Clinical Psychopharmacology and Neuroscience 2019; 17(3): 400-408  https://doi.org/10.9758/cpn.2019.17.3.400
Long-term Effects of Aripiprazole Treatment during Adolescence on Cognitive Function and Dopamine D2 Receptor Expression in Neurodevelopmentally Normal Rats
Hyung Jun Choi1, Soo Jung Im1, Hae Ri Park1, Subin Park2, Chul-Eung Kim3, Seunghyong Ryu1
1Department of Mental Health Research, 2Department of Research Planning, 3Mental Health Research Institute, National Center for Mental Health, Seoul, Korea
Correspondence to: Seunghyong Ryu
Department of Mental Health Research, National Center for Mental Health, 127 Youngmasan-ro, Gwangjin-gu, Seoul 04933, Korea
E-mail: seunghyongryu@gmail.com
ORCID: https://orcid.org/0000-0001-6127-760X
Received: May 2, 2018; Revised: July 23, 2018; Accepted: August 26, 2018; Published online: August 31, 2019.
© The Korean College of Neuropsychopharmacology. All rights reserved.

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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Objective

This study aimed to investigate the long-term effects of aripiprazole treatment during adolescence on behavior, cognitive function, and dopamine D2 receptor (D2R) expression in adult rats.

Methods

Adolescent male Sprague-Dawley rats were injected intraperitoneally with aripiprazole, risperidone, or vehicle control for 3 weeks (postnatal day 36–56). After a 2-week washout period, locomotion, anxiety, and spatial working memory were evaluated in adulthood (postnatal day 71–84), using an open field test, elevated plus maze, and Y-maze, respectively. In addition, we assessed D2R levels in the dorsolateral and medial prefrontal cortex (PFC), dorsal and ventral striatum, and hippocampus using western blot analysis.

Results

Spontaneous alternation performance (SAP) in the Y-maze, a measure of spatial working memory, differed significantly among the 3 groups (F = 3.89, p = 0.033). A post-hoc test confirmed that SAP in the aripiprazole group was significantly higher than that in the risperidone group (post-hoc test p = 0.013). D2R levels in the medial PFC (F = 8.72, p = 0.001) and hippocampus (F = 13.54, p < 0.001) were different among the 3 groups. D2R levels in the medial PFC and hippocampus were significantly lower in the aripiprazole-treated rats than that in the risperidone-treated rats (post-hoc test p = 0.025 and p < 0.001, respectively) and controls (post-hoc test p < 0.001, all).

Conclusion

This study showed that aripiprazole treatment in adolescence could influence cognitive function and dopaminergic neurotransmission into early adulthood.

Keywords: Aripiprazole; Adolescent; Cognition; Dopamine D2 receptors; Animal models.
INTRODUCTION

Since the introduction of atypical antipsychotics (AAPs) with relatively minor side effects, prescriptions of AAPs have increased in adolescent patients with mental illness.1) In particular, AAPs are commonly used off-label to control anger, irritability, violence, and mood instability in adolescent patients with non-psychotic disorders such as attention-deficit/hyperactivity disorder, oppositional defiant disorder, and depressive disorder.2) However, the US Food and Drug Administration has approved the use of AAPs in pediatric and adolescent patients only for the treatment of schizophrenia, bipolar disorder, autism, and Tourette’s syndrome.3) There is insufficient evidence for the off-label use of AAPs in non-psychotic adolescent patients, and there are many disagreements about its efficacy and safety.4) Moreover, little is known about the effects of AAP treatment during adolescence on brain development or the subsequent changes in behavior, mood, and cognitive function that may persist long after AAP withdrawal.

