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. Author manuscript; available in PMC: 2023 Jul 10.
Published in final edited form as: Psychopharmacology (Berl). 2023 May 9;240(7):1453–1464. doi: 10.1007/s00213-023-06379-7

Reinstatement of nicotine conditioned place preference in a transgenerational model of drug abuse vulnerability in psychosis: Impact of BDNF on the saliency of drug associations

Loren D Peeters 1, Liza J Wills 1, Anthony M Cuozzo 1, Kira L Ivanich 1, Russell W Brown 1
PMCID: PMC10330905  NIHMSID: NIHMS1905177  PMID: 37160431

Abstract

Rationale

Psychotic disorders such as schizophrenia are often accompanied by high rates of cigarette smoking, reduced quit success, and high relapse rates, negatively affecting patient outcomes. However, the mechanisms underlying altered relapse-like behaviors in psychosis are poorly understood.

Objectives

The present study analyzed changes in extinction and reinstatement of nicotine conditioned place preference (CPP) and resulting changes in brain-derived neurotrophic factor (BDNF) in a novel heritable rodent model of psychosis, demonstrating increased dopamine D2 receptor sensitivity, to explore mechanisms contributing to changes in relapse-like behaviors.

Methods

Male and female offspring of two neonatal quinpirole-treated (1 mg/kg quinpirole from postnatal day (P)1–21; QQ) and two neonatal saline-treated (SS) Sprague–Dawley rats (F1 generation) were tested on an extended CPP paradigm to analyze extinction and nicotine-primed reinstatement. Brain tissue was analyzed 60 min after the last nicotine injection for BDNF response in the ventral tegmental area (VTA), the infralimbic (IfL) and prelimbic (PrL) cortices.

Results

F1 generation QQ offspring demonstrated delayed extinction and more robust reinstatement compared to SS control animals. In addition, QQ animals demonstrated an enhanced BDNF response to nicotine in the VTA, IfL and Prl cortices compared to SS offspring.

Conclusions

This study is the first to demonstrate altered relapse-like behavior in a heritable rodent model with relevance to comorbid drug abuse and psychosis. This altered pattern of behavior is hypothesized to be related to elevated activity-dependent BDNF in brain areas associated with drug reinforcement during conditioning that persists through the extinction phase, rendering aberrantly salient drug associations resistant to extinction and enhancing relapse vulnerability.

Keywords: Psychosis, Schizophrenia, Heritable, Nicotine, Adolescence, BDNF, Extinction, Reinstatement, Conditioned place preference

Introduction

Schizophrenia and tobacco use disorder are chronic neuropsychiatric disorders that are highly comorbid, with prevalence rates as high as 50–75% compared to roughly 20–25% in the general population (Lohr and Flynn 1992; Sagud et al. 2019). In addition to increased nicotine dependence, quit success is considerably reduced in patients with schizophrenia (George et al. 2002), and relapse rates following smoking cessation are high in this population (Evins et al. 2005). Less than 15% of individuals diagnosed with schizophrenia remain abstinent six months after discontinuation (George et al. 2008), compared to 35–55% of psychiatrically healthy individuals (Andritsou et al. 2016). Extinction learning, which involves updating of previously learned associations to suppress a particular behavior, may play a role in the ability for an individual to successfully quit smoking (Torregrossa and Taylor 2013; Smith et al. 2014). Several studies have reported impaired extinction learning in schizophrenia, clinically manifesting in persistence of delusions and disruptions in emotional learning and memory (Holt et al. 2009; Clifton et al. 2017). Dysregulated synaptic plasticity, another prominent feature of schizophrenia, may contribute to these impairments in extinction learning (Sanderson 2012; Forsyth and Lewis 2017; Guterman et al. 2021). Long-lasting structural and functional changes at the synaptic level underlie the behavioral consequences of drug-taking that persist long past the cessation of drug-use, including compulsive drug-taking and relapse (Hyman 2007; Koob and Volkow 2010). Impaired synaptic stability and impaired long-term depression which are found to be present in schizophrenia may therefore confer risk of substance abuse and relapse vulnerability (Hasan et al. 2012; Nieto et al. 2013; Forsyth and Lewis 2017; Guterman et al. 2021).

