Behavioral and Serotonergic Changes in the Frontal Cortex Following Methamphetamine Self-Administration

Behavioral and Serotonergic Changes in the Frontal Cortex Following Methamphetamine... Background: Methamphetamine use is associated with a variety of negative health outcomes, including psychosis. The frontal cortex serotonin receptors are thought to contribute to psychosis-like behaviors. This study investigated changes in serotonergic markers in the frontal cortex following methamphetamine self-administration and hallucinogenic drug-induced behavior.  Methods: Consistent with previously published studies, freely cycling male and female rats were allowed to self-administer methamphetamine (males: 0.12 mg/infusion; females: 0.09 mg/infusion) or saline (10 µL) for 7 days. On the day following self- administration or following 10 days of extinction training, animals were given the serotonin 2A/2C agonist, 1-(2,5-Dimethoxy- 4-iodophenyl)-2-aminopropane hydrochloride (2  mg/kg, i.p.), and head twitches were analyzed.  Autoradiography was also used to assess serotonin receptors and transporters in the frontal cortex following self-administration. Results: Methamphetamine self-administration led to an increase in DOI-induced head-twitch behavior compared to saline only on the day following self-administration. Increases in serotonin receptors in the orbitofrontal cortex and decreases in serotonin transporters in the orbitofrontal cortex and infralimbic cortex were observed following methamphetamine self- administration as assessed by autoradiography.  Conclusions: Methamphetamine self-administration was associated with serotonergic alterations in the frontal cortex, which may underlie behavioral changes related to methamphetamine-associated psychosis. Keywords: females, methamphetamine, self-administration, serotonin-2 receptors Introduction Methamphetamine (METH) abuse is a serious worldwide health In approximately 30% of cases of METH-associated psychosis, problem. Epidemiology studies suggest approximately 40% of symptoms persisted for up to 6  months, whereas 10% to 25% METH users display psychiatric symptoms, including schizo- of cases had symptoms that persisted for more than 6 months phrenia-like symptoms (Glasner-Edwards and Mooney, 2014). (Hsieh et al., 2014). Understanding the underlying cause of these Recreational METH use was associated with a 2-fold increase in psychiatric symptoms is imperative to understanding METH- developing psychotic symptoms (McKetin et al., 2010). In many associated psychosis and developing effective treatments. cases of METH-associated psychosis, symptoms resolve soon Hallucinations are one symptom of METH-associated psych- after abstinence, but a smaller subset of patients have symp- osis (Zarrabi et  al., 2016), which may be due to an increase in toms that persist after continued abstinence (Hsieh et al., 2014). serotonin (5-HT) activity (Müller et al., 2015). Previous research Received: December 5, 2017; Revised: April 11, 2018; Accepted: May 11, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 1 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 2 | International Journal of Neuropsychopharmacology, 2018 suggests the 5-HT2 receptors play an important role in drug- Committee, in accordance with the National Institutes of Health associated hallucinations (Smith et  al., 2014). Drugs that Guide for the Care and Use of Laboratory Animals. stimulate the 5-HT2 receptors such as the psychedelics or 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochlor- Food Training, Self-Administration, and Extinction ide (DOI) produce hallucinations in humans and head-twitch Training behaviors in rodents (Halberstadt and Geyer, 2013). In humans, Food training, self-administration, and extinction training blockade of the 5-HT2 receptors with the antagonist ketanserin reduces the subjective effects of lysergic acid diethylamide occurred in an operant chamber (Coulbourn Instruments) as described previously (Johansen et  al., 2017). Prior to catheter (Preller et al., 2017). Further, many atypical antipsychotics work in part as an inverse agonist or antagonist to the 5-HT2A recep- surgery rats received 4 (14  h/night) food training sessions dur - ing which pressing the active lever resulted in a 45-mg food tor (Bozymski et  al., 2017), which may in turn reduce psych- osis and hallucination-like symptoms. These findings suggest pellet. Rats underwent 7  days of self-administration (8  h/ses- sion; FR1; male: 0.12  mg/infusion or female: 0.09  mg/infusion that the serotonergic system may play an important role in hallucinations. racemic-METH expressed as free-base; or saline) during the light cycle. For each active lever press, an infusion pump delivered Previously, we reported that METH self-administration in male rats decreases 5-HT content in the frontal cortex 10 µL of METH or saline over a 5-second duration. During this period, both levers were retracted. Following the infusion, the (McFadden et al., 2013). Previous research suggests the 5-HT2A receptor expression is inversely related to 5-HT levels or 5-HT levers remained retracted for an additional 20 seconds. Pressing the inactive lever resulted in no programmed consequences, transporter (SERT) densities in the frontal cortex (Cahir et  al., 2007; Urban et  al., 2012). The decrease in 5-HT content after although it was recorded. Each animal’s daily METH intake was normalized to their daily body weight (mg/kg). A subset of ani- METH self-administration may lead to alterations in 5-HT2 receptors in the frontal cortex and hallucinogenic drug-associ- mals continued to receive 10 days of extinction training (2 h/d). Animals were tethered and placed in the operant