Advances in Behavioral Psychopharmacology

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 19308

Special Issue Editor


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Guest Editor
Institute of Pharmacology, the Polish Academy of Sciences, Krakow, Poland
Interests: antidepressants; behavioral psychopharmacology; chronic stress; depression; ketamine; mGlu receptors

Special Issue Information

Dear Colleagues,

According to WHO the global burden of mental disorders continues to grow, despite decades of detailed research in the field of neuroscience, using modern methods, including brain imaging techniques. Depression, bipolar disorder, schizophrenia, and other psychoses, dementia, developmental disorders, including autism, and other disorders related to abnormal emotions, thoughts, perceptions, and behavior still pose a huge global medical, social, and economic problem. Behavioral research using animal models of mental illnesses or screening tests used for finding potential drugs, help in the search for new forms of therapy. Animal models of mental disorders or at least some disease symptoms, although imperfect, also help to determine the pathomechanism of mental illnesses, the study of which is very difficult in patients. Substance use disorders including drugs addiction, related to the compulsive search and intake of addictive substances as a result of loss of control over the behavior are also a serious problem to public health. Here, research in the field of behavioral psychopharmacology also offers huge opportunities in the study of the mechanisms of these pathological states, as well as new therapeutic strategies. Despite great achievements in behavioral psychopharmacology, new efforts are still needed to cope with the growing problem of the spread of mental illness and modern techniques appear to be essential in dealing with these challenges.

In this Special Issue, we would like to gather experts in the field of behavioral psychopharmacology that focus on the discovery of new therapeutic agents and strategies and on the studies of the mechanisms of changes in animal behavior in response to environmental fluctuations and pharmacological interventions. Original research articles, as well as stimulating reviews that provide new interpretations of the up-to-date results and extant literature are highly welcome.

Dr. Agnieszka Pałucha-Poniewiera
Guest Editor

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Keywords

  • addiction
  • behavioral models
  • behavioral pharmacology
  • cognition
  • depression
  • drug abuse
  • memory
  • psychoactive drugs

Published Papers (9 papers)

