Pub Date : 2025-09-04DOI: 10.1016/j.pbb.2025.174094
Elaheh Danesh , Mohammad Saghafi , Roghayeh Mozafari , Somaye Mesgar , Abbas Haghparast
Methamphetamine (METH) is a highly addictive psychostimulant, and despite its widespread abuse, there are no FDA-approved treatments for METH use disorder (MUD). Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise in reducing behaviors linked to psychostimulant use, including METH. However, the underlying neurobiological mechanisms remain unclear. Emerging evidence suggests that CBD may act on the dopamine system to influence drug-seeking behavior. D1-like dopamine receptors (D1Rs) in the hippocampus (HPC) are involved in memory processes related to rewards, which may contribute to CBD's effects. This study examined whether D1Rs in the dentate gyrus (DG) region of the HPC play a role in CBD's modulation of METH-induced conditioned place preference (CPP) during extinction and reinstatement. Adult male Wistar rats received the D1Rs antagonist SCH23390 (0.25, 1, and 4 μg/0.5 μl saline) into the DG region before intracerebroventricular injection of CBD (10 and 50 μg/5 μl of 12 % DMSO). Results show that the highest dose of SCH23390 (4 μg) significantly blocked CBD's ability to enhance extinction of METH-CPP. Moreover, SCH23390 (1 and 4 μg) reversed CBD's prevention of reinstatement of METH-CPP. These findings suggest that D1Rs in the DG region are involved in mediating CBD's effects and offer insights into its therapeutic potential for MUD.
{"title":"D1-like dopamine receptors in the dentate gyrus mediate cannabidiol's facilitation of extinction and prevention of reinstatement in methamphetamine-induced conditioned place preference","authors":"Elaheh Danesh , Mohammad Saghafi , Roghayeh Mozafari , Somaye Mesgar , Abbas Haghparast","doi":"10.1016/j.pbb.2025.174094","DOIUrl":"10.1016/j.pbb.2025.174094","url":null,"abstract":"<div><div>Methamphetamine (METH) is a highly addictive psychostimulant, and despite its widespread abuse, there are no FDA-approved treatments for METH use disorder (MUD). Cannabidiol (CBD), a non-psychoactive cannabinoid, has shown promise in reducing behaviors linked to psychostimulant use, including METH. However, the underlying neurobiological mechanisms remain unclear. Emerging evidence suggests that CBD may act on the dopamine system to influence drug-seeking behavior. D1-like dopamine receptors (D1Rs) in the hippocampus (HPC) are involved in memory processes related to rewards, which may contribute to CBD's effects. This study examined whether D1Rs in the dentate gyrus (DG) region of the HPC play a role in CBD's modulation of METH-induced conditioned place preference (CPP) during extinction and reinstatement. Adult male Wistar rats received the D1Rs antagonist SCH23390 (0.25, 1, and 4 μg/0.5 μl saline) into the DG region before intracerebroventricular injection of CBD (10 and 50 μg/5 μl of 12 % DMSO). Results show that the highest dose of SCH23390 (4 μg) significantly blocked CBD's ability to enhance extinction of METH-CPP. Moreover, SCH23390 (1 and 4 μg) reversed CBD's prevention of reinstatement of METH-CPP. These findings suggest that D1Rs in the DG region are involved in mediating CBD's effects and offer insights into its therapeutic potential for MUD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174094"},"PeriodicalIF":2.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145006447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-04DOI: 10.1016/j.pbb.2025.174093
Bo Jarrett Wood , Nicole M. Hall , M. Frances Vest , Papori Sharma , Kevin S. Murnane
Methamphetamine is a highly addictive psychostimulant with significant neurobiological consequences, yet strain-dependent differences in its effects remain poorly understood. This study investigated behavioral and molecular differences in Swiss-Webster and C57BL/6 mice following methamphetamine exposure. Swiss-Webster mice exhibited greater behavioral sensitivity to methamphetamine compared to C57BL/6 mice, as demonstrated by lower peak doses required to elicit locomotor stimulation and conditioned place preference. Gene expression analyses revealed significantly higher striatal dopamine D2 receptor mRNA levels in Swiss-Webster mice, alongside a main effect of strain across multiple dopaminergic receptors, suggesting broader transcriptional differences may contribute to their heightened behavioral response. However, no strain differences were observed in dopamine transporter or dopamine D1 receptor mRNA expression. Following a neurotoxic binge-dosing regimen, both strains showed significant dopamine depletion, but no differences in the dopamine metabolite DOPAC were observed between strains in the striatum. Given the role of dopaminergic signaling in stimulant sensitivity and reward, these findings suggest that strain-dependent differences in methamphetamine response may reflect broader alterations in dopamine system function between these strains. This is the first study to directly compare Swiss-Webster and C57BL/6 mice in methamphetamine-induced CPP and provides novel insight into strain-specific drug reward mechanisms.