chambers as ated behaviors following METH use. The purpose of this study was to investigate changes in hal- during self-administration, but lever presses resulted in no con- sequence, although they were recorded. lucinogenic drug-induced behavior following METH self-admin- istration in male and female rats. Given prior studies in humans suggesting METH use may lead to drug-associated psychosis, DOI-Induced Behavior the goals of this study were to: (1) establish if prior METH self- Animals underwent behavioral testing on the day following administration in rats would lead to behavioral changes using self-administration or after 10 days of extinction training. Rats a previously validated model of hallucinogenic drug-associated received a 2-mg/kg injection (i.p.) of DOI. The dose of DOI was behaviors, DOI-induced head twitches (González-Maeso et  al., carefully chosen based on previous work suggesting it pro- 2007; Fantegrossi et al., 2010); (2) establish if these changes per - duced robust head twitch behavior (González-Maeso et al., 2007; sisted following extinction training; (3) establish if these changes Fantegrossi et  al., 2010) and based on preliminary studies in differed by sex in freely cycling animals (i.e., neither castrated our laboratory suggesting it robustly increased head twitches nor ovariectomized animals); and (4) gain insight into the pos- in both sexes. Previous studies have found DOI has a preferen- sible changes in the cortex that may be associated with changes tial binding affinity to the 5-HT2A receptor (5-HT2A Ki: 0.7 nM; in hallucinogenic drug-associated behaviors. To test this, rats 5-HT2C Ki: 2.4 nM; Nelson et al., 1999). Animals were then placed were allowed to self-administer METH or saline for 7  days. On in a clean cage, recorded for 30 minutes for further assessment the day following self-administration or following 10  days of of head twitch behavior, and returned to their home cage. Head extinction training, animals were given the 5-HT2A/2C agon- twitches were assessed by a blinded coder. ist, DOI, and head twitches were analyzed. To understand the neurochemical changes underlying these responses, autoradi- ography was used to assess changes in the 5-HT2 and receptor Autoradiography SERT in the frontal cortex. Findings suggest METH self-admin- istration was associated with an increase in 5-HT2 receptors Rats were killed 1 hour after the last self-administration session and a decrease in SERT in the orbital frontal cortex (OFC),which via rapid decapitation to avoid anesthesia-induced alterations in may underlie behavioral changes related to METH-associated neurotransmitters (see Kalén et al., 1988 T ; ao et al., 1994). Brains psychosis. were removed, rapidly frozen on dry ice, and stored at -80°C until sliced. Coronal slices (12 µM) of the frontal cortex were sec- tioned on the cryostat. To assess 5-HT2 receptors in the frontal Methods cortex, [3H]-ketanserin was used as described in Preece et  al., 2004. Briefly, slides were incubated in 2  nM of [3H]-ketanserin Animals containing 100  nM prazosin for 15 minutes. Nonspecific bind- Adult male and female Sprague-Dawley rats (approximately ing was determined by the addition of M100907 (1 µM) to the [3H]-ketanserin buffer. Following 3 washes and dryings, slides 56  days old; Charles River Laboratories or Invigo) were housed 2 rats/cage. Following surgery, each rat was individually housed were placed on film and developed after 12 weeks of exposure. [125 I]-RTI-55 was used to assess SERT densities as described in a transparent plastic cage. Water was available in their home cage ad libitum. During food training, rats were food restricted in Furlong et al., 2016. Briefly, slides were incubated for 2 hours in 25 pmol of [125 I]-RTI-55 containing 200  nM GBR12935. such that no rat dropped below 90% of their starting body weight. Rats were maintained under the same light/dark cycle Fluoxetine (100  nM) was added to the [125 I]-RTI-55 to assess nonspecific binding. Following 3 washes and dryings, slides in the animal facility and in the operant chambers. Females were freely cycling. Animals were killed by decapitation. All were placed on a film and developed after a 15-hour exposure. Autoradiographic images were captured and analyzed in ImageJ experiments were approved by the University of Utah’s or the University of South Dakota’s Institutional Animal Care and Use by blinded experimenters. Densitometric analysis was used to Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 McFadden et al. | 3 determine average density values of the prelimbic (PrL), infral- Extinction: F(6,72) = 30.30, P < .05, Figure  1B]. No sex differences imbic (IL), and OFC across 2 sections (between +2.7 and 4.0 mm were observed in METH intake [Behavioral No Extinction: from bregma). Samples with tears in the region of interest were F(1,72) = 0.79, ns; Behavioral Extinction: F(1,72) = 0.03, ns] nor did excluded from analyses. sex interact with day [Behavioral No Extinction: F(6,72) = 0.26, ns; Behavioral Extinction: F(6,72)= 0.16, ns]. Self-administration for the autoradiography findings has been previously published (see Statistical Analysis Figure 1 of Johansen et al., 2017) but followed a similar pattern. Statistical analysis was conducted in SAS Studio or GraphPad Animals were treated with a 2-mg/kg (i.p.) injection of DOI, Prism 7.  