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Research

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12 pages, 618 KiB  
Article
A Comparison of the Anxiolytic Properties of Tofisopam and Diazepam: A Double-Blind, Randomized, Crossover, Placebo-Controlled Pilot Study
by Andrzej Kokoszka
Pharmaceuticals 2024, 17(1), 140; https://doi.org/10.3390/ph17010140 - 22 Jan 2024
Viewed by 996
Abstract
New clinical reports have recently been published on tofisopam—an anxiolytic drug currently registered as a benzodiazepine—after a long break in this research area. Neurobiological studies concerning its properties, which differ from those of benzodiazepines, are underway. The analyses presented in this study aimed [...] Read more.
New clinical reports have recently been published on tofisopam—an anxiolytic drug currently registered as a benzodiazepine—after a long break in this research area. Neurobiological studies concerning its properties, which differ from those of benzodiazepines, are underway. The analyses presented in this study aimed to compare the effects of tofisopam, diazepam, and a placebo in the treatment of anxiety symptoms. A total of 66 outpatients (43 women and 23 men) with generalized anxiety disorder aged 19 to 74 years (M = 41.4; SD = 13.2) were randomized in three groups receiving (1) tofisopam (50 mg three times a day), (2) diazepam (5 mg three times a day), or (3) a placebo for 2 weeks. Then, throughout a 2-week washout period, the patients were monitored for withdrawal symptoms. During the last 2 weeks, the effects of tofisopam (50 mg three times a day) and diazepam (5 mg three times a day) were compared (crossover design). The mean improvement on the Hamilton Anxiety Rating Scale was significantly higher in both the tofisopam and diazepam groups compared to the placebo group. There were no significant differences between the effects of diazepam and tofisopam, whereas adverse effects and withdrawal symptoms occurred less frequently in the tofisopam group. Tofisopam did not impair cognitive abilities, and related withdrawal symptoms resembled those of the placebo. If larger future studies corroborate these findings, tofisopam should be classified as a homophtalazine. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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21 pages, 3093 KiB  
Article
Targeting the Endoplasmic Reticulum Stress-Linked PERK/GRP78/CHOP Pathway with Magnesium Sulfate Attenuates Chronic-Restraint-Stress-Induced Depression-like Neuropathology in Rats
by Hany H. Arab, Ali Khames, Shuruq E. Alsufyani, Azza A. K. El-Sheikh and Amany M. Gad
Pharmaceuticals 2023, 16(2), 300; https://doi.org/10.3390/ph16020300 - 15 Feb 2023
Cited by 4 | Viewed by 1921
Abstract
Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to [...] Read more.
Magnesium sulfate has demonstrated marked neuroprotection in eclampsia, hypoxia, stroke, and post-traumatic brain injury rodent models. However, its potential impact against chronic-restraint-stress (CRS)-induced depression-like neuropathology and associated alterations in endoplasmic reticulum (ER) stress have not been adequately examined. The present study aimed to investigate the neuroprotective potential of magnesium sulfate in a rat model of CRS-triggered depression-like behavioral disturbance and the underlying molecular mechanisms. Herein, CRS was induced by placing rats into restraining tubes for 6 h/day for 21 days and the animals were intraperitoneally injected with magnesium sulfate (100 mg/kg/day) during the study period. After stress cessation, the depression-like behavior was examined by the open-field test, sucrose preference test, and forced swimming test. The present data demonstrated that CRS triggered typical depression-like behavioral changes which were confirmed by the Z-normalization scores. Mechanistically, serum circulating corticosterone levels spiked, and the hippocampi of CRS-exposed animals demonstrated a significant decline in serotonin, norepinephrine, and dopamine neurotransmitters. At the molecular level, the hippocampal pro-inflammatory TNF-alpha and IL-1β cytokines and the oxidative stress marker 8-hydroxy-2′-deoxyguanosine (8-HG) increased in stressed animals. In tandem, enhancement of hippocampal ER stress was evidenced by the activation of iNOS/PERK/GRP78/CHOP axis seen by increased protein expression of iNOS, PERK, GRP78, and CHOP signal proteins in the hippocampi of stressed rats. Interestingly, magnesium sulfate administration attenuated the depression-like behavioral outcomes and the histopathological changes in the brain hippocampi. These favorable actions were driven by magnesium sulfate’s counteraction of corticosterone spike, and hippocampal neurotransmitter decline, alongside the attenuation of neuroinflammation, pro-oxidation, and ER stress. In conclusion, the current results suggest the promising neuroprotective/antidepressant actions of magnesium sulfate in CRS by dampening inflammation, ER stress, and the associated PERK/GRP78/CHOP pathway. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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13 pages, 1838 KiB  
Article
The Antidepressant-like Activity and Cognitive Enhancing Effects of the Combined Administration of (R)-Ketamine and LY341495 in the CUMS Model of Depression in Mice Are Related to the Modulation of Excitatory Synaptic Transmission and LTP in the PFC
by Agnieszka Pałucha-Poniewiera, Bartosz Bobula and Anna Rafało-Ulińska
Pharmaceuticals 2023, 16(2), 288; https://doi.org/10.3390/ph16020288 - 14 Feb 2023
Cited by 2 | Viewed by 1596
Abstract
(S)-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have [...] Read more.
(S)-Ketamine is the first rapid-acting antidepressant drug (RAAD) introduced for the treatment of depression. However, research is still being carried out on the search for further RAADs that will be not only effective but also safe to use. Recent data have indicated that the combined administration of (R)-ketamine and the mGlu2/3 receptor antagonist LY341495 (mixRL) induces rapid and sustained effects in the chronic unpredictable mild stress (CUMS) model of depression in mice, and the use of this drug combination is associated with a low risk of undesirable effects. Considering the possible influence of stress on cortical plasticity and, on the other hand, the role of this plasticity in the mechanism of action of ketamine, we decided to investigate whether mixed RL affects synaptic plasticity in the prefrontal cortex (PFC) in the CUMS model of depression using electrophysiological techniques and explore whether these effects are related to memory impairments. Using behavioral methods, we found that a single administration of mixRL reversed CUMS-induced PFC-dependent memory deficits and alleviated depression-like effects induced by CUMS. In turn, electrophysiological experiments indicated that the amplitude of field potentials as well as paired-pulse responses in CUMS mice were increased, and mixRL was found to reverse these effects. Additionally, the magnitude of long-term potentiation (LTP) was reduced in CUMS mice, and mixRL was shown to restore this parameter. In summary, mixRL appeared to exert its antidepressant effects and cognitive enhancing effects in a mouse model of depression, at least in part, by mechanisms involving modulation of glutamatergic transmission and LTP in the PFC. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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8 pages, 1276 KiB  
Communication
The Effects of Positive Allosteric Modulators of α7–nAChR on Social Play Behavior in Adolescent Rats Prenatally Exposed to Valproic Acid
by Kinga Gzielo and Agnieszka Nikiforuk
Pharmaceuticals 2022, 15(11), 1417; https://doi.org/10.3390/ph15111417 - 16 Nov 2022
Cited by 2 | Viewed by 1489
Abstract
There is still no effective treatment that addresses the core symptoms of autism spectrum disorders (ASD), including social and communication deficits. A comprehensive body of evidence points to the cholinergic system, including alpha7–nicotinic acetylcholine receptors (α7–nAChRs), as a potential target of pharmacotherapy. A [...] Read more.
There is still no effective treatment that addresses the core symptoms of autism spectrum disorders (ASD), including social and communication deficits. A comprehensive body of evidence points to the cholinergic system, including alpha7–nicotinic acetylcholine receptors (α7–nAChRs), as a potential target of pharmacotherapy. A promising approach is based on positive allosteric modulators (PAMs) of these receptors due to their advantages over direct agonists. Nevertheless, α7 n–AChR ligands have not been widely studied in the context of autism. Therefore, using one of the most widely used rodent models of ASD, that is, prenatal exposure to valproic acid (VPA), we examined the impact of α7–nAChR PAMs (PNU–120596 and CCMI) on socio-communicative behavior during social play in adolescent male and female rats. The current study demonstrated that PAM treatment affected certain aspects of socio-communicative behavior in adolescent rats. Accordingly, PNU–120596 ameliorated deficient play abilities in VPA-exposed males, as revealed by increased play time during a social encounter. In addition, this compound enhanced the emission of ultrasonic vocalizations that accompanied playful interactions. Moreover, we observed the overall effect of PNU–120596 on non-playful forms of social behavior (i.e., social exploration) and acoustic parameters (i.e., the duration) of emitted calls. The present results suggest the ability of α7–nAChR PAMs to facilitate socio-communicative behavior in adolescent rats. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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Review