It is difficult to directly assess the effects of AAPs on human brain development. Instead, animal studies can indirectly predict behavioral and neurochemical changes following AAP treatment during adolescence. Some behavioral studies have reported that neurodevelopmentally normal animals treated with risperidone or olanzapine during adolescence developed altered locomotion and reward behaviors in adulthood.5,6) Risperidone or olanzapine treatment during adolescence has also been suggested to alter the dopaminergic, GABAergic, and glutamatergic neurotransmitter systems in the rat brain, especially in the prefrontal cortex (PFC) and nucleus accumbens.79) However, few studies have addressed the long-lasting effects of aripiprazole treatment during adolescence on behavior, cognitive function, or neurotransmission systems in adulthood. Aripiprazole has a unique pharmacological profile as a dopamine D2 receptor (D2R) partial agonist with partial agonistic activity at the serotonin-1A receptor and antagonistic activity at the serotonin-2A receptor,10) and it has been often prescribed to treat several non-psychotic conditions in adolescent patients due to its high tolerability.11)

This study investigated changes in behavior, cognitive function, and levels of D2R in adult rats after chronic adolescent treatment with aripiprazole. To this end, we administered aripiprazole, risperidone, or vehicle to neurodevelopmentally normal rats during adolescence, and evaluated their locomotion, anxiety, and spatial working memory in adulthood using behavioral tests. In addition, we examined D2R levels in PFC, striatum, and hippocampus of the rat brain via western blot analysis.

METHODS

Materials

Aripiprazole and risperidone (SML0935-50MG and #R3030-10MG, respectively; Sigma-Aldrich, St. Louis, MO, USA) were dissolved in 25% hydroxypropyl-β-cyclodextrin (332593-25G; Sigma-Aldrich) acidified with HCl and titrated to pH 5.5 to 6.0 with NaOH as described previously,12) and then diluted 10-fold with 0.9% normal saline. The respective vehicle control was 0.9% normal saline in 2.5% hydroxypropyl-β-cyclodextrin acidified with HCl and titrated to pH 5.5 to 6.0. Antibodies for western blot analysis against D2R (ab5084P) were purchased from EMD Millipore (Billerica, MA, USA).

Animals and Housing

Specific-pathogen-free male (postnatal day [PD] 29) Sprague-Dawley rats purchased from OrientBio (Seongnam, Korea) were maintained in the laboratory animal facility of the National Center for Mental Health (23 ± 2°C, 50 ± 10% relative humidity and 12-hour light/dark cycle). They were allowed ad-libitum access to water and a commercial diet of Altromin 1214 (Altromin GmbH., Lage, Germany). The animals were acclimatized for 7 days prior to beginning the study. All animal experiments were approved by the Institutional Animal Care and Use Committee of the National Center for Mental Health (approval number: NCMH-1703-001-001-02).

Experimental Design

The general study scheme is depicted in Figure 1. Animals were randomly divided into aripiprazole, risperidone, and control groups, and each group consisted of 10 male rats. The drug treatment period from PD 36 to PD 56 in the rats was equivalent to the period of mid-late adolescence in humans.13,14) The rats received an intraperitoneal (i.p.) injection of drugs or vehicle control for 3 weeks. A staggered drug treatment pattern, slowly titrated from a low starting dose, was used to mimic a clinical setting. The AAP doses were initiated during the first week of treatment at 1.5 mg/kg/day for aripiprazole and 0.5 mg/kg/day for risperidone, and then increased over the second and third weeks of treatment to 3 mg/kg/day for aripiprazole and 1 mg/kg/day for risperidone. The proposed dosages were selected based on preclinical efficacy or occupancy studies. Some previous studies had compared effects of oral aripiprazole (1 mg/kg three times a day [t.i.d.]) and risperidone (0.3 mg/kg t.i.d.) treatment during adolescence on behaviors and the dopamine system in rats.1517) Sub-chronic treatment with 1.0 mg/kg/day i.p. risperidone was reported to induce changes in fore-brain receptor levels in adolescent rats.18) In addition, it has been previously reported that, at the selected doses, aripiprazole and risperidone treatment reaches 60% to 80% D2R occupancy in the rat brain.19) Based on the body surface area formula for dosage translation between humans and rats,20) the selected doses were within the recommended dose ranges for the psychiatric treatment.

Behavioral Tests

After the 2-week washout period, behavioral tests were carried out from PD 71 to PD 84 (which was equivalent to adulthood in humans) in the following sequence: open field test (OFT), elevated plus maze (EPM), and Y-maze, as described below. The rats’ activities in the behavioral tests were analyzed using SMART 3.0® video tracking software (Panlab, Barcelona, Spain).