Statistical analyses among groups were conducted and head twitches were counted for 30 minutes following the using a 2-way ANOVA or repeated-measures ANOVA followed injection. METH self-administering rats had a greater number by Tukey’s posthoc analyses. Posthoc analyses can be found in of DOI-induced head twitches compared to saline self-admin- the supplemental information. The data represent means ± SEM istering rats when tested after the last self-administration ses- of 4 to 9 rats/group. Only animals with patient catheters were sion [Drug: F(1,23) = 11.92, P < .05; Drug x Sex: F(1,23) = 0.04, ns; included in analysis. Only METH rats that met the criteria for Figure  1C]. Females also had a greater number of DOI-induced high pressers (1: average of >10 active lever presses per day; and head twitches compared with males [F(1,23)= 7.18, P < .05]. When 2: the ratio of active/inactive lever presses of 2:1) were included 10 days of extinction training were given following self-admin- in analysis, resulting in the exclusion of one male for the auto- istration, METH and saline self-administering rats had a similar radiography experiments and one male for the behavioral number of DOI-induced head twitches [Drug: F(1,21)= 0.00, ns; experiments. An additional 4 males were excluded due to equip- Drug × Sex: F(1,21) = 1.37, ns; Figure 1D]. However, sex differences ment failure during one self-administration session. were observed [Sex: F(1,21) = 11.18, P < .05]. 5-HT2 receptors were altered in the frontal cortex of METH rats following self-administration as assessed by [3H]-ketanserin Results autoradiography (Supplemental Figure A). Because changes in In all cases of self-administration, METH animals escalated head twitch behavior were not observed following extinction intake over the course of self-administration [Behavioral training, changes in the frontal cortex were not investigated fol- No Extinction: F(6,72) = 45.72, P < .05, Figure  1A; Behavioral lowing extinction training. Higher 5-HT2 receptors were observed Figure  1. Methamphetamine (METH) intake and 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced changes in behavior. Animals were allowed to self-administer METH or saline for 7 days. METH intake (mg/kg) escalated over time but did not differ between the sexes in the animals tested immediately after self-administration (A) or following extinction training (B). Animals were injected with 2 mg/kg DOI. Head twitch behavior was quantified for 30 minutes following injection in animals tested after self-administration (C) or extinction training (D). (A, C) Saline Female: n = 6; METH F emale: n = 7; Saline Male: n = 7; METH Male: n = 7. (B, D) Saline Female: n = 5; METH Female: n = 5; Saline Male: n = 6; METH Male: n = 9. *P < .05 METH vs Saline; +P < .05 Female vs Male. Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 4 | International Journal of Neuropsychopharmacology, 2018 in the OFC [Drug: F(1,38)= 13.08, P < .05], and a trend towards head-twitch behavior is primarily mediated by the 5-HT2A higher receptors in the PrL occurred [Drug: F(1,36) = 2.88, P < .10], receptor (Gonzalez-Maeso et  al., 2007), but other receptors but no differences were found in the IL [Drug: F(1,36) = 0.00, ns] including the 5-HT2C receptor may also modulate this behav- in METH compared with saline self-administering rats (Table 1 ). ior (Fantegrossi et al., 2010). More specifically, cortical expression No sex differences were noted [sex: OFC: F(1,38)= 3.24, P = .08; of the 5-HT2A receptor is necessary to induce head twitches by PrL: F(1,36) = 0.33, ns; IL: F(1,36) = 0.02, ns; Sex x Drug: OFC: hallucinogenic drugs (González-Maeso et  al., 2007). Moreover, F(1,38) = 0.46, ns; PrL: F(1,36) = 0.09, ns; IL:F(1,36) = 0.39, ns]. this behavior may be mediated by stimulating heterocomplexes Serotonin transporters were also altered in the frontal cor - formed by the 5-HT2A and metabotropic glutamate-2 receptors tex of METH rats following self-administration as assessed (mGlu2), for mGlu2 knockout mice have reduced head twitch by [125 I]-RTI-55 autoradiography (Supplemental Figure B). behavior (Moreno et al., 2011; Holloway et al., 2016). The increase Lower SERT in METH self-administering rats was observed in in head twitch behavior in METH self-administering rats in the OFC [F(1,29) = 4.67, P < .05] and IL [F(1,25) = 8.16, P < .05], but the current study may not only be due to the slight increase in no statistical differences were found in the PrL [F(1,26) = 2.19, 5-HT2 receptors in the frontal cortex, but rather to an increase ns; Table  1]. No sex differences were noted [Sex: OFC: in the formation of 5-HT2A/mGlu2 heterocomplexes. Future F(1,29) = 0.39, ns; PrL: F(1,26) = 2.86, ns; IL: F(1,25) = 0.25, ns], studies are needed to investigate the formation of these com- but a significant Sex× Drug interaction occurred in the IL, plexes following METH self-administration. suggesting that these METH-induced decreases were specific Changes to 5-HT2 receptors were inversely related to to the males [IL: F(1,25)= 5.85, P < .05; OFC: F(1,29) = 2.79, ns; changes in SERT in the OFC. Previous research suggests that PrL: F(1,26) = 0.70, ns]. reducing 5-HT content via dietary tryptophan depletion for 3 weeks leads to an increase in 5-HT2A receptors in the cortex but not striatum (Cahir et al., 2007). Further, chronic human MDMA Discussion users have reduced SERT availability and increased 5-HT2A Overall, our findings suggest that prior METH self-administra- receptor binding in the cortex (Urban et al., 2012). We speculate that the increase in 5-HT2 receptor autoradiography following tion increases the responsiveness to a 5-HT2 agonist shortly after self-administration but not after extinction training, as self-administration may be associated with the decrease in SERT in the OFC and perhaps 5-HT content in the frontal cortex. evident by the behavioral responses to DOI. In separate animals, autoradiography was performed to assess changes in seroton- Previous research in our laboratory suggests that 5-HT content is reduced