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24 pages, 2703 KiB  
Review
Advances in Neuropathic Pain Research: Selected Intracellular Factors as Potential Targets for Multidirectional Analgesics
by Katarzyna Ciapała and Joanna Mika
Pharmaceuticals 2023, 16(11), 1624; https://doi.org/10.3390/ph16111624 - 17 Nov 2023
Cited by 1 | Viewed by 1473
Abstract
Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. Unlike acute pain, which is short-term and starts suddenly in response to an injury, neuropathic pain arises from somatosensory nervous system damage or disease, is usually chronic, and makes [...] Read more.
Neuropathic pain is a complex and debilitating condition that affects millions of people worldwide. Unlike acute pain, which is short-term and starts suddenly in response to an injury, neuropathic pain arises from somatosensory nervous system damage or disease, is usually chronic, and makes every day functioning difficult, substantially reducing quality of life. The main reason for the lack of effective pharmacotherapies for neuropathic pain is its diverse etiology and the complex, still poorly understood, pathophysiological mechanism of its progression. Numerous experimental studies, including ours, conducted over the last several decades have shown that the development of neuropathic pain is based on disturbances in cell activity, imbalances in the production of pronociceptive factors, and changes in signaling pathways such as p38MAPK, ERK, JNK, NF-κB, PI3K, and NRF2, which could become important targets for pharmacotherapy in the future. Despite the availability of many different analgesics, relieving neuropathic pain is still extremely difficult and requires a multidirectional, individual approach. We would like to point out that an increasing amount of data indicates that nonselective compounds directed at more than one molecular target exert promising analgesic effects. In our review, we characterize four substances (minocycline, astaxanthin, fisetin, and peimine) with analgesic properties that result from a wide spectrum of actions, including the modulation of MAPKs and other factors. We would like to draw attention to these selected substances since, in preclinical studies, they show suitable analgesic properties in models of neuropathy of various etiologies, and, importantly, some are already used as dietary supplements; for example, astaxanthin and fisetin protect against oxidative stress and have anti-inflammatory properties. It is worth emphasizing that the results of behavioral tests also indicate their usefulness when combined with opioids, the effectiveness of which decreases when neuropathy develops. Moreover, these substances appear to have additional, beneficial properties for the treatment of diseases that frequently co-occur with neuropathic pain. Therefore, these substances provide hope for the development of modern pharmacological tools to not only treat symptoms but also restore the proper functioning of the human body. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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32 pages, 461 KiB  
Review
Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression
by Courtney M. Vecera, Alan C. Courtes, Gregory Jones, Jair C. Soares and Rodrigo Machado-Vieira
Pharmaceuticals 2023, 16(11), 1572; https://doi.org/10.3390/ph16111572 - 07 Nov 2023
Cited by 2 | Viewed by 2422
Abstract
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). [...] Read more.
Treatment-resistant depression (TRD) is a term used to describe a particular type of major depressive disorder (MDD). There is no consensus about what defines TRD, with various studies describing between 1 and 4 failures of antidepressant therapies, with or without electroconvulsive therapy (ECT). That is why TRD is such a growing concern among clinicians and researchers, and it explains the necessity for investigating novel therapeutic targets beyond conventional monoamine pathways. An imbalance between two primary central nervous system (CNS) neurotransmitters, L-glutamate and γ-aminobutyric acid (GABA), has emerged as having a key role in the pathophysiology of TRD. In this review, we provide an evaluation and comprehensive review of investigational antidepressants targeting these two systems, accessing their levels of available evidence, mechanisms of action, and safety profiles. N-methyl-D-aspartate (NMDA) receptor antagonism has shown the most promise amongst the glutamatergic targets, with ketamine and esketamine (Spravato) robustly generating responses across trials. Two specific NMDA-glycine site modulators, D-cycloserine (DCS) and apimostinel, have also generated promising initial safety and efficacy profiles, warranting further investigation. Combination dextromethorphan-bupropion (AXS-05/Auvelity) displays a unique mechanism of action and demonstrated positive results in particular applicability in subpopulations with cognitive dysfunction. Currently, the most promising GABA modulators appear to be synthetic neurosteroid analogs with positive GABAA receptor modulation (such as brexanolone). Overall, advances in the last decade provide exciting perspectives for those who do not improve with conventional therapies. Of the compounds reviewed here, three are approved by the Food and Drug Administration (FDA): esketamine (Spravato) for TRD, Auvelity (dextromethorphan-bupropion) for major depressive disorder (MDD), and brexanolone (Zulresso) for post-partum depression (PPD). Notably, some concerns have arisen with esketamine and brexanolone, which will be detailed in this study. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
