Methamphetamine Conditioned Place Preference Research Articles

The role of D1-like dopamine receptors within the ventral tegmental area in the cannabidiol’s inhibitory effects on the methamphetamine-induced conditioned place preference in rats

Cannabidiol (CBD) is a non-psychoactive drug extracted from marijuana. It is well established that CBD attenuates the reinforcing effects of drugs of abuse, although its mechanism of action is not fully understood. The current study tries to clarify the role of D1-like dopamine receptors (D1R) in the ventral tegmental area (VTA) in the inhibitory effects of the CBD on the acquisition and expression of methamphetamine (METH)-conditioned place preference (CPP). In the CPP training, adult male Wistar rats were conditioned with subcutaneous administration of METH (1 mg/kg) for five days. Three groups of animals were treated with multiple doses of SCH23390 (as a D1R antagonist; 0.25, 1, and 4 μg/0.3 μl saline) in the VTA, respectively, before intracerebroventricular (ICV) injection of CBD (10 μg/5 μl DMSO) in the acquisition phase. In the second experiment of the study, rats received SCH23390 in the VTA before ICV administration of CBD (50 μg/5 μl DMSO) in the expression of METH CPP. Here, the current study demonstrated that CBD inhibits the acquisition and expression of METH CPP, while microinjection of D1R antagonists (1 and 4 μg) into the VTA significantly reduced CBD’s suppressive effect on the acquisition and expression of METH place preference. Furthermore, this research demonstrated that either SCH23390 or CBD alone does not lead to place preference in the CPP paradigm. Based on these data, this study suggests that pharmacological manipulations of D1R may alter the CBD’s effect on METH-conditioned preference.

The role of heterodimers formed by histamine H3 receptors and dopamine D1 receptors on the methamphetamine-induced conditioned place preference

RationaleThe rewarding effect of Methamphetamine (METH) is commonly believed to play an important role in METH use disorder. The altered expression of dopamine D1 receptor (D1R) has been suggested to be essential to the rewarding effect of METH. Notably, D1R could interact with histamine H3 receptors (H3R) by forming a H3R-D1R heteromer (H3R-D1R). ObjectivesThis study was designed to specifically investigate the involvement of H3R-D1R in the rewarding effect of METH. MethodsC57BL/6 mice were treated with intraperitoneal injections of a selective H3R antagonist (Thioperamide, THIO; 20 mg/kg), an H1R antagonist (Pyrilamine, PYRI; 10 mg/kg), or microinjections of cytomegalovirus (CMV)-transmembrane domain 5 (TM5) into the nucleus accumbens (NAc). The animal model of Conditioned Place Preference (CPP) was applied to determine the impact of H3R-D1R on the rewarding effect of METH. ResultsMETH resulted in a significant preference for the drug-associated chamber, in conjunction with increased H3R and decreased D1R expression in both NAc and the ventral tegmental area (VTA). THIO significantly attenuated the rewarding effect of METH, accompanied by decreased H3R and increased D1R expression. In contrast, pyrilamine failed to produce the similar effects. Moreover, the inhibitory effect of THIO on METH-induced CPP was reversed by SKF38393, a D1R agonist. Furthermore, SCH23390, a D1R antagonist, counteracted the ameliorative effect of SKF38393 on THIO. Co-immunoprecipitation (CO-IP) experiments further demonstrated the specific interaction between H3R and D1R in METH CPP mice. The rewarding effect of METH was also significantly blocked by the interruption of CMV-transmembrane domain 5 (TM5), but not CMV-transmembrane domain 7 (TM7) in NAc. ConclusionThese results suggest that modulating the activity of H3R-D1R complex holds promise for regulating METH use disorder and serves as a potential drug target for its treatment.

VTA glutamatergic projections to the nucleus accumbens suppress psychostimulant-seeking behavior.

Converging evidence indicates that both dopamine and glutamate neurotransmission within the nucleus accumbens (NAc) play a role in psychostimulant self-administration and relapse in rodent models. Increased NAc dopamine release from ventral tegmental area (VTA) inputs is critical to psychostimulant self-administration and NAc glutamate release from prelimbic prefrontal cortex (PFC) inputs synapsing on medium spiny neurons (MSNs) is critical to reinstatement of psychostimulant-seeking after extinction. The regulation of the activity of MSNs by VTA dopamine inputs has been extensively studied, and recent findings have demonstrated that VTA glutamate neurons target the NAc medial shell. Here, we determined whether the mesoaccumbal glutamatergic pathway plays a role in psychostimulant conditioned place preference and self-administration in mice. We used optogenetics to induce NAc release of glutamate from VTA inputs during the acquisition, expression, and reinstatement phases of cocaine- or methamphetamine-induced conditioned place preference (CPP), and during priming-induced reinstatement of cocaine-seeking behavior. We found that NAc medial shell release of glutamate resulting from the activation of VTA glutamatergic fibers did not affect the acquisition of cocaine-induced CPP, but it blocked the expression, stress- and priming-induced reinstatement of cocaine- and methamphetamine CPP, as well as it blocked the priming-induced reinstatement of cocaine-seeking behavior after extinction. These findings indicate that in contrast to the well-recognized mesoaccumbal dopamine system that is critical to psychostimulant reward and relapse, there is a parallel mesoaccumbal glutamatergic system that suppresses reward and psychostimulant-seeking behavior.