{"title":"Swiss-Webster and C57BL/6 mice are differentially sensitive to the stimulant effects of methamphetamine","authors":"Bo Jarrett Wood , Nicole M. Hall , M. Frances Vest , Papori Sharma , Kevin S. Murnane","doi":"10.1016/j.pbb.2025.174093","DOIUrl":"10.1016/j.pbb.2025.174093","url":null,"abstract":"<div><div>Methamphetamine is a highly addictive psychostimulant with significant neurobiological consequences, yet strain-dependent differences in its effects remain poorly understood. This study investigated behavioral and molecular differences in Swiss-Webster and C57BL/6 mice following methamphetamine exposure. Swiss-Webster mice exhibited greater behavioral sensitivity to methamphetamine compared to C57BL/6 mice, as demonstrated by lower peak doses required to elicit locomotor stimulation and conditioned place preference. Gene expression analyses revealed significantly higher striatal dopamine D2 receptor mRNA levels in Swiss-Webster mice, alongside a main effect of strain across multiple dopaminergic receptors, suggesting broader transcriptional differences may contribute to their heightened behavioral response. However, no strain differences were observed in dopamine transporter or dopamine D1 receptor mRNA expression. Following a neurotoxic binge-dosing regimen, both strains showed significant dopamine depletion, but no differences in the dopamine metabolite DOPAC were observed between strains in the striatum. Given the role of dopaminergic signaling in stimulant sensitivity and reward, these findings suggest that strain-dependent differences in methamphetamine response may reflect broader alterations in dopamine system function between these strains. This is the first study to directly compare Swiss-Webster and C57BL/6 mice in methamphetamine-induced CPP and provides novel insight into strain-specific drug reward mechanisms.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174093"},"PeriodicalIF":2.5,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-26DOI: 10.1016/j.pbb.2025.174092
Yi Chun Yu , Anna Kozłowska , Chi-Wen Wu , Cai-N Cheng , Yung-Chen Hsu , Lu Lu Fang , Andrew Chih Wei Huang
The impact of stress on the behaviors and neural substrates underlying opioid use disorder (OUD) remains unclear. To investigate this, we employed a footshock treatment before the pre- and post-conditioning procedures for conditioned taste aversion (CTA) and conditioned place preference (CPP) with morphine injections. In the experiment, all rats were subjected to 10-second footshock (3 mA) or no footshock treatments. Subsequently, CTA was established by allowing all rats to drink a 0.1 % saccharin solution for 15 min before intraperitoneal injection with normal saline or 20 mg/kg of morphine. Aftre that, rats were placed in a CPP compartment for 30 min to induce CPP learning. The results showed that footshock enhanced freezing time during the situational reminder. Morphine simultaneously induced aversion in the CTA and reward in the CPP. Footshock stress attenuated morphine-induced aversion in the CTA and facilitated morphine-induced reward in the CPP task. c-Fos expression was downregulated in the basolateral amygdala (BLA) under morphine administration and upregulated in the PrL and IL under footshock stress. Combined footshock stress and morphine injections increased c-Fos expression in the prelimbic cortex (PrL), infralimbic cortex (IL), and BLA. Footshock stress appeared to disrupt the neural connectivities among the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc), and basolateral amygdala (BLA). The network data indicated that footshock stress facilitated addiction-related neural pathways for the NAc and the PrL, IL, and BLA after morphine administration. The findings extend the paradoxical hypothesis of abused drugs and provide clinical contributions to the literature on OUD.