31 pages, 6157 KiB  
Review
Liposome-Derived Nanosystems for the Treatment of Behavioral and Neurodegenerative Diseases: The Promise of Niosomes, Transfersomes, and Ethosomes for Increased Brain Drug Bioavailability
by Patrícia C. Pires, Ana Cláudia Paiva-Santos and Francisco Veiga
Pharmaceuticals 2023, 16(10), 1424; https://doi.org/10.3390/ph16101424 - 08 Oct 2023
Cited by 3 | Viewed by 1767
Abstract
Psychiatric and neurodegenerative disorders are amongst the most prevalent and debilitating diseases, but current treatments either have low success rates, greatly due to the low permeability of the blood–brain barrier, and/or are connected to severe side effects. Hence, new strategies are extremely important, [...] Read more.
Psychiatric and neurodegenerative disorders are amongst the most prevalent and debilitating diseases, but current treatments either have low success rates, greatly due to the low permeability of the blood–brain barrier, and/or are connected to severe side effects. Hence, new strategies are extremely important, and here is where liposome-derived nanosystems come in. Niosomes, transfersomes, and ethosomes are nanometric vesicular structures that allow drug encapsulation, protecting them from degradation, and increasing their solubility, permeability, brain targeting, and bioavailability. This review highlighted the great potential of these nanosystems for the treatment of Alzheimer’s disease, Parkinson’s disease, schizophrenia, bipolar disorder, anxiety, and depression. Studies regarding the encapsulation of synthetic and natural-derived molecules in these systems, for intravenous, oral, transdermal, or intranasal administration, have led to an increased brain bioavailability when compared to conventional pharmaceutical forms. Moreover, the developed formulations proved to have neuroprotective, anti-inflammatory, and antioxidant effects, including brain neurotransmitter level restoration and brain oxidative status improvement, and improved locomotor activity or enhancement of recognition and working memories in animal models. Hence, albeit being relatively new technologies, niosomes, transfersomes, and ethosomes have already proven to increase the brain bioavailability of psychoactive drugs, leading to increased effectiveness and decreased side effects, showing promise as future therapeutics. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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21 pages, 725 KiB  
Review
Progesterone and Its Metabolites Play a Beneficial Role in Affect Regulation in the Female Brain
by Małgorzata Stefaniak, Ewa Dmoch-Gajzlerska, Katarzyna Jankowska, Artur Rogowski, Anna Kajdy and Radosław B. Maksym
Pharmaceuticals 2023, 16(4), 520; https://doi.org/10.3390/ph16040520 - 31 Mar 2023
Cited by 5 | Viewed by 4446
Abstract
Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, [...] Read more.
Premenstrual dysphoric disorder is a female affective disorder that is defined by mood symptoms. The condition is linked to unstable progesterone concentrations. Progestin supplementation is given in cases of threatened or recurrent miscarriage and for luteal phase support. Progesterone is essential for implantation, immune tolerance, and modulation of uterine contractility. For a long time, the administration of progestins was associated with an unfavorable impact on mood, leading to negative affect, and, therefore, was contraindicated in existing mood disorders. Establishing the role of the natural progesterone derivative allopregnanolone in advances in the treatment of postpartum depression has shed new light on the general pathophysiology of mood disorders. Allopregnanolone directly interacts with gamma-aminobutyric acid type A (GABA-A) receptors even at nanomolar concentrations and induces significant anti-depressant, anti-stress, sedative, and anxiolytic effects. Postpartum depression is caused by a rapid drop in hormones and can be instantly reversed by the administration of allopregnanolone. Premenstrual dysphoric disorder can also be considered to result from insufficient neuroactive steroid action due to low progesterone derivative concentration, unstable hormone levels, or decreased receptor sensitivity. The decrease in progesterone levels in perimenopause is also associated with affective symptoms and an exacerbation of some psychosomatic syndromes. Bioidentical progesterone supplementation encounters several obstacles, including limited absorption, first-pass effect, and rapid metabolism. Hence, non-bioidentical progestins with better bioavailability were widely applied. The paradoxical, unfavorable effect of progestins on mood can be explained by the fact that progestins suppress ovulation and disturb the endocrine function of the ovary in the luteal phase. Moreover, their distinct chemical structure prevents their metabolism to neuroactive, mood-improving derivatives. A new understanding of progesterone-related mood disorders can translate the study results from case series and observational studies to cohort studies, clinical trials, and novel, effective treatment protocols being developed. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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Other