Past work in our laboratory has established that rats neonatally treated with the dopamine D2 (DAD2)-like receptor agonist quinpirole display lifelong increases in DAD2 receptor sensitivity, consistent with a number of clinical observations in psychosis and as such is considered a hallmark for schizophrenia and other disorders related to psychosis (Kostrzewa 1995; Kostrzewa et al. 2008, 2018; Belzung and Lemoine 2011; Brown et al. 2012). We have shown that neonatal quinpirole- (NQ) treated animals display characteristic behavioral phenotypes of drug abuse vulnerability and psychosis during adolescence, including enhanced amphetamine and nicotine conditioned place preference (CPP), behavioral sensitization to nicotine, and enhanced dopamine release in the nucleus accumbens (NAcc) in response to both amphetamine (Cope et al. 2010) and nicotine (Perna and Brown 2013). There is a significant contribution of genetic vulnerabilities that are thought to lead to the development of schizophrenia, with a concordance rate of between 40–50% for monozygotic twins (Gejman et al. 2010). We have more recently shown heritable transmission of these phenotypes in the offspring of NQ-treated animals, establishing the first known heritable model of drug abuse vulnerability with relevance to psychosis. Most notably, F1 offspring of at least one NQ-treated founder display enhanced CPP and an elevated BDNF response to nicotine in the NAcc shell, equivalent to findings in F0 generation rats given NQ treatment. RNAseq analyses of the dorsal striatum revealed enrichment of several biological processes relevant to drug abuse vulnerability in psychosis in F1 generation offspring of two NQ-treated founders, including increased cortisol synthesis and secretion, indicative of an enhanced response to stress, as well as changes in pathways related to learning, memory, and cognition, which is consistent with drug abuse vulnerability (Gill et al. 2021).

Neuroadaptations following exposure to drugs of abuse are hypothesized to occur first in the ventral tegmental area (VTA), which is rich in dopamine cell bodies. Exposure to drugs of abuse results in the strengthening of synaptic connections between glutamatergic and dopaminergic neurons, facilitating dopamine release upon subsequent exposure to the drug (Fitzgerald et al. 1996; Ungless et al. 2001; Lüscher 2013; Huijstee and Mansvelder 2015). Increased activation of the VTA then promotes neuroplastic changes in other downstream regions, including the NAcc and subregions of the prefrontal cortex (PFC; Kauer and Malenka 2007; Lüscher and Malenka 2011). Neurotrophic factors promote survival and function of adult neurons and modulate learning and memory by promoting long-lasting changes in synaptic strength, including long-term potentiation (LTP) and long-term depression (LTD) which increase and decrease the efficacy of synaptic connections, respectively (Mansvelder and McGehee 2000; Hyman 2007; Ghitza et al. 2010; Sheynikhovich et al. 2013). Brain-derived neurotrophic factor (BDNF) has reliably been shown to be a critical mediator of synaptic plasticity in dopaminergic neurons (Hyman et al. 1991; Nieto et al. 2013; Baydyuk and Xu 2014), and plays an integral role in contextual learning (Pu et al. 2006). As such, BDNF has long been associated with the neuroplastic changes that result from drug-taking. Due to its known role in the differentiation and survivability of dopaminergic neurons, BDNF has been implicated in the etiology of impaired synaptic connectivity and cognitive function that are prominent features of schizophrenia (Nieto et al. 2013; Gören 2016). BDNF is also thought to be associated with drug abuse vulnerability and susceptibility for relapse (Hall et al. 2003; Tsai 2007; Nikulina et al. 2014), suggesting that this neurotrophic factor may be involved in the aberrant synaptic plasticity that is believed to impact relapse vulnerability in this population.

The effects of BDNF on relapse-like behavior have been shown to be region specific and have largely been characterized following exposure to cocaine. Increased BDNF in the NAcc increases cocaine reward and reinstatement, while increased BDNF in the PFC has been shown to reduce cocaine-seeking (Graham et al. 2007; Bahi et al. 2008; Cooper et al. 2017). Studies of relapse typically focus on later stages of neuroplasticity involving the NAcc and PFC, which are generally recognized as components in the final common pathway for relapse circuitry (Kalivas and McFarland 2003; Stewart 2008; Kalivas 2009). In particular, the medial PFC is subdivided into the prelimbic (PrL) and infralimbic (IfL) cortices and has been heavily implicated in the regulation of drug-seeking and relapse. These two subregions drive distinct behavioral responses. The PrL cortex is critical for drug-seeking behavior and is activated by re-exposure to a drug of abuse during drug-primed reinstatement (McFarland and Kalivas 2001; Lasseter et al. 2009). Conversely, the IfL cortex inhibits certain behaviors related to drug seeking by updating the relationship between contextual information and behavioral outcomes. This regulation of contingency learning facilitates extinction of drug-seeking behaviors (Nett and LaLumiere 2021). Several lines of evidence suggest the VTA may be an additional common mediator of relapse (Sun 2011). Dopaminergic projections from the VTA to the core of the NAcc have been shown to be critical in the reinstatement of cocaine self-administration (Shen et al. 2014). Exposure to conditioned cues activates VTA dopamine neurons (Ciano et al. 1998), and drug-seeking behavior can be reinstated by direct activation of VTA dopamine neurons and conversely blocked by irreversible inactivation (Sun 2011). However, these lines of evidence come predominantly from studies of self-administration paradigms, where daily exposure to drugs is generally greater than in other behavioral paradigms such as CPP and is known to involve discrete circuitry (Green and Bardo 2020).