{"title":"Footshock stress enhances morphine-induced reward but attenuates aversion in behavior and neural mechanisms","authors":"Yi Chun Yu , Anna Kozłowska , Chi-Wen Wu , Cai-N Cheng , Yung-Chen Hsu , Lu Lu Fang , Andrew Chih Wei Huang","doi":"10.1016/j.pbb.2025.174092","DOIUrl":"10.1016/j.pbb.2025.174092","url":null,"abstract":"<div><div>The impact of stress on the behaviors and neural substrates underlying opioid use disorder (OUD) remains unclear. To investigate this, we employed a footshock treatment before the pre- and post-conditioning procedures for conditioned taste aversion (CTA) and conditioned place preference (CPP) with morphine injections. In the experiment, all rats were subjected to 10-second footshock (3 mA) or no footshock treatments. Subsequently, CTA was established by allowing all rats to drink a 0.1 % saccharin solution for 15 min before intraperitoneal injection with normal saline or 20 mg/kg of morphine. Aftre that, rats were placed in a CPP compartment for 30 min to induce CPP learning. The results showed that footshock enhanced freezing time during the situational reminder. Morphine simultaneously induced aversion in the CTA and reward in the CPP. Footshock stress attenuated morphine-induced aversion in the CTA and facilitated morphine-induced reward in the CPP task. c-Fos expression was downregulated in the basolateral amygdala (BLA) under morphine administration and upregulated in the PrL and IL under footshock stress. Combined footshock stress and morphine injections increased c-Fos expression in the prelimbic cortex (PrL), infralimbic cortex (IL), and BLA. Footshock stress appeared to disrupt the neural connectivities among the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), nucleus accumbens (NAc), and basolateral amygdala (BLA). The network data indicated that footshock stress facilitated addiction-related neural pathways for the NAc and the PrL, IL, and BLA after morphine administration. The findings extend the paradoxical hypothesis of abused drugs and provide clinical contributions to the literature on OUD.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174092"},"PeriodicalIF":2.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Administering medication during pregnancy is always a challenging task. Levetiracetam (LEV), a second-generation antiepileptic drug, has been recognized as relatively safe based on studies assessing neurodevelopmental outcomes of children exposed to it in utero, despite some animal research reporting skeletal abnormalities. The potential link between intrauterine exposure to subtherapeutic or therapeutic doses of LEV and behavioral abnormalities in adolescent offspring has not yet been examined. The present study aimed to investigate the effects of maternal exposure to LEV at doses of 158, 211, and 316 mg/kg/day during mating and throughout gestation on behavioral abnormalities in offspring during the periadolescent period, using a mouse model. The selected doses correspond to clinical human LEV doses of 750, 1000, and 1500 mg/day. To assess the quantitative and qualitative parameters of behavioral response, the elevated plus-maze test (EPMT) on postnatal day (PND) 37 and the open field test (OFT) on PND45 were used. Experimental animals prenatally exposed to subtherapeutic or therapeutic doses of LEV exhibited complex and qualitatively different behaviors during the periadolescent period. The study's findings suggest that different doses of LEV administered throughout gestation may alter brain maturation patterns in offspring, leading to behavioral changes during periadolescence. In both the EPMT and OFT, offspring of mothers exposed to different doses of LEV displayed hyperactivity and stereotypy, observed in both females and males. The results revealed a non-linear, dose-dependent effect on behavior. This suggests that the model may be applicable as an animal model for attention-deficit/hyperactivity disorder (ADHD).
{"title":"ADHD-like behaviors in adolescent mice prenatally exposed to levetiracetam: No safe gestational dose across sexes","authors":"Jelena Podgorac Kojadinović , Gordana Stojadinović , Sanela Popović , Slobodan Sekulić","doi":"10.1016/j.pbb.2025.174091","DOIUrl":"10.1016/j.pbb.2025.174091","url":null,"abstract":"<div><div>Administering medication during pregnancy is always a challenging task. Levetiracetam (LEV), a second-generation antiepileptic drug, has been recognized as relatively safe based on studies assessing neurodevelopmental outcomes of children exposed to it <em>in utero</em>, despite some animal research reporting skeletal abnormalities. The potential link between intrauterine exposure to subtherapeutic or therapeutic doses of LEV and behavioral abnormalities in adolescent offspring has not yet been examined. The present study aimed to investigate the effects of maternal exposure to LEV at doses of 158, 211, and 316 mg/kg/day during mating and throughout gestation on behavioral abnormalities in offspring during the periadolescent period, using a mouse model. The selected doses correspond to clinical human LEV doses of 750, 1000, and 1500 mg/day. To assess the quantitative and qualitative parameters of behavioral response, the elevated plus-maze test (EPMT) on postnatal day (PND) 37 and the open field test (OFT) on PND45 were used. Experimental animals prenatally exposed to subtherapeutic or therapeutic doses of LEV exhibited complex and qualitatively different behaviors during the periadolescent period. The study's findings suggest that different doses of LEV administered throughout gestation may alter brain maturation patterns in offspring, leading to behavioral changes during periadolescence. In both the EPMT and OFT, offspring of mothers exposed to different doses of LEV displayed hyperactivity and stereotypy, observed in both females and males. The results revealed a non-linear, dose-dependent effect on behavior. This suggests that the model may be applicable as an animal model for attention-deficit/hyperactivity disorder (ADHD).</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174091"},"PeriodicalIF":2.5,"publicationDate":"2025-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-23DOI: 10.1016/j.pbb.2025.174085
Agata Płoska , Adrianna Radulska , Anna Siekierzycka , Paulina Cieślik , Michał Santocki , Iwona T. Dobrucki , Leszek Kalinowski , Joanna M. Wierońska
Background
Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production.