Open Field Test

The OFT has often been used to assess locomotion,21) and the procedure was performed according to previous reports.22) The open field consisted of a 60 × 60 × 40 cm high plastic enclosure, and the field was divided into 25 squares, defined as 9 central and 16 peripheral squares. Each rat was placed in the central square and allowed to move freely and explore the environment for 10 seconds. Next, a video camera above the center of the arena recorded the behavior of the rats for 5 minutes. The arena was cleaned between tests with 75% ethanol. The rats’ locomotion at the periphery and the center were analyzed.

Elevated Plus Maze

The EPM is one of the most widely used tests for measuring anxiety-like behaviors in laboratory rodents.21) The apparatus consisted of two 45 × 10 cm open arms and two 45 × 10 × 45 cm closed arms. Open and closed arms were cross-shaped; the cross center was a 10 × 10 cm open platform. The maze was 50 cm above the ground. The rats were placed on the central platform facing an open arm. A video camera above the maze was used to record the activity of the animals for 5 minutes. Test variables included the number of open and closed arm entries as well as the time spent in the center, open arms, and closed arms. When the head and forelimbs of a rat were in one arm, it was recorded as one entry.

Y-maze

The Y-maze spontaneous alternation paradigm is used to assess spatial working memory in rodents and is based on the innate tendency of rodents to explore a prior unexplored arm of a Y-maze.23) The Y-maze apparatus, made of Plexiglas, had three identical arms (45 × 10 × 35 cm) placed at 120° with respect to each other. Each rat was placed at the end of one arm and allowed to freely explore the apparatus for 8 minutes. A rat was considered to have entered an arm when the head and forelimbs were positioned in the arm runway. We assessed spontaneous alternation performance (SAP), a measure of working memory, which was defined as actual alternation (total arm entries)/possible alternations (total arm entries – 2) × 100. Alternations were operationally defined as successive entries into each of the 3 arms on overlapping triplet sets. Alternate arm returns (AAR) and same arm returns (SAR) in the Y-maze (AAR = alternate arm returns/total arm entries × 100, SAR = same arm return/total arm entries × 100) were used as indicators of memory impairment.24)

Necropsy

All animals were subjected to a necropsy examination at PD 86 to 87, which included evaluation of the cranial cavity and external surfaces of the brain. All tissue samples of the brain (dorsolateral and medial PFC, dorsal and ventral striatum, and hippocampus) were obtained after exsanguination under isoflurane anesthesia. Coronal brain slices (0.5 mm thick) were prepared, and all steps of the preparation were carried out in ice-cold rodent brain matrix for further analysis.

Western Blot Analysis

To quantify D2R expression, tissues were lysed by RIPA lysis buffer without EDTA (R4100-050; GeneDepot, Barker, TX, USA) containing Phosphatase Inhibitor Cocktail (P2300; GeneDepot) and Protease Inhibitor Cocktail (P3100). Prepared cell lysates with sodium dodecyl sulfate were run on an 8% polyacrylamide gel, and transferred onto a polyvinylidene fluoride membrane (162-0174; Bio-rad, Hercules, CA, USA) via the semidry transfer method. The membrane was blocked with 5% skimmed milk with tris-buffered saline-tween (TBS-T) for 1 hour, and incubated with antibodies against D2R (ab5084P; EMD Millipore) dissolved in 5% bovine serum albumin in TBS-T, overnight in a cold room (5 ± 3°C). The membrane was incubated with a Goat anti-Rabbit IgG coupled with horseradish peroxidase (#31460; Thermo Fisher Scientific, Rockford, IL, USA). The expression of the endogenous control β-actin was probed (sc-47778 HRP; Santa Cruz Biotechnology, Dallas, TX, USA). Blots were visualized using ClarityTM Western ECL Substrate (170-5060) with ChemiDocTM XRS+ System (170-8256; Bio-rad) and measured using Image LabTM software (170-9690; Bio-rad).