In the present study, we sought to analyze changes in BDNF in the VTA, as well as the IfL and PrL cortices following nicotine-primed reinstatement of CPP in a novel heritable model of drug abuse vulnerability in psychosis. Since BDNF is the only neurotrophic factor found to be significantly expressed in the VTA (Conner et al. 1997; Nikulina et al. 2014), and altered BDNF expression in specific subregions within the PFC following exposure to nicotine has not been well studied, we sought to characterize how the BDNF response to nicotine in these regions following conditioning may relate to altered relapse-like phenotypes in F1 generation offspring of NQ-treated founders. This study provides insight into the nature of aberrant plasticity in psychosis that may confer relapse vulnerability.

Methods

Subjects

Male and female Sprague–Dawley rats were used in this experiment. Male and female breeders were first obtained from Envigo, Inc. (Indianapolis, IN) and were used to produce eight male and eight female F0 generation breeders (founders). Of these founders, half (four males and four females) were administered saline (0.9% NaCl; i.p.) and half were administered quinpirole HCl (1 mg/kg; i.p.; Sigma, CAS# 85,798–08–9) from postnatal day (P)1–21. These ‘founder’ animals were raised in our colony and mated at P60, producing F1 generation crosses that were the offspring of either two neonatal quinpirole-treated animals or two neonatal saline-treated animals. A total of 49 offspring (F1 generation: 27 male, 22 female) from a total of seven litters were used as subjects. A total of 1–2 males and 1–2 females were assigned to each drug condition (saline, nicotine) from each litter. All animals were raised in a climate-controlled vivarium at East Tennessee State University with food and water available ad libitum, and all animals were socially housed throughout the experiment (2–4 per cage).

Behavioral Methods

A three chambered shuttle box was used, containing a vertically striped, horizontally striped, and a neutral gray context, each with distinct tactile cues, separated by a removable divider. All rats were given two 10 min pre-conditioning trials on P41 and P42. On these trials, rats were i.p. administered saline and 10 min later were allowed to explore the entire apparatus. Time spent in each context was recorded using AnyMaze Behavioral Tracking Software (Stoelting Inc., Wood Dale, IL, USA), and percent time for each context was averaged over the two days. For subsequent conditioning trials, the paired context was assigned against initial preference, defined as greater than 60% time spent in either the horizontally or vertically striped context, or randomly assigned if no preference was found. Conditioning trials occurred twice a day for eight days (P43–50) with walls placed in the apparatus. During conditioning, rats were ip administered saline in the morning (10AM) and placed in the non-paired context for 10 min. In the afternoon (2PM), rats were administered either saline or nicotine (0.6 mg/kg base) 10 min prior to being placed in the paired context for 10 min. A single post-conditioning test was given on P51 identical to the pre-conditioning tests, with walls removed and time recorded using AnyMaze software (Stoelting Inc., Wood Dale, IL). Following the post-test on P51, all animals received 8 days of extinction from P52–59, identical to both pre- and post-conditioning trials, with saline administered i.p. 10 min before each trial. Time spent in each chamber was recorded daily to confirm extinction. A 10 min reinstatement trial was administered on P60. On this trial, animals were i.p. administered nicotine (0.6 mg/kg base) or saline according to their conditioning treatment and allowed to explore the entire apparatus 10 min later.

BDNF ELISA Methods

Brain tissue was harvested 1 h after nicotine was administered during the reinstatement trial, placed into cold isopentane and stored in a −80 °C freezer (SoLow Inc., Cincinnati, OH). The VTA, PrL, and IfL were micropunched between the following stereotaxic coordinates using a rat brain mold: VTA AP −5.8 to −6.8, ML ± 0.5, DV −8.5; IfL AP + 3.24, ML ± 0.6. DV −3.8; PrL AP + 3.24, ML ± 0.6, DV −2.2. A radioimmunoprecipitation assay (RIPA) buffer made up of 150mM NaCl, 50 mM Tris HCl, 0.5% sodium deoxycholate, 0.1% sodium dodecyl sulfate, and 1% NP-40, was used for homogenization. A phosphatase/protease inhibitor cocktail was added to the RIPA buffer to protect breakdown of BDNF (Sigma-Aldrich P0044, P5726, P8340, and phenylmethanesulfonyl fluoride solution; PMSF). Total BDNF was analyzed using ELISA kits from Biotechne/R&D systems (Minneapolis, MN, USA) and the protocol was closely followed. In brief, standards and samples were pipetted onto the plate and incubated for 2 h on a microplate shaker at room temperature. After emptying the plate and applying 4 washes with a wash buffer, 200ul of total BDNF conjugate was added to each well. After 4 more washes of the plate with the wash buffer, 200ul of the substrate solution was added, incubated for 30 min and protected from light. After this, a stop solution was applied to the entire plate and the plate was immediately read on a BioTek 808 plate reader (BioTek, Winooski, VT) at 450 nm. This assay is for quantitative determination of both free and Trk-receptor bound BDNF in tissue homogenates.