Methods
Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M1) and VU0152100 (M4). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO• releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia.
Results
Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR.
Conclusions
eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.
{"title":"Allosteric modulation of M1 or M4 muscarinic receptors restores eNOS expression and L-arginine metabolism in dementia models and synergizes with NO releasers","authors":"Agata Płoska , Adrianna Radulska , Anna Siekierzycka , Paulina Cieślik , Michał Santocki , Iwona T. Dobrucki , Leszek Kalinowski , Joanna M. Wierońska","doi":"10.1016/j.pbb.2025.174085","DOIUrl":"10.1016/j.pbb.2025.174085","url":null,"abstract":"<div><h3>Background</h3><div>Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production.</div></div><div><h3>Methods</h3><div>Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M<sub>1</sub>) and VU0152100 (M<sub>4</sub>). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO<sup>•</sup> releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia.</div></div><div><h3>Results</h3><div>Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR.</div></div><div><h3>Conclusions</h3><div>eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174085"},"PeriodicalIF":2.5,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144916342","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-22DOI: 10.1016/j.pbb.2025.174088
F.J. Cano, C.J.E. Denning, H. Udayashankar, S.D. Adler, K.E. Smith, V. Dang, K. Mohammadi, A.T. Reed Aparicio, A. Jotwani, L.L. Huerta Sanchez, K.K. Szumlinski
The similar temporal profile of incubated food- vs. drug-craving has led to the hypothesis that these behavioral phenomena may involve common, time-dependent, biochemical adaptations within neural circuits governing motivated behavior. Previously, we reported that the mTOR inhibitor Everolimus dose-dependently blocks incubated cocaine-seeking and reverses incubation-related changes in mTOR activation in the prelimbic (PL) subregion of the prefrontal cortex (PFC). Herein, we examined the biomolecular correlates of incubated sucrose-craving within these PFC subregions. Female and male rats were trained to lever-press for 45 mg banana-flavored sucrose pellets, paired with a light + tone compound stimulus during daily 6-h sessions over 10 consecutive days. One or 30 days following the last operant-conditioning session, cue-reinforced responding was assessed. Rats of both sexes exhibited comparable incubated sucrose-craving, yet the majority of incubation-related protein changes were sex-specific. In males, incubated craving was associated with increased indices of Akt/mTOR activation in the IL, and increased mGlu5 dimer expression within both subregions, while females exhibited reduced indices of Akt and PKCε activation, as well as, mGlu5 monomer levels in the PL only. Systemic pretreatment with Everolimus (1.0 mg/kg) produced a modest effect on sucrose cue-reinforced responding that was sufficient to block the incubated response. Taken together, our immunoblotting and behavioral pharmacological data to date argue that different biomolecular mechanisms operate with the IL and PL to drive incubated cocaine- versus sucrose-craving, with mTOR playing a lesser role in the manifestation of incubated sucrose-craving.