Statistical Analyses

We compared the distance traveled in the peripheral and central areas and total distance traveled in the OFT, the number of open and closed arm entries and the time spent in the center, open arms, and closed arms of the EPM, and the SAP, AAR, and SAR in the Y-maze, among the aripiprazole, risperidone, and control groups using analysis of variance (ANOVA), followed by pair-wise comparisons using the least significant difference (LSD) post-hoc test. In addition, we compared D2R levels in dorsolateral and medial PFC, dorsal and ventral striatum, and hippocampus among the 3 groups in the same way. All statistical analyses were performed using SPSS version 21.0 (IBM Corp., Armonk, NY, USA). The p values less than 0.05 were considered statistically significant.

RESULTS

Behavioral Tests

In the OFT, we found no differences in distance traveled at the periphery (F = 0.26, p = 0.775), in the center (F = 0.99, p = 0.386), or total distance traveled (F = 0.32, p = 0.727), among the 3 groups. In the EPM, there were also no significant differences in the number of open arm entries (F = 0.11, p = 0.901) or closed arm entries (F = 0.43, p = 0.658) as well as time spent in the center (F = 0.51, p = 0.606), open arms (F = 0.23, p = 0.797), and closed arms (F = 0.36, p = 0.704). In the Y-maze, we found a significant difference in SAP among the 3 groups (F = 3.89, p = 0.033). LSD post-hoc test confirmed that there was a significant difference between aripiprazole and risperidone groups (p = 0.013), and there was also a marginal difference between aripiprazole and control groups (p = 0.054) (Fig. 2). Comparing the 3 groups using ANOVA revealed no significant difference in AAR (F = 2.99, p = 0.067), but showed a trend where AAR was higher in the risperidone group (mean±standard error of mean [SEM], 33.30 ± 10.71) than that in the aripiprazole group (mean ± SEM, 22.14 ± 10.05) (Fig. 2). Furthermore, we observed no difference in SAR among the 3 groups (F = 1.55, p = 0.230). The detailed results of OFT, EPM, and Y-maze are shown in Table 1.

Neurochemical Outcomes

D2R levels were significantly different among the 3 groups in the medial PFC (F = 8.72, p = 0.001) and hippocampus (F = 13.54, p < 0.001) (Fig. 3). LSD post-hoc test confirmed that D2R levels in the medial PFC were significantly lower in the aripiprazole group than in the risperidone (p = 0.025) and control (p < 0.001) groups. D2R levels in the hippocampus were also significantly lower in the aripiprazole group than in risperidone (p < 0.001) and control (p < 0.001) groups. D2R levels were not significantly different among the 3 groups in the dorsolateral PFC (F = 2.71, p = 0.085), dorsal striatum (F = 1.50, p = 0.241), and ventral striatum (F = 1.90, p = 0.170). The detailed results of D2R levels in dorsolateral and medial PFC, dorsal and ventral striatum, and hippocampus are shown in Table 2.

Figures
Fig. 1. Study scheme. Timeline and group table illustrate the timing of treatment, the experimental measures obtained, and dosage.

OFT, open field test; EPM, elevated plus maze; IP, intraperitoneally.


Fig. 2. Differences in spatial working memory among groups of adult rats treated with aripiprazole (3 mg/kg/day), risperidone (1 mg/kg/day), and vehicle (control) during adolescence. Spontaneous alternation performance (SAP) (A) and alternate arm returns (AAR) (B) in Y-maze.

*p=0.013 in the least significant difference post-hoc test.


Fig. 3. Differences in dopamine D2 receptor (D2R) levels in the medial prefrontal cortex (A) and the hippocampus (B) among groups of adult rats treated with aripiprazole (3 mg/kg/day), risperidone (1 mg/kg/day), and vehicle (control) during adolescence. Data are presented as mean ± standard error of mean.

*p = 0.025, p < 0.001 in the least significant difference post-hoc test.