Group Codes and Statistical Analysis

Offspring of two founders both neonatally treated with saline are coded as ‘SS’, and offspring of two founders neonatally treated with quinpirole are coded as ‘QQ’. This variable is termed ‘founder treatment’. Adolescent drug treatment is coded as ‘S’ for saline and ‘N’ for nicotine. For analysis of post-conditioning acquisition and reinstatement tests of CPP, an initial three-way analysis of the variance (ANOVA) was used with sex, founder treatment group (SS, QQ) and adolescent drug treatment (S, N) used as factors. For the analysis of extinction, we used an initial four-way ANOVA with sex, founder treatment, adolescent drug treatment and day of testing as the repeated measure. Post hoc group comparisons across all analyses were performed with a Bonferroni post hoc test (p < 0.05). The dependent variable for post-conditioning, extinction, and reinstatement was percent time spent in the paired context during each phase minus percent time in the paired context during the pre-conditioning test. The dependent variable for BDNF analysis was picograms of total BDNF protein per milligrams of tissue (pg/mg). A hierarchical regression analysis to determine the impact of factors accounting for the variance in BDNF was also conducted, using founder treatment, adolescent drug treatment, and reinstatement test performance as predictors in each brain region. All statistical analyses were conducted using SPSS statistical software (Version 28.0 for Mac).

Results

Across all analyses, sex as a factor was dropped and data from males and females were pooled together, as no sex differences were revealed. Post-conditioning test results are presented as a function of drug and the percent difference spent in the paired context on the pre-conditioning test subtracted away from the post-conditioning test in Fig. 1A. A two-way ANOVA with founder treatment (SS, QQ) and adolescent drug treatment (S, N) as variables revealed significant main effects of founder treatment F (1,45) = 4.17, p < 0.048; and adolescent drug treatment F(1,45) = 40.29, p < 0.001) as well as a significant interaction of founder treatment x adolescent drug treatment (F(1,45) = 7.07, p < 0.001). Bonferroni post hoc test analysis revealed that Group QQ-N displayed a significantly greater preference for the nicotine-paired context compared to all other groups (indicated by **, p < 0.05), and Group SS-N was significantly greater than Groups QQ-S and SS-S (indicated by *, p < 0.05). These results demonstrate that F1 generation offspring of two NQ-treated rats demonstrate enhanced nicotine CPP compared to controls, which replicates past work (Gill et al. 2021).

Fig. 1.

Fig. 1

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F1 generation offspring of two quinpirole treated animals (QQ) display altered relapse-like behavior compared to control animals that were the offspring of saline-treated rats (SS). (A) Difference in time between pre-conditioning paired context and post-conditioning paired context is presented as a function of adolescent treatment group and founder treatment group. Nicotine treatment during conditioning lead to significant CPP acquisition across all groups, as demonstrated by increased percent time spent in the paired context during a post-conditioning test. QQ animals demonstrated enhanced significantly greater preference for nicotine-paired contexts during the post-conditioning test compared to all other groups. (B) Difference in time between pre-conditioning paired context and paired context during extinction day is presented as a function of adolescent drug treatment and founder treatment. QQ-N animals displayed delayed extinction learning, as demonstrated by significantly greater percent time spent in the paired context from Days 1 through 6 of extinction training. Days 7 and 8 were equivalent across all groups. (C) Difference in time spent in the paired context between pre-conditioning and reinstatement is presented as a function of adolescent drug treatment and founder treatment. QQ-N rats demonstrated robust nicotine-induced reinstatement compared to all other groups. SS-N animals did not significantly differ from SS-S controls. Bars represent mean ± SEM. * p < 0.05, **p < 0.05

Extinction is presented as a function of day and the percent time spent in the paired context on each day in Fig. 1B. A three-way ANOVA with founder treatment (SS, QQ), adolescent drug treatment (S, N), and extinction day revealed significant main effects of founder treatment F(1,45) = 7.11, p < 0.011, adolescent drug treatment F(1,45) = 6.48, p < 0.014, and a significant founder treatment x adolescent drug treatment interaction (F(1,45) = 4.63, p < 0.037). Bonferroni post hoc analysis revealed Group QQ-N demonstrated a significantly higher preference for the paired context on Days 1 through 6 during extinction (indicated by *, p < 0.05), and there were no significant differences between groups on days 7 and 8. These data demonstrate that offspring of two NQ-treated animals are more resistant to extinction than controls.

Reinstatement results are presented as a function of drug and the percent difference spent in the paired context on the pre-conditioning test subtracted away from the reinstatement test in Fig. 1C. A two-way ANOVA revealed significant main effects of founder treatment F(1,45) = 8.03, p < 0.007 adolescent drug treatment F(1,45 = 16.79, p < 0.001) and a significant interaction of founder treatment x drug treatment (F(1,45) = 5.38, p < 0.025). Bonferroni post hoc analysis revealed that Group QQ-N demonstrated robust reinstatement of nicotine CPP (indicated by *, p < 0.05) compared to all other groups, and there were no other group differences. These results establish that, whereas re-exposure to nicotine was sufficient to reinstate previously extinguished nicotine CPP in the offspring of two NQ-treated animals, offspring of two NS-treated rats did not display reinstatement of extinguished nicotine CPP.