{"title":"Biomolecular correlates of incubated sucrose-seeking within ventromedial prefrontal cortex are sex- and subregion-selective","authors":"F.J. Cano, C.J.E. Denning, H. Udayashankar, S.D. Adler, K.E. Smith, V. Dang, K. Mohammadi, A.T. Reed Aparicio, A. Jotwani, L.L. Huerta Sanchez, K.K. Szumlinski","doi":"10.1016/j.pbb.2025.174088","DOIUrl":"10.1016/j.pbb.2025.174088","url":null,"abstract":"<div><div>The similar temporal profile of incubated food- vs. drug-craving has led to the hypothesis that these behavioral phenomena may involve common, time-dependent, biochemical adaptations within neural circuits governing motivated behavior. Previously, we reported that the mTOR inhibitor Everolimus dose-dependently blocks incubated cocaine-seeking and reverses incubation-related changes in mTOR activation in the prelimbic (PL) subregion of the prefrontal cortex (PFC). Herein, we examined the biomolecular correlates of incubated sucrose-craving within these PFC subregions. Female and male rats were trained to lever-press for 45 mg banana-flavored sucrose pellets, paired with a light + tone compound stimulus during daily 6-h sessions over 10 consecutive days. One or 30 days following the last operant-conditioning session, cue-reinforced responding was assessed. Rats of both sexes exhibited comparable incubated sucrose-craving, yet the majority of incubation-related protein changes were sex-specific. In males, incubated craving was associated with increased indices of Akt/mTOR activation in the IL, and increased mGlu5 dimer expression within both subregions, while females exhibited reduced indices of Akt and PKCε activation, as well as, mGlu5 monomer levels in the PL only. Systemic pretreatment with Everolimus (1.0 mg/kg) produced a modest effect on sucrose cue-reinforced responding that was sufficient to block the incubated response. Taken together, our immunoblotting and behavioral pharmacological data to date argue that different biomolecular mechanisms operate with the IL and PL to drive incubated cocaine- versus sucrose-craving, with mTOR playing a lesser role in the manifestation of incubated sucrose-craving.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174088"},"PeriodicalIF":2.5,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144903590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-21DOI: 10.1016/j.pbb.2025.174087
Shadan Rahmani , Rachel Crupi , Anthony L. Riley , Terry Davidson
After many years of stigma and neglect, there is a resurgence of interest in the therapeutic use of psychedelic drugs. Anecdotal and evidence-based reports indicate psychedelics as a possible treatment for depression, anxiety, PTSD, substance abuse, and other disorders resistant to conventional medical interventions. The available data, however, are limited and the use of psychedelic substances in therapy remains controversial. This paper presents a collection of reports based on the talks of eighteen renowned experts in science, policy, and law who spoke at a recent symposium organized by American University's Center for Neuroscience and Behavior titled “The Therapeutic Uses of Psychedelic Drugs: Legal, Policy, and Neuroscientific Perspectives.” These speakers presented their ideas and perspectives concerning (a) the safety and effectiveness of psychedelic-assisted therapies; (b) the brain systems on which psychedelic drugs act; (c) ethical issues for both research and clinical settings; (d) pathways to increasing access to psychedelics for medical and nonmedical purposes; (e) federal and state regulation of psychedelic drugs for research, therapy, and nonmedical uses; and (f) procedures and requirements for psychedelic drug patents and commercialization. In considering these topics, each speaker strove to make their views accessible to diverse audiences of professionals outside of their own disciplines. This paper aims to faithfully convey the substance of each talk, while also providing additional context and updates relevant to the presentations. The symposium revealed the potential of psychedelics for treating psychiatric and behavioral disorders and the scientific, legal, and policy challenges that must be met to realize this potential.
{"title":"The therapeutic use of psychedelic drugs: Legal, policy, and neuroscientific perspectives","authors":"Shadan Rahmani , Rachel Crupi , Anthony L. Riley , Terry Davidson","doi":"10.1016/j.pbb.2025.174087","DOIUrl":"10.1016/j.pbb.2025.174087","url":null,"abstract":"<div><div>After many years of stigma and neglect, there is a resurgence of interest in the therapeutic use of psychedelic drugs. Anecdotal and evidence-based reports indicate psychedelics as a possible treatment for depression, anxiety, PTSD, substance abuse, and other disorders resistant to conventional medical interventions. The available data, however, are limited and the use of psychedelic substances in therapy remains controversial. This paper presents a collection of reports based on the talks of eighteen renowned experts in science, policy, and law who spoke at a recent symposium organized by American University's Center for Neuroscience and Behavior titled “The Therapeutic Uses of Psychedelic Drugs: Legal, Policy, and Neuroscientific Perspectives.” These speakers presented their ideas and perspectives concerning (a) the safety and effectiveness of psychedelic-assisted therapies; (b) the brain systems on which psychedelic drugs act; (c) ethical issues for both research and clinical settings; (d) pathways to increasing access to psychedelics for medical and nonmedical purposes; (e) federal and state regulation of psychedelic drugs for research, therapy, and nonmedical uses; and (f) procedures and requirements for psychedelic drug patents and commercialization. In considering these topics, each speaker strove to make their views accessible to diverse audiences of professionals outside of their own disciplines. This paper aims to faithfully convey the substance of each talk, while also providing additional context and updates relevant to the presentations. The symposium revealed the potential of psychedelics for treating psychiatric and behavioral disorders and the scientific, legal, and policy challenges that must be met to realize this potential.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174087"},"PeriodicalIF":2.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-18DOI: 10.1016/j.pbb.2025.174086
Ariel Frajerman , Aude Marzo , Boris Chaumette , Thérèse M. Jay , Fanny Demars , Antonin Lamazière , Oussama Kebir , Marie-Odile Krebs , Gwenaëlle Le Pen
Background
Alterations in membrane lipids are well established in schizophrenia, and diet could be an accessible, modifiable etiological factor. We examined the influence of Polyunsaturated fatty acids (PUFAs) intake throughout the lifespan on behaviour in adult rats. We further explored a possible interaction with adolescent exposure to delta-9-tetrahydrocannabinol (THC), the lipidic psychoactive compound responsible for cannabis's psychotic effects.