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16 pages, 1551 KiB  
Perspective
Efficacy of Ketamine with and without Lamotrigine in Treatment-Resistant Depression: A Preliminary Report
by Boney Joseph, Nicolas A. Nunez, Simon Kung, Jennifer L. Vande Voort, Vanessa K. Pazdernik, Kathryn M. Schak, Stacey M. Boehm, Brooke Carpenter, Emily K. Johnson, Grigoriy Malyshev, Nathan Smits, Daniel O. Adewunmi, Sarah K. Brown and Balwinder Singh
Pharmaceuticals 2023, 16(8), 1164; https://doi.org/10.3390/ph16081164 - 16 Aug 2023
Cited by 3 | Viewed by 2007 | Correction
Abstract
Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with [...] Read more.
Intravenous (IV) ketamine and FDA-approved intranasal (IN) esketamine are increasingly used for treatment-resistant depression (TRD). Preliminary studies have suggested a synergistic effect of ketamine and lamotrigine, although the data are inconclusive. Herein, we report the response to serial ketamine/esketamine treatment among patients with TRD with or without lamotrigine therapy. In this historical cohort study, we included adult patients with TRD who received serial IV racemic ketamine (0.5 mg/kg over 40−100 min) or IN esketamine (56/84 mg) treatments. A change in depressive symptoms was assessed using the 16-item Quick Inventory of Depressive Symptomatology self-report (QIDS-SR) scale. There were no significant differences in response or remission rates among the patients on or not on lamotrigine during the ketamine/esketamine treatments. For a percent change in the QIDS-SR from baseline, no interaction was found between the lamotrigine groups and treatment number (p = 0.70), nor the overall effect of the group (p = 0.38). There was a trend towards lower dissociation (based on the CADSS score) among current lamotrigine users, especially in patients who received IV ketamine. A major limitation is the limited number of patients taking lamotrigine (n = 13). This preliminary study provides insufficient evidence that continuing lamotrigine therapy attenuates the antidepressant effect of repeated ketamine/esketamine; however, there seems to be a signal toward attenuating dissociation with lamotrigine in patients receiving serial ketamine treatments. Further observational studies or randomized controlled trials are needed to replicate these findings. Full article
(This article belongs to the Special Issue Advances in Behavioral Psychopharmacology)
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