BDNF results are presented in Fig. 2 as a function of founder treatment and adolescent drug treatment. For the VTA analysis, the total N of each group was 8–9. For PrL and IfL, the total N of each group was 6–7 so that all tissue would fit onto one 96 well plate. As presented in Fig. 2A, in the VTA, a two-way ANOVA with founder treatment and adolescent drug treatment revealed a significant main effect of adolescent drug treatment (F(1,32) = 8.76, p < 0.006) and a significant interaction of F1 generation cross x adolescent drug treatment (F(1,32) = 6.96, p < 0.013). Bonferroni post hoc analysis revealed that Group QQ-N demonstrated significantly higher levels of BDNF in the VTA than all other groups (indicated by *, p < 0.05). These results indicate that offspring of two quinpirole-treated animals display an enhanced BDNF response to nicotine in the VTA compared to offspring of saline-treated controls. In the PrL cortex (Fig. 2B), a two-way ANOVA revealed significant main effects of founder treatment (F(1,26) = 10.26, p < 0.004) and adolescent drug treatment (F(1,26) = 15.01, p < 0.001) and a significant two-way interaction of founder treatment x adolescent drug treatment (F(1,26) = 6.30, p < 0.018). Group QQ-N demonstrated a significant increase of BDNF in the PfL compared to all other groups (indicated by *, p < 0.05). As presented in Fig. 2C, in the IfL cortex, a two-way ANOVA revealed significant main effects of founder treatment F(1,25) = 6.78, p < 0.15) and adolescent drug treatment (F(1,25) = 6.72, p < 0.017), and a significant two-way interaction of founder treatment x adolescent drug treatment (F(1,25) = 5.73, p < 0.026). Group QQ-N demonstrated a significant increase of BDNF in the IfL compared to all other groups (indicated by *, p < 0.05). Therefore, across three brain areas we observed the same pattern, with Group QQ-N demonstrating robustly significant increases in BDNF compared to all other groups.

Fig. 2.

Fig. 2

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For Figs. 2 a–c, BDNF (pg/mg) is presented as a function of adolescent drug treatment and founder group for the (A) VTA, and (B) PrL and (C) IfL cortices. F1 generation offspring of two quinpirole treated animals display an enhanced BDNF response to nicotine. Brain tissue was taken 60 min following reinstatement testing and analyzed for total BDNF protein via ELISA. QQ-N animals demonstrated an enhanced BDNF response to nicotine in the VTA as well as the PrL and IfL cortices compared to all other groups. Bars represent mean ± SEM. *p < 0.05

Results from the hierarchical regression are presented in Fig. 3. A hierarchical regression was used to analyze which factors as well as the behavioral results of reinstatement best accounted for the variance in BDNF. Thus, there were three models: founder treatment, founder treatment included with adolescent drug treatment, and founder treatment included with adolescent drug treatment and performance on the reinstatement test. Results for the BDNF analysis in the VTA are presented in Fig. 3A. The founder treatment model was not significant by itself, accounting for only 6% of the variance [adjusted R2 = 0.058; F(1,32) = 2.98, p = 0.097]. The best model included both founder treatment and adolescent drug treatment as factors, which accounted for 18% of the variance [adjusted R2 = 0.180, F(2,32) = 4.52, p = 0.024]. When founder treatment, adolescent drug treatment and reinstatement behavioral performance were included in the model, it also accounted for 18% of the variance, although the model was slightly less statistically significant [adjusted R2 = 0.183; F(2,32) = 3.38, p = 0.031]. The BDNF analysis in the PrL is presented in Fig. 3B, and all three models were statistically significant. The founder treatment accounted for 14.5% of the variance [adjusted R2 = 0.145; F(1,26) = 5.4 p < 0.029], and the best model again included both founder treatment and adolescent drug treatment as factors accounting for 40% of the variance [adjusted R2 = 0.403; F(2,26) = 9.788, p = 7.79 × 10−4]. When founder treatment, adolescent drug treatment and reinstatement were all included, they also accounted for 40% of the variance, although again, slightly less statistically significant [adjusted R2 = 0.401; F(3,26) = 6.88, p = 0.0018]. Finally, BDNF analysis in the IfL is presented in Fig. 3C, and all three models were again statistically significant, however the founder treatment accounted for 12.5% of the variance and just reached statistical significance [adjusted R2 = 0.125; F(1,25) = 4.68, p = 0.048]. The founder treatment and adolescent drug treatment model was robustly statistically significant and accounted for an improved 34.7% of the variance [adjusted R2 = 0.347; F(2,25) = 6.17, p = 0.007]. The final model with founder treatment, adolescent drug treatment and reinstatement accounted for a slightly higher amount of the variance at 37.6%, although less statistically significant [adjusted R2 = 0.376; F(3,25) = 4.43, p = 0.014]. Therefore, hierarchical regression revealed that founder treatment along with adolescent drug treatment were the best predictors across all three brain areas. Reinstatement performance in general was slightly less predictive, although it did account for more variance in the IfL cortex than other factors included in the model.