in the frontal cortex following METH self-administra- ergic markers in the frontal cortex when sacrificed shortly after the last self-administration session. Results revealed a decrease tion in males (McFadden et al., 2013). This may be due to a loss of serotonergic neuronal terminal integrity in the frontal cortex as in SERT autoradiography and an increase in 5-HT2 receptor autoradiography in METH self-administering animals compared reflected by the reduction in SERT, which in turn may lead to an upregulation in 5-HT2 receptors, especially in the OFC. with saline animals in the OFC. These changes may contribute to the behavioral changes observed. Females also had greater head twitch behavior compared with males regardless of self-administration group. This may Changes to the 5-HT2 receptors in the frontal cortex may contribute to hallucinations associated with METH use. The be due to sex hormones. Estradiol benzoate replacement ther - apy in ovariectomized rats results in increases in 5-HT2A recep- self-administration of METH lead to an increase in DOI-induced head twitches compared to saline self-administering animals. tors in the frontal cortex (Sumner et al., 1999). Further, estradiol replacement therapy in postmenopausal women has been In addition to the increase in head twitch behavior, an increase in 5-HT2 receptors in the OFC was observed. Because METH shown to increase 5-HT2A receptor binding in the frontal cortex (Kugaya et al., 2003). The sex differences observed in the current increases 5-HT activity rather than binding to specific 5-HT receptors (Müller et al., 2015), the less specific 5-HT2 agonist was study may have been due to sex differences in estrogen levels. Although it was beyond the scope of the current study investi- used to more closely mimic that of METH. Although DOI and ketanserin both have a higher affinity for the 5-HT2A receptor gating METH-induced changes in and hallucinogenic drug-asso- ciated behaviors, future studies are warranted to investigate the compared with the 5-HT2C receptor (Nelson et al., 1999; Rashid et al., 2003), one limitation of this study is that these drugs bind influence of sex hormones on 5-HT2 receptor expression and behavioral pharmacology. to both 5-HT2 receptors. However, the changes observed in both behavior and autoradiography warrant the need for future stud- The behavioral changes induced by METH self-administra- tion were not long lasting. This is consistent with clinical reports ies to investigate the specific 5-HT2 receptor subtype underlying these changes. that in the majority of patients with METH-associated psych- osis, these symptoms go into remission shortly after achieving Previous studies have investigated the pharmacology under - lying drug-induced head twitch behavior. Studies suggest this abstinence from drug use (Zorick et al., 2010; Hsieh et al., 2014). Table 1. Frontal Cortex Autoradiograph (% of Saline Male) in Animals Sacrificed 1 Hour after Self-Administration Ligand Region Saline Male METH Male Saline Female METH Female [3H] Ketanserin PrL# 100.00 ± 2.28 (10) 102.65 ± 1.99 (10) 100.52 ± 1.59 (11) 104.29 ± 1.60 (9) IL 100.00 ± 3.45 (10) 102.16 ± 2.66 (10) 101.52 ± 2.30 (11) 99.78 ± 4.11 (10) OFC* 100.00 ± 1.86 (11) 106.22 ± 1.92 (10) 102.37 ± 2.36 (11) 111.47 ± 2.26 (9) [125 I] RTI-55 PrL 100.00 ± 1.53 (4) 87.59 ± 3.79 (9) 104.56 ± 5.83 (8) 101.13 ± 5.30 (9) IL* 100.00 ± 1.88 (4) 80.96 ± 3.97 (8) 93.06 ± 3.33 (8) 91.48 ± 2.85 (9) OFC* 100.00 ± 3.56 (6) 89.72 ± 2.24 (10) 97.19 ± 2.55 (8) 95.87 ± 2.55 (9) Mean ± SEM (n). P < .10 METH vs saline; & P < .05 saline male vs METH male. *P < .05 METH vs saline; Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 McFadden et al. | 5 In an in-patient sample of METH users, the majority of psych- Fantegrossi WE, Simoneau J, Cohen MS, Zimmerman SM, Henson otic symptoms resolved within 1 week of abstinence from the CM, Rice KC, Woods JH (2010) Interaction of 5-HT2A and 5-HT2C drug (Zorick et al., 2010). The results of the current study suggest receptors in R(-)-2,5-dimethoxy-4-iodoamphetamine-elicited that changes in 5-HT2-mediated behavior diminish quickly after head twitch behavior in mice. J Pharmacol Exp Ther 335:728–734. abstinence from METH use. Other clinical studies suggest that Furlong TM, Leavitt LS, Keefe KA, Son JH (2016) up to 30% of individuals with METH-associated psychosis had Methamphetamine-, d-amphetamine-, and p-chloroamphet- symptoms that persisted up to 6 months (Hsieh et al., 2014), but amine-induced neurotoxicity differentially effect impulsive it is unclear if these persisting symptoms are associated with responding on the stop-signal task in rats. Neurotox Res the duration of drug use. Future studies can alter the duration 29:569–582. of METH self-administration to assess if this leads to a subset of Glasner-Edwards S, Mooney LJ (2014) Methamphetamine animals with persistent behavioral changes. Alternatively, it can psychosis: epidemiology and management. 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Behavioral and Serotonergic Changes in the Frontal Cortex Following Methamphetamine Self-Administration

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Abstract

