the accumbal BDNF response to nicotine in NQ-treated rats we have previously reported (Perna and Brown, 2013). However, nicotine increases accumbal BDNF in NS-treated rats, so in this past work, NQ may have sensitized the accumbal BDNF response to nicotine. In the present study, GDNF was increased in NQ-treated rats given saline, and then was synergistically increased in NQ-treated rats conditioned with the rewarding dose of nicotine. GDNF can directly increase dopamine release from striatal nerve endings (Gomes et al., 2006), which may influence the behavioral response to nicotine and be an important underlying mechanism of the enhanced response to nicotine observed in NQ-treated rats. Past work has shown that D2 or D3 activation results in significant increases of GDNF in vitro via an ERK-dependent mechanism which was blocked by dopamine antagonists (Li et al 2010; Ahmadiantehrani and Ron, 2013). Further, infusion of GDNF into the striatum produced increased behavioral activation that was blocked by D2-like receptor antagonism (Kobayashi et al., 1998). Future studies may focus on GDNF or its downstream effectors as a possible target for the effects of nicotine, especially with its known relationship to neurotrophic factors in brain areas that mediate addiction (Leão et al., 2013).

Haloperidol in NS-treated rats did not affect the accumbal GDNF response to nicotine, but it was effective at blocking the enhanced GDNF response to nicotine in NQ-treated rats. However, clozapine co-administered with nicotine resulted in significant decreases of GDNF compared to all other groups. Although there is no past work that has analyzed the effects of clozapine and haloperidol on GDNF in the NAc directly, anti-Parkinsonian agents which enhance dopaminergic activity have been shown to increase GDNF in dopamine terminal regions of the forebrain (Du et al., 2005; Li et al., 2010). Therefore, it is sensible that drugs which act as antagonists to the dopamine system may result in an overall decrease of GDNF. Somewhat surprisingly, haloperidol, which is a potent dopamine D2-like receptor antagonist, resulted in a mild effect on GDNF, whereas clozapine was very effective at producing a significant reduction in accumbal GDNF. Undoubtedly, the mechanism as to how these antipsychotics affect GDNF is complex, especially when these drugs are co-administered with nicotine. Regardless, it appears that clozapine has a more potent effect on accumbal GDNF than does haloperidol, which may relate to more robust changes in accumbal dopaminergic plasticity.

When the aversive properties were tested in Experiment 2, NQ blocked conditioned place aversion (CPA) that was observed in the NS-treated rats conditioned with the high (1.8 mg/kg free base) dose of nicotine, suggesting that increasing of dopamine D2 sensitivity may blunt the aversive associative properties of nicotine. There is considerable evidence that implicates the mesolimbic dopamine system in the processing of nicotine’s reinforcing properties, specifically the VTA dopaminergic projections to the NAc. Past work by Laviolette and colleagues (2008) demonstrated that a dopamine antagonist infused into the NAc shell switched the motivational valence of intra-VTA nicotine from aversive to rewarding and potentiated nicotine reward sensitivity to sub-threshold intra-VTA doses of nicotine. In the present case, dopamine D2 sensitivity is increased, however, it appears to enhance only the rewarding properties of nicotine. Recent work from our lab is congruent with this finding in that NQ substantially enhanced nicotine self-administration at doses that NS-treated rats typically find less rewarding (90 ug/kg, iv infused). With the relevance of the NQ model towards schizophrenia, this may imply that individuals diagnosed with schizophrenia that smoke heavily may be able to tolerate doses of nicotine typically found to be rewarding in smokers that are not diagnosed with psychosis, and this may be directly related to changes in dopamine D2 receptor function.

Interestingly, neither clozapine nor haloperidol blocked the aversive properties of nicotine, and groups which were conditioned with haloperidol or clozapine, regardless of neonatal drug treatment, resulted in a significant conditioned place aversion (CPA). This may be due to a floor effect, in that animals cannot demonstrate any stronger aversion given the parameters of the behavioral test. Interestingly, haloperidol has been shown in past work to attenuate the aversive properties of a benzodiazepine (Di Scala and Sandner, 1989), but neither antipsychotic has been tested regarding the aversive properties of nicotine. This was not completely consistent with GDNF results, as clozapine paired with the aversive dose of nicotine resulted in a significantly lower accumbal GDNF response compared to haloperidol. Further, the aversive dose of nicotine resulted in a significant decrease of GDNF in NQ animals, but this was not the case in NS-treated controls. Presumably, this decrease in GDNF is due to an interaction between the aversive dose of nicotine and increased of sensitivity D2 receptors, including the inhibitory D2 autoreceptor, in NQ animals, but the precise mechanism underlying this effect is not known. It is clear there is an interaction between changes in dopamine D2 receptor sensitivity and GDNF that may have important implications towards dopamine plasticity in brain regions that mediate the effects of drug addiction.

In conclusion, this study demonstrates that increases of dopamine D2 receptor sensitivity enhanced the rewarding associative properties of nicotine, but blocks the aversive associative properties of nicotine using a CPP behavioral paradigm. Further, NQ significantly increased the accumbal GDNF response to the rewarding dose of nicotine, which has implications for dopaminergic synaptogenesis in the NAc and increased tobacco smoking within the population diagnosed with schizophrenia, especially in the context of our past discovery of NQ sensitizing the accumbal BDNF response to nicotine (Perna and Brown, 2013). Regarding the antipsychotics tested in the present study, haloperidol blocked the associative effects of the rewarding nicotine dose, whereas clozapine only blocked the enhanced associative effects of nicotine in the NQ-treated rats. This is the first study to analyze the effects of both the rewarding and aversive properties of nicotine in a rodent model of schizophrenia and its effects on GDNF, and future work will analyze whether this may be an effective target for smoking cessation in this population.

Acknowledgments

This work was supported by NIH R15 grant DA 034912-01A1 to RWB. The authors would like to thank James D. Wherry and Charlotte Kaestner for their contribution to this work.

Footnotes

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Contributors

All authors contributed to this work. Dr. Brown was the principal investigator of the project and impetus behind the project. Seth Kirby, Adam Denton, and Beth Cummins contributed to research design and behavioral testing. Katherine Burgess aided Dr. Brown in conducting the project.

Conflict of Interest

The authors report no conflict of interest with this work.

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