Fig. 3.

Fig. 3

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BDNF (pg/mg) is presented as a function of the standardized predictors in the hierarchical regression analyses. Groups are presented in scatterplots for the (A) VTA (B) PrL and (C) IfL. Adjusted R2 is presented on each figure

Discussion

The findings presented are, to our knowledge, the first to describe nicotine extinction and reinstatement using a CPP paradigm with both male and female Sprague–Dawley rats as subjects, as well as the first to demonstrate changes in relapse-like behavior in a heritable rodent model of increased dopamine D2 receptor sensitivity with relevance to drug abuse vulnerability in schizophrenia. Our results revealed delayed extinction and robust reinstatement of nicotine CPP in F1 generation animals that were the offspring of two NQ-treated founders, behavioral phenotypes not observed in controls. In addition, results of BDNF analyses indicate that F1 generation offspring of two neonatal quinpirole-treated founders display heightened BDNF responses in the VTA and its cortical projections suggesting that extinction and reinstatement of nicotine CPP is correlated with changes in BDNF in these regions, contributing to both delayed extinction and enhanced reinstatement of nicotine CPP.

Behaviorally, three endpoints were analyzed. Post-conditioning results in Fig. 1A confirm past work from our lab indicating enhanced reward associative learning in the QQ animals compared to SS controls. Importantly, post-conditioning results demonstrate that F1 generation offspring, regardless of founder treatment, given nicotine display a significant place preference for contexts paired with the drug. Daily analysis of extinction learning revealed several significant results (Fig. 1B). From the first day of extinction training to the sixth day of extinction training, QQ animals displayed delayed extinction learning compared to controls. On Days 7 and 8 of extinction, there were no group differences, indicating that, though delayed, nicotine treated QQ animals were able to extinguish from nicotine CPP. When administered a challenge dose of nicotine, QQ animals displayed robust reinstatement of previously extinguished CPP (Fig. 1C). Nicotine-treated SS controls did not reinstate following the challenge dose, suggesting that appropriate extinction learning may be protective against relapse-like behaviors.

Extinction learning is known to be an active, inhibitory learning process (Clifton et al. 2017; Goode and Maren 2019). Inhibitory memories formed during extinction training compete with the original drug-association memories for control over behavior, with the more salient memory typically driving behavior (Gass and Chandler 2013; Rafei et al. 2021). In the case of relapse, the more salient memory is assumed to be the drug association memory. Drug associations may be particularly salient in systems with enhanced dopamine sensitivity. Firing of dopamine neurons in the VTA regulates perceived salience by driving neuroplastic changes that enhance the persistence of memories for novel or rewarding stimuli (Kutlu et al. 2021; Osorio-Gómez et al. 2022). Persistent drug-associated memories are implicated in the ability for CPP to be reinstated (McKendrick and Graziane 2020). As such, the enhanced dopamine D2 receptor sensitivity of dopamine D2 receptors found in F1 animals may render drug-associations particularly salient following conditioning, making them more resistant to “masking” by extinction memories formed in the absence of drugs which are perceived to be less salient.

The impaired extinction learning demonstrated by F1 animals is consistent with several clinical and preclinical studies indicating deficits in extinction learning in psychosis. Generally, individuals diagnosed with schizophrenia display deficits in cognitive flexibility, clinically defined as the inability for an individual to update beliefs or alter their behavior in light of new information. Deficits in cognitive flexibility in psychosis manifest in persistent delusions and are often attributed to hypofrontality (Waltz 2017; García-Mieres et al. 2020). Seemingly in line with these findings, individuals diagnosed with schizophrenia have difficulty quitting cigarette smoking and consequently have significantly higher rates of relapse compared to the general population (George et al. 2002, 2008; Cather et al. 2013). Recent studies have shown that the neonatal ventral hippocampal lesion model of schizophrenia displays delayed extinction and greater reinstatement for nicotine self-administration in adulthood in a polydrug study (Sentir et al. 2020). However, direct comparisons cannot be made due to methodological differences, including self-administration as opposed to CPP, use of only male Sprague–Dawley rats, testing during adulthood vs adolescence, and analysis of polydrug use vs nicotine only. Results reported here therefore confirm and expand on previous findings, indicating a consistent deficit in extinction learning that appears to impact relapse-like behavior across multiple models of psychosis, consistent with clinical findings.

The current results are also in line with previous reported findings from our own lab. Our past work has identified an exaggerated BDNF response in the NAcc as a mediator of the enhanced behavioral responses to nicotine that we have demonstrated in both F0 founders and their F1 generation offspring, including behavioral sensitization and CPP (Perna and Brown 2013; Peterson et al. 2017; Gill et al. 2021). In the current study, we suggest that this enhanced BDNF response is generalized to other brain regions critical for reinstatement, contributing to the delayed extinction and subsequently enhanced reinstatement in these animals. It is interesting to note elevations in BDNF appear to correlate with enhanced reinstatement behavior in F1 generation offspring of two neonatal quinpirole-treated founders, implicating increased plasticity and dopamine cell survival in the expression of reinstatement.