Background: Methamphetamine use is associated with a variety of negative health outcomes, including psychosis. The frontal cortex serotonin receptors are thought to contribute to psychosis-like behaviors. This study investigated changes in serotonergic markers in the frontal cortex following methamphetamine self-administration and hallucinogenic drug-induced behavior.  Methods: Consistent with previously published studies, freely cycling male and female rats were allowed to self-administer methamphetamine (males: 0.12 mg/infusion; females: 0.09 mg/infusion) or saline (10 µL) for 7 days. On the day following self- administration or following 10 days of extinction training, animals were given the serotonin 2A/2C agonist, 1-(2,5-Dimethoxy- 4-iodophenyl)-2-aminopropane hydrochloride (2  mg/kg, i.p.), and head twitches were analyzed.  Autoradiography was also used to assess serotonin receptors and transporters in the frontal cortex following self-administration. Results: Methamphetamine self-administration led to an increase in DOI-induced head-twitch behavior compared to saline only on the day following self-administration. Increases in serotonin receptors in the orbitofrontal cortex and decreases in serotonin transporters in the orbitofrontal cortex and infralimbic cortex were observed following methamphetamine self- administration as assessed by autoradiography.  Conclusions: Methamphetamine self-administration was associated with serotonergic alterations in the frontal cortex, which may underlie behavioral changes related to methamphetamine-associated psychosis. Keywords: females, methamphetamine, self-administration, serotonin-2 receptors Introduction Methamphetamine (METH) abuse is a serious worldwide health In approximately 30% of cases of METH-associated psychosis, problem. Epidemiology studies suggest approximately 40% of symptoms persisted for up to 6  months, whereas 10% to 25% METH users display psychiatric symptoms, including schizo- of cases had symptoms that persisted for more than 6 months phrenia-like symptoms (Glasner-Edwards and Mooney, 2014). (Hsieh et al., 2014). Understanding the underlying cause of these Recreational METH use was associated with a 2-fold increase in psychiatric symptoms is imperative to understanding METH- developing psychotic symptoms (McKetin et al., 2010). In many associated psychosis and developing effective treatments. cases of METH-associated psychosis, symptoms resolve soon Hallucinations are one symptom of METH-associated psych- after abstinence, but a smaller subset of patients have symp- osis (Zarrabi et  al., 2016), which may be due to an increase in toms that persist after continued abstinence (Hsieh et al., 2014). serotonin (5-HT) activity (Müller et al., 2015). Previous research Received: December 5, 2017; Revised: April 11, 2018; Accepted: May 11, 2018 © The Author(s) 2018. Published by Oxford University Press on behalf of CINP. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http:// creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, 1 provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 2 | International Journal of Neuropsychopharmacology, 2018 suggests the 5-HT2 receptors play an important role in drug- Committee, in accordance with the National Institutes of Health associated hallucinations (Smith et  al., 2014). Drugs that Guide for the Care and Use of Laboratory Animals. stimulate the 5-HT2 receptors such as the psychedelics or 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochlor- Food Training, Self-Administration, and Extinction ide (DOI) produce hallucinations in humans and head-twitch Training behaviors in rodents (Halberstadt and Geyer, 2013). In humans, Food training, self-administration, and extinction training blockade of the 5-HT2 receptors with the antagonist ketanserin reduces the subjective effects of lysergic acid diethylamide occurred in an operant chamber (Coulbourn Instruments) as described previously (Johansen et  al., 2017). Prior to catheter (Preller et al., 2017). Further, many atypical antipsychotics work in part as an inverse agonist or antagonist to the 5-HT2A recep- surgery rats received 4 (14  h/night) food training sessions dur - ing which pressing the active lever resulted in a 45-mg food tor (Bozymski et  al., 2017), which may in turn reduce psych- osis and hallucination-like symptoms. These findings suggest pellet. Rats underwent 7  days of self-administration (8  h/ses- sion; FR1; male: 0.12  mg/infusion or female: 0.09  mg/infusion that the serotonergic system may play an important role in hallucinations. racemic-METH expressed as free-base; or saline) during the light cycle. For each active lever press, an infusion pump delivered Previously, we reported that METH self-administration in male rats decreases 5-HT content in the frontal cortex 10 µL of METH or saline over a 5-second duration. During this period, both levers were retracted. Following the infusion, the (McFadden et al., 2013). Previous research suggests the 5-HT2A receptor expression is inversely related to 5-HT levels or 5-HT levers remained retracted for an additional 20 seconds. Pressing the inactive lever resulted in no programmed consequences, transporter (SERT) densities in the frontal cortex (Cahir et  al., 2007; Urban et  al., 2012). The decrease in 5-HT content after although it was recorded. Each animal’s daily METH intake was normalized to their daily body weight (mg/kg). A subset of ani- METH self-administration may lead to alterations in 5-HT2 receptors in the frontal cortex and hallucinogenic drug-associ- mals continued to receive 10 days of extinction training (2 h/d). Animals were tethered and placed in the operant chambers as ated behaviors following METH use. The purpose of this study was to investigate changes in hal- during self-administration, but lever presses resulted in no con- sequence, although they were recorded. lucinogenic drug-induced behavior following METH self-admin- istration in male and female rats. Given prior studies in humans suggesting METH use may lead to drug-associated psychosis, DOI-Induced Behavior the goals of this study were to: (1) establish if prior METH self- Animals underwent behavioral testing on the day following administration in rats would