Methods
Sprague Dawley rats (n = 164, male and female) were separated into 3 groups exposed from conception to specific diets enriched in omega 3, 6, or 9, controlled by gas chromatography, with ratios determined to stay close to physiological balance. They were explored in adulthood in tests acknowledged as modelling symptomatic dimensions of schizophrenia, including locomotor activity, short-term recognition memory, sensorimotor gating, social interactions, anxiety, impulsivity, response inhibition and attention.
Results
The effects of diet on social interactions, locomotor activity, anxiety, cognitive flexibility, response inhibition, and impulse control were significant. Omega-3-enriched diet rats were less anxious and more impulsive than those receiving an omega-6 diet. THC exposure in adolescence interacts with diet and gender to influence adult anxiety and impulsivity.
Limitations
The diet's impacts are difficult to compare with previous data because we used new ratios of PUFA to be more physiological.
Conclusion
These results underline the importance of considering the relative influence of the 3 different families of Unsaturated Fatty acids and the importance of the omega-6/omega-3 ratio in controlled and balanced diets. The results could explain why omega-3 supplementation has only a moderate effect at high dosages and/or possibly only in patients with an initial alteration in lipid membrane composition.
{"title":"Lifelong dietary Omega-3, -6, and -9 ratios shape adult behavior and response to adolescent THC exposure in rats","authors":"Ariel Frajerman , Aude Marzo , Boris Chaumette , Thérèse M. Jay , Fanny Demars , Antonin Lamazière , Oussama Kebir , Marie-Odile Krebs , Gwenaëlle Le Pen","doi":"10.1016/j.pbb.2025.174086","DOIUrl":"10.1016/j.pbb.2025.174086","url":null,"abstract":"<div><h3>Background</h3><div>Alterations in membrane lipids are well established in schizophrenia, and diet could be an accessible, modifiable etiological factor. We examined the influence of Polyunsaturated fatty acids (PUFAs) intake throughout the lifespan on behaviour in adult rats. We further explored a possible interaction with adolescent exposure to delta-9-tetrahydrocannabinol (THC), the lipidic psychoactive compound responsible for cannabis's psychotic effects.</div></div><div><h3>Methods</h3><div>Sprague Dawley rats (<em>n</em> = 164, male and female) were separated into 3 groups exposed from conception to specific diets enriched in omega 3, 6, or 9, controlled by gas chromatography, with ratios determined to stay close to physiological balance. They were explored in adulthood in tests acknowledged as modelling symptomatic dimensions of schizophrenia, including locomotor activity, short-term recognition memory, sensorimotor gating, social interactions, anxiety, impulsivity, response inhibition and attention.</div></div><div><h3>Results</h3><div>The effects of diet on social interactions, locomotor activity, anxiety, cognitive flexibility, response inhibition, and impulse control were significant. Omega-3-enriched diet rats were less anxious and more impulsive than those receiving an omega-6 diet. THC exposure in adolescence interacts with diet and gender to influence adult anxiety and impulsivity.</div></div><div><h3>Limitations</h3><div>The diet's impacts are difficult to compare with previous data because we used new ratios of PUFA to be more physiological.</div></div><div><h3>Conclusion</h3><div>These results underline the importance of considering the relative influence of the 3 different families of Unsaturated Fatty acids and the importance of the omega-6/omega-3 ratio in controlled and balanced diets. The results could explain why omega-3 supplementation has only a moderate effect at high dosages and/or possibly only in patients with an initial alteration in lipid membrane composition.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"256 ","pages":"Article 174086"},"PeriodicalIF":2.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.pbb.2025.174077
Javad Riyahi , Parvaneh Shamsipour Dehkordi , Behrouz Abdoli , Francesca Gelfo , Laura Petrosini , Abbas Haghparast