Tables

Behavioral analyses of adult rats treated with aripiprazole (3 mg/kg/day), risperidone (1 mg/kg/day), and vehicle (control) during adolescence

Behavioral test Aripiprazole Risperidone Control
Open field test
 Distance traveled in the peripheral area (cm) 1,340.38 ± 86.67 1,334.85 ± 209.97 1,188.82 ± 186.38
 Distance traveled in the central area (cm) 235.59 ± 27.52 380.11 ± 107.09 277.22 ± 67.88
 Total distance traveled (cm) 1,575.97 ± 90.18 1,714.96 ± 300.41 1,466.04 ± 214.76
Elevated plus maze
 Number of open arm entries (n) 3.00 ± 0.60 2.90 ± 0.74 2.60 ± 0.58
 Number of closed arm entries (n) 17.50 ± 2.45 14.30 ± 2.07 15.70 ± 2.81
 Time spent in the center (sec) 79.09 ± 7.57 65.70 ± 11.75 75.87 ± 9.62
 Time spent in the open arms (sec) 44.62 ± 11.95 37.84 ± 14.29 32.73 ± 10.97
 Time spent in the closed arms (sec) 176.28 ± 14.58 196.46 ± 22.07 191.40 ± 15.12
Y-maze
 Spontaneous alternation performance (%)* 63.48 ± 3.10 47.57 ± 4.72 51.51 ± 4.60
 Alternate arm returns (%) 22.14 ± 3.18 33.30 ± 3.39 22.89 ± 4.18
 Same arm returns (%) 5.77 ± 1.69 7.86 ± 2.11 11.09 ± 2.57
 Number of total arm entries (n) 22.7 ± 1.80 24.7 ± 1.95 20.5 ± 2.25

Values are presented as mean ± standard error of mean.

Significantly different among aripiprazole, risperidone, and control groups (p < 0.05 in ANOVA).

Aripiprazole vs. risperidone (p < 0.05 in the least significant differenc post-hoc test).

Dopamine D2 receptor protein expression of adult rats treated with aripiprazole (3 mg/kg/day), risperidone (1 mg/kg/day), and vehicle (control) during adolescence in the Western Blot assay

Brain region Aripiprazole Risperidone Control
Dorsolateral prefrontal cortex 1.15 ± 0.076 1.02 ± 0.047 1.78 ± 0.419
Medial prefrontal cortex* 0.30 ± 0.031, 0.61 ± 0.090 0.85 ± 0.130
Dorsal striatum 0.28 ± 0.035 0.21 ± 0.019 0.20 ± 0.042
Ventral striatum 0.04 ± 0.004 0.08 ± 0.020 0.05 ± 0.008
Hippocampus* 0.20 ± 0.031,§ 0.76 ± 0.123 0.88 ± 0.115

Values are presented as mean ± standard error of mean (% of β-actin).

Significantly different among aripiprazole, risperidone, and control groups (p < 0.05 in ANOVA).

Aripiprazole vs. control (p < 0.001 in the least significant differenc [LSD] post-hoc test).

Aripiprazole vs. risperidone (p < 0.05 in LSD post-hoc test).

Aripiprazole vs. risperidone (p < 0.001 in LSD post-hoc test).