Activating Lobule VI PCTH+-Med Pathway in Cerebellum Blocks the Acquisition of Methamphetamine Conditioned Place Preference in Mice.

Cerebellum has been implicated in drug addiction; however, its underlying cellular populations and neuronal circuitry remain largely unknown. In the current study, we identified a neural pathway from tyrosine hydroxylase (TH)-positive Purkinje cells (PCTH+) in cerebellar lobule VI to calcium/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the medial cerebellar nucleus (MedCaMKII), forming the lobule VI PCTH+-MedCaMKII pathway in male mice. In naive male mice, inhibition of PCTH+ neurons activated Med neurons. During conditioned place preference (CPP) training, exposure to methamphetamine (METH) inhibited lobule VI PCTH+ neurons while excited MedCaMKII neurons in mice. Silencing MedCaMKII using a tetanus toxin light chain (tettox) suppressed the acquisition of METH CPP in mice but resulted in motor coordination deficits in naive mice. In contrast, activating lobule VI PCTH+ terminals within Med inhibited the activity of Med neurons and subsequently blocked the acquisition of METH CPP in mice without affecting motor coordination, locomotor activity, and sucrose reinforcements in naive mice. Our findings identified a novel lobule VI PCTH+-MedCaMKII pathway within the cerebellum and explored its role in mediating the acquisition of METH-preferred behaviors.

Effects of adolescent methylphenidate administration on methamphetamine conditioned place preference in an animal model of attention-deficit/hyperactivity disorder: Examination of potential sex differences

BackgroundIndividuals with attention-deficit/hyperactivity disorder (ADHD) are more likely to be diagnosed with a substance use disorder; however, the effects of long-term psychostimulant treatment on addiction are mixed. Preclinical studies are useful for further elucidating the relationship between ADHD and addiction-like behaviors, but these studies have focused on male subjects only. The goal of the current study was to determine if early-life administration of methylphenidate (MPH) augments methamphetamine (METH) conditioned place preference (CPP) and/or potentiates reinstatement of CPP in both male and female rats. MethodsMale and female spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats (WKYs) received either MPH (1.5mg/kg; p.o.) or vehicle (1.0ml/kg) during adolescence (postnatal day [PND] ~29–57). Two weeks after cessation of MPH treatment, rats were tested for METH CPP (1.0mg/kg or 2.0mg/kg; s.c.). Rats were then given extinction sessions. Once rats met extinction criteria, they were tested for reinstatement of CPP following a priming injection of METH (0.25mg/kg; s.c.). ResultsAll groups developed METH CPP, except vehicle-treated SHR males and vehicle-treated WKY females conditioned with the higher dose of METH (2.0mg/kg). Female SHRs treated with MPH showed greater reinstatement of METH CPP compared to female SHRs treated with vehicle. Adolescent MPH treatment did not augment the locomotor-stimulant effects of METH in adulthood. ConclusionsThese results demonstrate the importance of considering biological sex when prescribing psychostimulant medications for ADHD as long-term MPH administration may increase the risk of continued drug use in females with ADHD following a period of abstinence.

The blockade of orexin receptors within the dentate gyrus of the hippocampus attenuated methamphetamine-induced reward learning during conditioning place preference