Following previous studies on the intergenerational transmission of cognitive abilities, the present research aimed to answer whether parental training on a specific cognitive task may facilitate the learning process of other cognitive tasks in the next generation. Namely, to investigate whether in addition to improving spatial memory acquisition in male offspring, paternal spatial training can also lead to improvements in working memory, short-term memory, and long-term memory, we tested in Morris Water Maze (MWM) or Y-maze and Novel Object Recognition (NOR) tests groups of male offspring of fathers spatially trained (or not spatially trained) in the MWM. Then, we analyzed the immunocontent levels of BDNF, p-ERK1/2, SYT1, and acetylated H3K14 in the hippocampus of the offspring performing MWM, or Y-maze and NOR tests. Paternal MWM training facilitated learning and memory processes of the male offspring in the MWM task, and in parallel, increased hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and also H3K14 acetylation. On the other hand, the paternal MWM training did not affect the processes of working memory, short-term, and long-term memory of the male offspring, and did not change the hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and H3K14 acetylation level after cognitive training. Overall, the present results show that the intergenerational effects of paternal training in cognitive tasks are task-specific, not causing improvements in cognitive tasks other than those in which the fathers had been trained.
{"title":"The task-specific intergenerational transmission of paternal cognitive experiences on male offspring memory","authors":"Javad Riyahi , Parvaneh Shamsipour Dehkordi , Behrouz Abdoli , Francesca Gelfo , Laura Petrosini , Abbas Haghparast","doi":"10.1016/j.pbb.2025.174077","DOIUrl":"10.1016/j.pbb.2025.174077","url":null,"abstract":"<div><div>Following previous studies on the intergenerational transmission of cognitive abilities, the present research aimed to answer whether parental training on a specific cognitive task may facilitate the learning process of other cognitive tasks in the next generation. Namely, to investigate whether in addition to improving spatial memory acquisition in male offspring, paternal spatial training can also lead to improvements in working memory, short-term memory, and long-term memory, we tested in Morris Water Maze (MWM) or Y-maze and Novel Object Recognition (NOR) tests groups of male offspring of fathers spatially trained (or not spatially trained) in the MWM. Then, we analyzed the immunocontent levels of BDNF, p-ERK1/2, SYT1, and acetylated H3K14 in the hippocampus of the offspring performing MWM, or Y-maze and NOR tests. Paternal MWM training facilitated learning and memory processes of the male offspring in the MWM task, and in parallel, increased hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and also H3K14 acetylation. On the other hand, the paternal MWM training did not affect the processes of working memory, short-term, and long-term memory of the male offspring, and did not change the hippocampal immunocontent levels of BDNF, SYT1, p-ERK1/2, and H3K14 acetylation level after cognitive training. Overall, the present results show that the intergenerational effects of paternal training in cognitive tasks are task-specific, not causing improvements in cognitive tasks other than those in which the fathers had been trained.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174077"},"PeriodicalIF":2.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144789670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-05DOI: 10.1016/j.pbb.2025.174078
Gang Zhao , Xian Tian , Kangwei Peng , Lin Guo , Yuhuang Chen , Yonggang Cao , Hongmei Wu , Min Zhang
Objective
We investigated the role of sphingosine-1-phosphate receptor 1 (S1PR1) in blood-brain barrier (BBB) function and associated behavioral abnormalities using the BTBR T + tf/J (BTBR) mouse model of autism.
Methods
Male C57BL/6 J (C57) and BTBR mice (4-week-old, n = 16/group) were assigned to three groups: C57 + Veh, BTBR+Veh, and BTBR+W146. The BTBR+W146 group received daily intraperitoneal injections of W146 (1 mg/kg) for 21 days, while control groups received equivalent volumes of vehicle (DMSO+0.9 % saline). Learning and memory were assessed using the Morris water maze. S1PR1 expression was determined via RT-PCR and Western blot analysis. Hippocampal neuronal morphology was examined by Nissl staining, while microvascular endothelial markers (CD31) and apoptotic pathway proteins (p-ERK, Caspase-3) were assessed by immunohistochemistry and Western blot.