lead to behavioral changes using self-administration or after 10 days of extinction training. Rats a previously validated model of hallucinogenic drug-associated received a 2-mg/kg injection (i.p.) of DOI. The dose of DOI was behaviors, DOI-induced head twitches (González-Maeso et  al., carefully chosen based on previous work suggesting it pro- 2007; Fantegrossi et al., 2010); (2) establish if these changes per - duced robust head twitch behavior (González-Maeso et al., 2007; sisted following extinction training; (3) establish if these changes Fantegrossi et  al., 2010) and based on preliminary studies in differed by sex in freely cycling animals (i.e., neither castrated our laboratory suggesting it robustly increased head twitches nor ovariectomized animals); and (4) gain insight into the pos- in both sexes. Previous studies have found DOI has a preferen- sible changes in the cortex that may be associated with changes tial binding affinity to the 5-HT2A receptor (5-HT2A Ki: 0.7 nM; in hallucinogenic drug-associated behaviors. To test this, rats 5-HT2C Ki: 2.4 nM; Nelson et al., 1999). Animals were then placed were allowed to self-administer METH or saline for 7  days. On in a clean cage, recorded for 30 minutes for further assessment the day following self-administration or following 10  days of of head twitch behavior, and returned to their home cage. Head extinction training, animals were given the 5-HT2A/2C agon- twitches were assessed by a blinded coder. ist, DOI, and head twitches were analyzed. To understand the neurochemical changes underlying these responses, autoradi- ography was used to assess changes in the 5-HT2 and receptor Autoradiography SERT in the frontal cortex. Findings suggest METH self-admin- istration was associated with an increase in 5-HT2 receptors Rats were killed 1 hour after the last self-administration session and a decrease in SERT in the orbital frontal cortex (OFC),which via rapid decapitation to avoid anesthesia-induced alterations in may underlie behavioral changes related to METH-associated neurotransmitters (see Kalén et al., 1988 T ; ao et al., 1994). Brains psychosis. were removed, rapidly frozen on dry ice, and stored at -80°C until sliced. Coronal slices (12 µM) of the frontal cortex were sec- tioned on the cryostat. To assess 5-HT2 receptors in the frontal Methods cortex, [3H]-ketanserin was used as described in Preece et  al., 2004. Briefly, slides were incubated in 2  nM of [3H]-ketanserin Animals containing 100  nM prazosin for 15 minutes. Nonspecific bind- Adult male and female Sprague-Dawley rats (approximately ing was determined by the addition of M100907 (1 µM) to the [3H]-ketanserin buffer. Following 3 washes and dryings, slides 56  days old; Charles River Laboratories or Invigo) were housed 2 rats/cage. Following surgery, each rat was individually housed were placed on film and developed after 12 weeks of exposure. [125 I]-RTI-55 was used to assess SERT densities as described in a transparent plastic cage. Water was available in their home cage ad libitum. During food training, rats were food restricted in Furlong et al., 2016. Briefly, slides were incubated for 2 hours in 25 pmol of [125 I]-RTI-55 containing 200  nM GBR12935. such that no rat dropped below 90% of their starting body weight. Rats were maintained under the same light/dark cycle Fluoxetine (100  nM) was added to the [125 I]-RTI-55 to assess nonspecific binding. Following 3 washes and dryings, slides in the animal facility and in the operant chambers. Females were freely cycling. Animals were killed by decapitation. All were placed on a film and developed after a 15-hour exposure. Autoradiographic images were captured and analyzed in ImageJ experiments were approved by the University of Utah’s or the University of South Dakota’s Institutional Animal Care and Use by blinded experimenters. Densitometric analysis was used to Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 McFadden et al. | 3 determine average density values of the prelimbic (PrL), infral- Extinction: F(6,72) = 30.30, P < .05, Figure  1B]. No sex differences imbic (IL), and OFC across 2 sections (between +2.7 and 4.0 mm were observed in METH intake [Behavioral No Extinction: from bregma). Samples with tears in the region of interest were F(1,72) = 0.79, ns; Behavioral Extinction: F(1,72) = 0.03, ns] nor did excluded from analyses. sex interact with day [Behavioral No Extinction: F(6,72) = 0.26, ns; Behavioral Extinction: F(6,72)= 0.16, ns]. Self-administration for the autoradiography findings has been previously published (see Statistical Analysis Figure 1 of Johansen et al., 2017) but followed a similar pattern. Statistical analysis was conducted in SAS Studio or GraphPad Animals were treated with a 2-mg/kg (i.p.) injection of DOI, Prism 7.  Statistical analyses among groups were conducted and head twitches were counted for 30 minutes following the using a 2-way ANOVA or repeated-measures ANOVA followed injection. METH self-administering rats had a greater number by Tukey’s posthoc analyses. Posthoc analyses can be found in of DOI-induced head twitches compared to saline self-admin- the supplemental information. The data represent means ± SEM istering rats when tested after the last self-administration ses- of 4 to 9 rats/group. Only animals with patient catheters were sion [Drug: F(1,23) = 11.92, P < .05; Drug x Sex: F(1,23) = 0.04, ns; included in analysis. Only METH rats that met the criteria for Figure  1C]. Females also had a greater number of DOI-induced high pressers (1: average of >10 active lever presses per day; and head twitches compared with males [F(1,23)= 7.18, P < .05]. When 2: the ratio of active/inactive lever presses of 2:1) were included 10 days of extinction training were given following self-admin- in analysis, resulting in the exclusion of one male for the auto- istration, METH and saline self-administering rats had a similar radiography experiments and one male for the behavioral number of DOI-induced head twitches [Drug: F(1,21)= 0.00, ns; experiments. An additional 4 males were excluded due to equip- Drug × Sex: F(1,21) = 1.37, ns; Figure 1D]. However, sex differences ment failure during one self-administration session. were observed [Sex: F(1,21) = 11.18, P < .05]. 