The time-course of BDNF mRNA and protein expression has been characterized following a single exposure to cocaine. As an effector immediate early gene, BDNF mRNA becomes elevated within 60 min, though significant changes in protein expression are not detectable until 120 min following injection (Graham et al. 2007). While differences in the duration and type of drug exposure differ between studies, this does suggest that the time-course for changes in BDNF protein that is outlined precludes the idea that the elevated BDNF found in our animals is the result of nicotine challenge during reinstatement. No change in BDNF was found in SS control animals in the current study, further indicating that the elevated BDNF found in QQ animals is likely not the result of an acute response to the nicotine challenge. It is more likely that elevated BDNF that is the result of the initial conditioning is aberrantly maintained at an elevated level, contributing to both the delayed extinction and enhanced reinstatement displayed in these animals. In further support of this idea, augmented BDNF expression via intra-NAcc infusions in the above study was also found to delay extinction and significantly increase reinstatement responding for cocaine in a self-administration paradigm (Graham et al. 2007).

Elevated BDNF activity in the VTA has been suggested to be a permissive factor for long-term potentiation (LTP; Pu et al. 2006). However, drug-induced synaptic plasticity in the VTA is typically transient, implicating counterbalanced long-term depression (LTD) in maintaining homeostasis (Ungless et al. 2001; Huijstee and Mansvelder 2015). Interestingly, BDNF is known to play a role in the maintenance of LTP at synaptic connections as well (Pu et al. 2006), and extinction learning has been shown to be accompanied by reduced BDNF expression (Aicardi et al. 2004; Graham et al. 2007; Kabir et al. 2013; Barker et al. 2015). Interestingly, enhanced dopaminergic signaling via the D2 receptor suppresses LTD (Chen et al. 2010), suggesting that this particular type of synaptic plasticity may be affected in our heritable model as well as clinical conditions linked to enhanced D2 signaling such as schizophrenia. Evidence of disruptions in LTD-like plasticity would be consistent with clinical work, as individuals diagnosed with schizophrenia have been shown to display deficits in LTD-like plasticity (Hasan et al. 2012). Deficits in LTD-like plasticity may therefore underlie the reduced quit success and higher rates of relapse that have been noted in patients with schizophrenia. Speculatively, BDNF protein that becomes elevated in the VTA during conditioning may remain elevated during extinction in QQ animals, preventing LTD from occurring at drug-related synapses. This could indicate maintenance of LTP by BDNF which could render the aberrantly salient drug associations resistant to “masking” by extinction learning, increasing the animals’ susceptibility to relapse. Future work will need to be done to confirm this hypothesis.

Nicotine-specific effects of BDNF in the PrL or IfL cortices have not been well-established. However, it has been shown that dendritic spine plasticity in the PrL cortex is affected by drugs of abuse, and the magnitude of new, stable spines generated following cocaine conditioning positively correlate with the strength of cocaine-paired preference during CPP (Muñoz-Cuevas et al. 2013; Otis and Mueller 2017). Pharmacologically induced reversal of this plasticity was additionally shown to disrupt memory retrieval during CPP testing (Otis and Mueller 2017), suggesting synapses formed by new spines that persist past CPP testing may be required for expression of reinstatement. In addition, deletion of the bdnf gene in the PrL cortex has been shown to reduce cocaine CPP (Choi et al. 2012). We therefore anticipated that reinstatement in the current study would be accompanied by increased BDNF in the PrL cortex in QQ animals. As expected, protein analysis revealed enhanced BDNF in this region in QQ animals given nicotine, correlating with the enhanced reinstatement demonstrated by these animals (Fig. 2B). Similar to the VTA, persistent expression of BDNF in the PrL cortex may aberrantly maintain the salience of drug associations, promoting drug-seeking behaviors in these animals.

Plasticity changes in the IfL cortex induced by extinction learning are necessary to inhibit both conditioned fear and drugseeking behaviors (LaLumiere et al. 2010; Sepulveda-Orengo et al. 2013; Gass et al. 2014; Do-Monte et al. 2015). Infusion of BDNF into the IfL cortex facilitates the extinction of both conditioned fear (Peters et al. 2010), and cocaine CPP (Otis and Mueller 2017). We therefore expected BDNF to be elevated in the IfL cortex of SS animals, facilitating appropriate extinction learning and contributing to the inability for a nicotine priming injection to promote reinstatement in these animals. We additionally expected there to be no significant change in BDNF expression in this region in QQ animals, given that these animals demonstrated delayed acquisition of extinction learning and robust reinstatement. However, protein analysis indicated no significant elevations in BDNF in the IfL cortex of SS animals, but a significant increase in QQ animals conditioned with nicotine (Fig. 2C). These data suggest that simple activation of the IfL cortex is not sufficient to suppress reinstatement of drug seeking. In fact, retrograde tracing using Fos expression has shown that, while there is significantly more dopamine-dependent recruitment of the PrL cortex during reinstatement compared to extinction, activation of the IfL cortex does not differ between extinction training and reinstatement of cocaine seeking (McGlinchey et al. 2016). The elevated BDNF response in both the IfL and PrL cortices in QQ animals given nicotine may reflect an inadequate attempt for the IfL-driven extinction learning to over-ride the PrL-driven reinstatement of drug-seeking.