References
  1. Olfson M, Blanco C, Liu SM, Wang S, Correll CU. National trends in the office-based treatment of children, adolescents, and adults with antipsychotics. Arch Gen Psychiatry 2012;69:1247-1256.
    Pubmed CrossRef
  2. Olfson M, King M, Schoenbaum M. Treatment of young people with antipsychotic medications in the United States. JAMA Psychiatry 2015;72:867-874.
    Pubmed CrossRef
  3. Correll CU, Kratochvil CJ, March JS. Developments in pediatric psychopharmacology: focus on stimulants, anti-depressants, and antipsychotics. J Clin Psychiatry 2011;72:655-670.
    Pubmed CrossRef
  4. Correll CU, Blader JC. Antipsychotic use in youth without psychosis: a double-edged sword. JAMA Psychiatry 2015;72:859-860.
    Pubmed CrossRef
  5. Bardgett ME, Franks-Henry JM, Colemire KR, Juneau KR, Stevens RM, Marczinski CA, et al. Adult rats treated with risperidone during development are hyperactive. Exp Clin Psychopharmacol 2013;21:259-267.
    Pubmed KoreaMed CrossRef
  6. Vinish M, Elnabawi A, Milstein JA, Burke JS, Kallevang JK, Turek KC, et al. Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function. Int J Neuropsychopharmacol 2013;16:1599-1609.
    Pubmed KoreaMed CrossRef
  7. Milstein JA, Elnabawi A, Vinish M, Swanson T, Enos JK, Bailey AM, et al. Olanzapine treatment of adolescent rats causes enduring specific memory impairments and alters cortical development and function. PLoS One 2013;8:e57308.
    Pubmed KoreaMed CrossRef
  8. Moran-Gates T, Grady C, Shik Park Y, Baldessarini RJ, Tarazi FI. Effects of risperidone on dopamine receptor subtypes in developing rat brain. Eur Neuropsychopharmacol 2007;17:448-455.
    Pubmed KoreaMed CrossRef
  9. Xu S, Gullapalli RP, Frost DO. Olanzapine antipsychotic treatment of adolescent rats causes long term changes in glutamate and GABA levels in the nucleus accumbens. Schizophr Res 2015;161:452-457.
    Pubmed KoreaMed CrossRef
  10. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, et al. Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 2002;302:381-389.
    Pubmed CrossRef
  11. Kirino E. Efficacy and safety of aripiprazole in child and adolescent patients. Eur Child Adolesc Psychiatry 2012;21:361-368.
    Pubmed KoreaMed CrossRef
  12. Dawe GS, Nagarajah R, Albert R, Casey DE, Gross KW, Ratty AK. Antipsychotic drugs dose-dependently suppress the spontaneous hyperactivity of the chakragati mouse. Neuroscience 2010;171:162-172.
    Pubmed CrossRef
  13. Renard J, Krebs MO, Le Pen G, Jay TM. Long-term consequences of adolescent cannabinoid exposure in adult psychopathology. Front Neurosci 2014;8:361.
    Pubmed KoreaMed CrossRef
  14. Semple BD, Blomgren K, Gimlin K, Ferriero DM, Noble-Haeusslein LJ. Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Prog Neurobiol 2013;106–107:1-16.
    Pubmed KoreaMed CrossRef
  15. Lian J, Pan B, Deng C. Early antipsychotic exposure affects serotonin and dopamine receptor binding density differently in selected brain loci of male and female juvenile rats. Pharmacol Rep 2016;68:1028-1035.
    Pubmed CrossRef
  16. De Santis M, Lian J, Huang XF, Deng C. Early antipsychotic treatment in juvenile rats elicits long-term alterations to the dopamine neurotransmitter system. Int J Mol Sci 2016;17:1944.
    Pubmed KoreaMed CrossRef
  17. De Santis M, Lian J, Huang XF, Deng C. Early antipsychotic treatment in childhood/adolescent period has long-term effects on depressive-like, anxiety-like and locomotor behaviours in adult rats. J Psychopharmacol 2016;30:204-214.
    Pubmed CrossRef
  18. Choi YK, Moran-Gates T, Gardner MP, Tarazi FI. Effects of repeated risperidone exposure on serotonin receptor subtypes in developing rats. Eur Neuropsychopharmacol 2010;20:187-194.
    Pubmed KoreaMed CrossRef
  19. Natesan S, Reckless GE, Nobrega JN, Fletcher PJ, Kapur S. Dissociation between in vivo occupancy and functional antagonism of dopamine D2 receptors: comparing aripiprazole to other antipsychotics in animal models. Neuropsychopharmacology 2006;31:1854-1863.
    Pubmed CrossRef
  20. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J 2008;22:659-661.
    Pubmed CrossRef