Results
BTBR mice showed significantly higher hippocampal S1P and S1PR1 than C57 controls (P < 0.01). W146 treatment reduced escape latency and increased platform crossings in the Morris water maze (P < 0.05). Treatment with W146 also increased phospho-Ca2+/calmodulin-dependent protein kinase II (p-CaMKII), and phospho-cAMP-response element binding protein (p-CREB) expression in the hippocampus. Histologically, W146 restored neuronal density in the hippocampal CA1 region and preserved microvascular integrity, as shown by increased CD31 expression (P < 0.05). The observed neuroprotective effect was linked to significant decreases in the expression of phosphorylated ERK (P < 0.05) and Caspase-3 (P < 0.05).
Conclusion
Elevated S1P/S1PR1 signaling in BTBR mice is associated with hippocampal neurovascular dysfunction. Treatment with the S1PR1 antagonist W146 improves learning and memory deficits, coinciding with reduced ERK/Caspase-3-mediated apoptotic signaling and preserved CA1 neuronal integrity. These findings highlight S1PR1 as a potential therapeutic target for autism-related cognitive impairments.
{"title":"Targeting S1PR1 with W146 Ameliorates autism-associated cognitive deficits by restoring neurovascular integrity via ERK/Caspase-3 pathway modulation","authors":"Gang Zhao , Xian Tian , Kangwei Peng , Lin Guo , Yuhuang Chen , Yonggang Cao , Hongmei Wu , Min Zhang","doi":"10.1016/j.pbb.2025.174078","DOIUrl":"10.1016/j.pbb.2025.174078","url":null,"abstract":"<div><h3>Objective</h3><div>We investigated the role of sphingosine-1-phosphate receptor 1 (S1PR1) in blood-brain barrier (BBB) function and associated behavioral abnormalities using the BTBR T + tf/J (BTBR) mouse model of autism.</div></div><div><h3>Methods</h3><div>Male C57BL/6 J (C57) and BTBR mice (4-week-old, <em>n</em> = 16/group) were assigned to three groups: C57 + Veh, BTBR+Veh, and BTBR+W146. The BTBR+W146 group received daily intraperitoneal injections of W146 (1 mg/kg) for 21 days, while control groups received equivalent volumes of vehicle (DMSO+0.9 % saline). Learning and memory were assessed using the Morris water maze. S1PR1 expression was determined via RT-PCR and Western blot analysis. Hippocampal neuronal morphology was examined by Nissl staining, while microvascular endothelial markers (CD31) and apoptotic pathway proteins (p-ERK, Caspase-3) were assessed by immunohistochemistry and Western blot.</div></div><div><h3>Results</h3><div>BTBR mice showed significantly higher hippocampal S1P and S1PR1 than C57 controls (<em>P</em> < 0.01). W146 treatment reduced escape latency and increased platform crossings in the Morris water maze (<em>P</em> < 0.05). Treatment with W146 also increased phospho-Ca<sup>2+</sup>/calmodulin-dependent protein kinase II (p-CaMKII), and phospho-cAMP-response element binding protein (p-CREB) expression in the hippocampus. Histologically, W146 restored neuronal density in the hippocampal CA1 region and preserved microvascular integrity, as shown by increased CD31 expression (<em>P</em> < 0.05). The observed neuroprotective effect was linked to significant decreases in the expression of phosphorylated ERK (<em>P</em> < 0.05) and Caspase-3 (<em>P</em> < 0.05).</div></div><div><h3>Conclusion</h3><div>Elevated S1P/S1PR1 signaling in BTBR mice is associated with hippocampal neurovascular dysfunction. Treatment with the S1PR1 antagonist W146 improves learning and memory deficits, coinciding with reduced ERK/Caspase-3-mediated apoptotic signaling and preserved CA1 neuronal integrity. These findings highlight S1PR1 as a potential therapeutic target for autism-related cognitive impairments.</div></div>","PeriodicalId":19893,"journal":{"name":"Pharmacology Biochemistry and Behavior","volume":"255 ","pages":"Article 174078"},"PeriodicalIF":2.5,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144780616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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