It is unclear why elevated BDNF was not found in SS animals given nicotine, which demonstrated appropriate extinction learning and a subsequent reduction in reinstatement. However, this discrepancy could be related to the time in which brain tissue was analyzed. Past work by McGlinchey et al. has shown that cocaine self-administration produces an elevation in BDNF protein expression at 120 min that returns to basal levels after 24 h (McGlinchey et al. 2016). It is possible that 60 min following nicotine challenge may have been too early to detect activity-dependent changes in BDNF induced during the final reinstatement trial. It is likely that analysis between 2 and 24 h after either extinction criteria was met or following the reinstatement trial could reveal elevated IfL-BDNF expression in control animals. Further study would be required to more fully elucidate the time course for BDNF expression throughout the extended CPP paradigm in both SS control animals and in the heritable model.

Hierarchical regression analysis revealed that the most predictive model of changes in BDNF was that including both founder treatment and adolescent drug treatment, which was true across all three brain areas analyzed. Interestingly, the founder treatment by itself was not significantly predictive of BDNF in the VTA, which may be related to neurobiological changes produced in this brain area in the F1 generation. It is well-known that the VTA receives primarily glutamatergic inputs (Rizzi et al. 2021), and it may be that F1 generation animals do not have as robust of changes in this area as they may have in the dopaminergic terminals in the frontal cortex. Regardless, founder neonatal drug treatment combined with adolescent drug treatment provided the best predictor of changes in BDNF across three brain areas that play critical roles in associative learning known to occur in CPP.

In conclusion, more complete characterization of aberrant synaptic plasticity and its effects on relapse-like behavior in the heritable model in the future may elucidate potential treatment targets for facilitating extinction learning in schizophrenia. Regarding specific targets, there is evidence that the neurotransmitters glutamate and adenosine mediate the rewarding effects of nicotine and reinstatement to nicotine-seeking, respectively (Castañé et al. 2006; Gipson et al. 2013), and there is substantial evidence of adenosinergic and glutamatergic dysfunction in schizophrenia (Boison et al. 2012; Moghaddam and Javitt 2012; Hu et al. 2015; Menne and Chesworth 2020; Valle-León et al. 2021). Dysregulated adenosinergic and glutamatergic signaling may therefore contribute to the altered relapse-like phenotypes in the heritable model. Interestingly, the dopamine D2 receptor forms a mutually inhibitory triple heteromer in the striatum with both the adenosine A(2A) and metabotropic glutamate type 5 (mGlu5) receptors. Activation of A(2A) or mGlu5 receptors have been shown to decrease D2 signaling, and we have shown in rats neonatally treated with quinpirole that activation of either the A(2A) or mGlu5 blocks enhanced nicotine CPP as well as nicotine-induced increases of BDNF in the NAcc (Gill et al. 2020), and alleviates sensorimotor gating deficits, a behavioral hallmark of psychosis (Brown et al. 2020, 2021). Studies in the future will target these receptors to analyze their therapeutic efficacy toward relapse-like behaviors in the novel heritable model of drug abuse vulnerability in psychosis.

Future studies will also seek to elucidate the route of epigenetic transmission between rats neonatally treated with quinpirole and their offspring. Due to the influence of heritable factors in schizophrenia, this could elucidate potential mechanisms of epigenetic transmission that contribute to the etiology of the disorder. Previous studies in our lab have suggested a greater contribution of the phenotype from male animals given neonatal quinpirole treatment as compared to their female counterparts, such that offspring of a female given neonatal quinpirole treatment and a male administered neonatal saline display nicotine CPP that is equivalent to controls (Gill et al. 2021). Chronic 15-day treatment with quinpirole in adult mice has been shown to affect methylation of a lysine residue on histone 3, mediating transcriptional silencing of genes (Brami-Cherrier et al. 2014), suggesting that this may be a potential epigenetic mechanism influencing phenotypic changes in F1 generation offspring of rats administered neonatal quinpirole treatment. Future studies will analyze DNA methylation of male spermatozoa and female oocytes to identify differences in methylation cites across the germ cell genome in F0 founders as well as their F1 generation offspring. Analysis of DNA methyltransferases and other permissive and repressive mechanisms not related to methylation that are known to regulate gene expression will also be analyzed for a comprehensive determination of possible mechanisms of epigenetic transmission in F1 generation animals.

Funding

This project was supported in part by NIH R15DA046926 grant awarded to RWB.

Footnotes

Conflict of interest All authors claim no conflicts of interest.

Data availability

The data that supports the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that supports the findings of this study are available from the corresponding author upon reasonable request.

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