5-HT2 receptors were altered in the frontal cortex of METH rats following self-administration as assessed by [3H]-ketanserin Results autoradiography (Supplemental Figure A). Because changes in In all cases of self-administration, METH animals escalated head twitch behavior were not observed following extinction intake over the course of self-administration [Behavioral training, changes in the frontal cortex were not investigated fol- No Extinction: F(6,72) = 45.72, P < .05, Figure  1A; Behavioral lowing extinction training. Higher 5-HT2 receptors were observed Figure  1. Methamphetamine (METH) intake and 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride (DOI)-induced changes in behavior. Animals were allowed to self-administer METH or saline for 7 days. METH intake (mg/kg) escalated over time but did not differ between the sexes in the animals tested immediately after self-administration (A) or following extinction training (B). Animals were injected with 2 mg/kg DOI. Head twitch behavior was quantified for 30 minutes following injection in animals tested after self-administration (C) or extinction training (D). (A, C) Saline Female: n = 6; METH F emale: n = 7; Saline Male: n = 7; METH Male: n = 7. (B, D) Saline Female: n = 5; METH Female: n = 5; Saline Male: n = 6; METH Male: n = 9. *P < .05 METH vs Saline; +P < .05 Female vs Male. Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 4 | International Journal of Neuropsychopharmacology, 2018 in the OFC [Drug: F(1,38)= 13.08, P < .05], and a trend towards head-twitch behavior is primarily mediated by the 5-HT2A higher receptors in the PrL occurred [Drug: F(1,36) = 2.88, P < .10], receptor (Gonzalez-Maeso et  al., 2007), but other receptors but no differences were found in the IL [Drug: F(1,36) = 0.00, ns] including the 5-HT2C receptor may also modulate this behav- in METH compared with saline self-administering rats (Table 1 ). ior (Fantegrossi et al., 2010). More specifically, cortical expression No sex differences were noted [sex: OFC: F(1,38)= 3.24, P = .08; of the 5-HT2A receptor is necessary to induce head twitches by PrL: F(1,36) = 0.33, ns; IL: F(1,36) = 0.02, ns; Sex x Drug: OFC: hallucinogenic drugs (González-Maeso et  al., 2007). Moreover, F(1,38) = 0.46, ns; PrL: F(1,36) = 0.09, ns; IL:F(1,36) = 0.39, ns]. this behavior may be mediated by stimulating heterocomplexes Serotonin transporters were also altered in the frontal cor - formed by the 5-HT2A and metabotropic glutamate-2 receptors tex of METH rats following self-administration as assessed (mGlu2), for mGlu2 knockout mice have reduced head twitch by [125 I]-RTI-55 autoradiography (Supplemental Figure B). behavior (Moreno et al., 2011; Holloway et al., 2016). The increase Lower SERT in METH self-administering rats was observed in in head twitch behavior in METH self-administering rats in the OFC [F(1,29) = 4.67, P < .05] and IL [F(1,25) = 8.16, P < .05], but the current study may not only be due to the slight increase in no statistical differences were found in the PrL [F(1,26) = 2.19, 5-HT2 receptors in the frontal cortex, but rather to an increase ns; Table  1]. No sex differences were noted [Sex: OFC: in the formation of 5-HT2A/mGlu2 heterocomplexes. Future F(1,29) = 0.39, ns; PrL: F(1,26) = 2.86, ns; IL: F(1,25) = 0.25, ns], studies are needed to investigate the formation of these com- but a significant Sex× Drug interaction occurred in the IL, plexes following METH self-administration. suggesting that these METH-induced decreases were specific Changes to 5-HT2 receptors were inversely related to to the males [IL: F(1,25)= 5.85, P < .05; OFC: F(1,29) = 2.79, ns; changes in SERT in the OFC. Previous research suggests that PrL: F(1,26) = 0.70, ns]. reducing 5-HT content via dietary tryptophan depletion for 3 weeks leads to an increase in 5-HT2A receptors in the cortex but not striatum (Cahir et al., 2007). Further, chronic human MDMA Discussion users have reduced SERT availability and increased 5-HT2A Overall, our findings suggest that prior METH self-administra- receptor binding in the cortex (Urban et al., 2012). We speculate that the increase in 5-HT2 receptor autoradiography following tion increases the responsiveness to a 5-HT2 agonist shortly after self-administration but not after extinction training, as self-administration may be associated with the decrease in SERT in the OFC and perhaps 5-HT content in the frontal cortex. evident by the behavioral responses to DOI. In separate animals, autoradiography was performed to assess changes in seroton- Previous research in our laboratory suggests that 5-HT content is reduced in the frontal cortex following METH self-administra- ergic markers in the frontal cortex when sacrificed shortly after the last self-administration session. Results revealed a decrease tion in males (McFadden et al., 2013). This may be due to a loss of serotonergic neuronal terminal integrity in the frontal cortex as in SERT autoradiography and an increase in 5-HT2 receptor autoradiography in METH self-administering animals compared reflected by the reduction in SERT, which in turn may lead to an upregulation in 5-HT2 receptors, especially in the