  21. Sestakova N, Puzserova A, Kluknavsky M, Bernatova I. Determination of motor activity and anxiety-related behaviour in rodents: methodological aspects and role of nitric oxide. Interdiscip Toxicol 2013;6:126-135.
    Pubmed KoreaMed CrossRef
  22. Moon SJ, Kim CJ, Lee YJ, Hong M, Han J, Bahn GH. Effect of atomoxetine on hyperactivity in an animal model of attention-deficit/hyperactivity disorder (ADHD). PLoS One 2014;9:e108918.
    Pubmed KoreaMed CrossRef
  23. Lalonde R. The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 2002;26:91-104.
    Pubmed CrossRef
  24. Thompson BL, Levitt P, Stanwood GD. Prenatal cocaine exposure specifically alters spontaneous alternation behavior. Behav Brain Res 2005;164:107-116.
    Pubmed CrossRef
  25. Xu H, Yang HJ, Rose GM. Chronic haloperidol-induced spatial memory deficits accompany the upregulation of D(1) and D(2) receptors in the caudate putamen of C57BL/6 mouse. Life Sci 2012;91:322-328.
    Pubmed CrossRef
  26. Burda K, Czubak A, Kus K, Nowakowska E, Ratajczak P, Zin J. Influence of aripiprazole on the antidepressant, anxiolytic and cognitive functions of rats. Pharmacol Rep 2011;63:898-907.
    Pubmed CrossRef
  27. Ratajczak P, Kus K, Jarmuszkiewicz Z, Wozniak A, Cichocki M, Nowakowska E. Influence of aripiprazole and olanzapine on behavioral dysfunctions of adolescent rats exposed to stress in perinatal period. Pharmacol Rep 2013;65:30-43.
    Pubmed CrossRef
  28. Lee BJ, Lee SJ, Kim MK, Lee JG, Park SW, Kim GM, et al. Effect of aripiprazole on cognitive function and hyperprolactinemia in patients with schizophrenia treated with risperidone. Clin Psychopharmacol Neurosci 2013;11:60-66.
    Pubmed KoreaMed CrossRef
  29. Kim SW, Shin IS, Kim JM, Lee JH, Lee YH, Yang SJ, et al. Effectiveness of switching to aripiprazole from atypical antipsychotics in patients with schizophrenia. Clin Neuropharmacol 2009;32:243-249.
    Pubmed CrossRef
  30. Riedel M, Spellmann I, Schennach-Wolff R, Musil R, Dehning S, Cerovecki A, et al. Effect of aripiprazole on cognition in the treatment of patients with schizophrenia. Pharmacopsychiatry 2010;43:50-57.
    Pubmed CrossRef
  31. Shin S, Kim S, Seo S, Lee JS, Howes OD, Kim E, et al. The relationship between dopamine receptor blockade and cognitive performance in schizophrenia: a [11C]-raclopride PET study with aripiprazole. Transl Psychiatry 2018;8:87.
    Pubmed KoreaMed CrossRef
  32. Kim E, Howes OD, Turkheimer FE, Kim BH, Jeong JM, Kim JW, et al. The relationship between antipsychotic D2 occupancy and change in frontal metabolism and working memory: a dual [(11)C]raclopride and [(18) F]FDG imaging study with aripiprazole. Psychopharmacology (Berl) 2013;227:221-229.
    Pubmed CrossRef
  33. Wahlstrom D, Collins P, White T, Luciana M. Developmental changes in dopamine neurotransmission in adolescence: behavioral implications and issues in assessment. Brain Cogn 2010;72:146-159.
    Pubmed KoreaMed CrossRef
  34. Moran-Gates T, Gan L, Park YS, Zhang K, Baldessarini RJ, Tarazi FI. Repeated antipsychotic drug exposure in developing rats: dopamine receptor effects. Synapse 2006;59:92-100.
    Pubmed CrossRef
  35. Li Z, Ichikawa J, Dai J, Meltzer HY. Aripiprazole, a novel antipsychotic drug, preferentially increases dopamine release in the prefrontal cortex and hippocampus in rat brain. Eur J Pharmacol 2004;493:75-83.
    Pubmed CrossRef
  36. Spellman T, Rigotti M, Ahmari SE, Fusi S, Gogos JA, Gordon JA. Hippocampal-prefrontal input supports spatial encoding in working memory. Nature 2015;522:309-314.
    Pubmed KoreaMed CrossRef
  37. Wilkerson A, Levin ED. Ventral hippocampal dopamine D1 and D2 systems and spatial working memory in rats. Neuroscience 1999;89:743-749.
    Pubmed CrossRef
  38. Druzin MY, Kurzina NP, Malinina EP, Kozlov AP. The effects of local application of D2 selective dopaminergic drugs into the medial prefrontal cortex of rats in a delayed spatial choice task. Behav Brain Res 2000;109:99-111.
    Pubmed CrossRef


This Article


Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information

Services
Social Network Service

e-submission

Archives