OFC. with saline animals in the OFC. These changes may contribute to the behavioral changes observed. Females also had greater head twitch behavior compared with males regardless of self-administration group. This may Changes to the 5-HT2 receptors in the frontal cortex may contribute to hallucinations associated with METH use. The be due to sex hormones. Estradiol benzoate replacement ther - apy in ovariectomized rats results in increases in 5-HT2A recep- self-administration of METH lead to an increase in DOI-induced head twitches compared to saline self-administering animals. tors in the frontal cortex (Sumner et al., 1999). Further, estradiol replacement therapy in postmenopausal women has been In addition to the increase in head twitch behavior, an increase in 5-HT2 receptors in the OFC was observed. Because METH shown to increase 5-HT2A receptor binding in the frontal cortex (Kugaya et al., 2003). The sex differences observed in the current increases 5-HT activity rather than binding to specific 5-HT receptors (Müller et al., 2015), the less specific 5-HT2 agonist was study may have been due to sex differences in estrogen levels. Although it was beyond the scope of the current study investi- used to more closely mimic that of METH. Although DOI and ketanserin both have a higher affinity for the 5-HT2A receptor gating METH-induced changes in and hallucinogenic drug-asso- ciated behaviors, future studies are warranted to investigate the compared with the 5-HT2C receptor (Nelson et al., 1999; Rashid et al., 2003), one limitation of this study is that these drugs bind influence of sex hormones on 5-HT2 receptor expression and behavioral pharmacology. to both 5-HT2 receptors. However, the changes observed in both behavior and autoradiography warrant the need for future stud- The behavioral changes induced by METH self-administra- tion were not long lasting. This is consistent with clinical reports ies to investigate the specific 5-HT2 receptor subtype underlying these changes. that in the majority of patients with METH-associated psych- osis, these symptoms go into remission shortly after achieving Previous studies have investigated the pharmacology under - lying drug-induced head twitch behavior. Studies suggest this abstinence from drug use (Zorick et al., 2010; Hsieh et al., 2014). Table 1. Frontal Cortex Autoradiograph (% of Saline Male) in Animals Sacrificed 1 Hour after Self-Administration Ligand Region Saline Male METH Male Saline Female METH Female [3H] Ketanserin PrL# 100.00 ± 2.28 (10) 102.65 ± 1.99 (10) 100.52 ± 1.59 (11) 104.29 ± 1.60 (9) IL 100.00 ± 3.45 (10) 102.16 ± 2.66 (10) 101.52 ± 2.30 (11) 99.78 ± 4.11 (10) OFC* 100.00 ± 1.86 (11) 106.22 ± 1.92 (10) 102.37 ± 2.36 (11) 111.47 ± 2.26 (9) [125 I] RTI-55 PrL 100.00 ± 1.53 (4) 87.59 ± 3.79 (9) 104.56 ± 5.83 (8) 101.13 ± 5.30 (9) IL* 100.00 ± 1.88 (4) 80.96 ± 3.97 (8) 93.06 ± 3.33 (8) 91.48 ± 2.85 (9) OFC* 100.00 ± 3.56 (6) 89.72 ± 2.24 (10) 97.19 ± 2.55 (8) 95.87 ± 2.55 (9) Mean ± SEM (n). P < .10 METH vs saline; & P < .05 saline male vs METH male. *P < .05 METH vs saline; Downloaded from https://academic.oup.com/ijnp/advance-article-abstract/doi/10.1093/ijnp/pyy044/4995604 by guest on 13 July 2018 McFadden et al. | 5 In an in-patient sample of METH users, the majority of psych- Fantegrossi WE, Simoneau J, Cohen MS, Zimmerman SM, Henson otic symptoms resolved within 1 week of abstinence from the CM, Rice KC, Woods JH (2010) Interaction of 5-HT2A and 5-HT2C drug (Zorick et al., 2010). The results of the current study suggest receptors in R(-)-2,5-dimethoxy-4-iodoamphetamine-elicited that changes in 5-HT2-mediated behavior diminish quickly after head twitch behavior in mice. J Pharmacol Exp Ther 335:728–734. abstinence from METH use. Other clinical studies suggest that Furlong TM, Leavitt LS, Keefe KA, Son JH (2016) up to 30% of individuals with METH-associated psychosis had Methamphetamine-, d-amphetamine-, and p-chloroamphet- symptoms that persisted up to 6 months (Hsieh et al., 2014), but amine-induced neurotoxicity differentially effect impulsive it is unclear if these persisting symptoms are associated with responding on the stop-signal task in rats. Neurotox Res the duration of drug use. Future studies can alter the duration 29:569–582. of METH self-administration to assess if this leads to a subset of Glasner-Edwards S, Mooney LJ (2014) Methamphetamine animals with persistent behavioral changes. Alternatively, it can psychosis: epidemiology and management. 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These changes may quences of methamphetamine self-administration in male underlie METH-associated psychosis observed in METH users. and female rats. Drug Alcohol Depend 178:70–74. Further, 5-HT2 or 5-HT2A antagonist/inverse agonists may hold Kalén P, Strecker RE, Rosengren E, Björklund A (1988) Endogenous potential in reducing these symptoms in METH users. release of neuronal serotonin and 5-hydroxyindoleacetic acid in the caudate-putamen of the rat as revealed by intracere- bral dialysis coupled to high-performance liquid chromatog- Supplementary Materials raphy with fluorimetric detection. J Neurochem 51:1422–1435. Supplementary data are available at The International Journal of Kugaya A, Epperson CN, Zoghbi S, van Dyck CH, Hou Y, Fujita M, Staley JK, Garg PK, Seibyl JP, Innis RB (2003) Increase in Neuropsychopharmacology online. prefrontal cortex serotonin 2A receptors following estro- gen treatment in postmenopausal women. Am J Psychiatry Funding 160:1522–1524. 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International Journal of NeuropsychopharmacologyOxford University Press

Published: May 14, 2018

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