Orexins and orexinergic receptors have been shown to play a critical role in reward processing and drug addiction. Previous studies showed that the orexinergic system in the dentate gyrus (DG) region of the hippocampus affects the conditioning (acquisition) and post-conditioning (expression) phases of morphine-induced conditioned place preference (CPP). The action of each orexin receptor within the DG during conditioning and expression phases for methamphetamine (METH)-induced CPP remains unclear. The present study aimed to determine the role of orexin-1 and -2 receptors in the hippocampal DG in METH CPP acquisition and expression. During the 5-day conditioning phase, rats received an intra-DG microinjection of SB334867, a selective orexin-1 receptor (OX1R) antagonist, or TCS OX2-29, a selective orexin-2 receptor (OX2R) antagonist, before injection of METH (1 mg/kg; sc). In different sets of animals on the expression day, rats received each antagonist before the CPP test. The results showed that SB334867 (3, 10, and 30 nmol) and TCS OX2-29 (3, 10, and 30 nmol) significantly decreased the acquisition of METH CPP during the conditioning phase. Furthermore, administration of SB 334867 (10 and 30 nmol) and TCS OX2-29 (3 and 10 nmol) on the post-conditioning day significantly reduced METH-induced CPP expression. The results also indicated that orexin receptors play a more critical role in the conditioning phase than in the expression phase. In summary, the orexin receptors in the DG play a crucial role in drug learning and memory and are essential for METH reward acquisition and expression.

Distinct suppressing effects of deep brain stimulation in the orbitofrontal cortex on the development, extinction, and reinstatement of methamphetamine-seeking behaviors

AimsThe orbitofrontal cortex (OFC) is implicated in compulsive drug-seeking and relapse, the characteristics that result in addiction treatment failure. Structural and functional impairments within the OFC have been detected in many substance use disorders (SUDs). Deep brain stimulation (DBS) is proposed as a promising therapeutic option in treating SUDs. Therefore, the present study aimed to investigate the potential efficacy of DBS application on the various stages of the methamphetamine-conditioned place preference (CPP) paradigm in rats. Main methodsElectrodes were implanted unilaterally in the rat's right OFC. DBS in the form of high- or low-frequency stimulation (HFS: 130 Hz, LFS: 13 Hz) was applied during the 5-day conditioning phase (a daily 30-min session) or extinction period (30-min session, daily, ten days) of methamphetamine-induced CPP in two separate sets of experiments. Following extinction, place preference was reinstated by injecting a priming dose of methamphetamine (0.25 mg/kg). Key findingsThe HFS and LFS significantly decreased the methamphetamine place preference when applied over the conditioning period. In the extinction experiment, only HFS could remarkably accelerate the extinction of reward-context associations and even reduce the methamphetamine-induced reinstatement of seeking behaviors. SignificanceConclusively, DBS administration in the OFC demonstrated some positive results, including suppressing effects on the development, maintenance, and relapse of methamphetamine-seeking behavior. These findings encourage conducting more preclinical studies to strongly suggest a wide range of DBS applications in cortical areas such as OFC as an efficient treatment modality for psychostimulant use disorder.

Troriluzole inhibits methamphetamine place preference in rats and normalizes methamphetamine-evoked glutamate carboxypeptidase II (GCPII) protein levels in the mesolimbic pathway

Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ.

A 1:1 ratio of cannabidiol: tetrahydrocannabinol attenuates methamphetamine conditioned place preference in mice: A prospective study of antidopaminergic mechanism

A 1:1 ratio of cannabidiol to tetrahydrocannabinol (CT) was suggested to be safer for therapeutic purposes in many illnesses. However, CT effects on methamphetamine (METH) conditioned place preference (CPP) remained largely unexplored. This study aimed to examine the effects of CT on METH CPP mice evaluated by animal behaviors accompanied by local field potential (LFP) signals analysis. Male ICR mice were implanted with the LFP electrode in the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Animals were next subjected to induce METH CPP by peritoneal injection with 1 mg/kg METH and 0.9 % NaCl on an alternate day for ten sessions and confined to the corresponding compartment for 30 min meanwhile control mice were given normal saline all day for both compartments. On testing day, either 10 mg/kg CT or 20 mg/kg bupropion (BP), a dopamine reuptake inhibitor, and VTA GABAergic suppressor were orally administered before CPP testing. The results revealed that CPP scores elevation was observed in the METH+vehicle and METH+BP mice, but this was reversed by CT treatment. Although both METH+vehicle and METH+BP enhanced the VTA delta power, NAc gamma I power, NAc delta-gamma coupling, and VTA-NAc gamma I coherence, changes in opposite trends of all mentioned parameters were seen by CT application. These improvements were postulated to involve the antidopaminergic effects of CT via modulations of neural signaling in the VTA and NAc. Altogether, the evidence-based study may suggest the use of CT as alternative drug for METH-seeking and craving therapy.

Purinergic P2X7 receptor antagonist inhibits methamphetamine-induced reward, hyperlocomotion, and cortical IL-7A levels in mice: A role for P2X7/IL-17A crosstalk in methamphetamine behaviors?

P2X7 receptors are dysregulated during psychostimulant exposure. Furthermore, P2X7 receptors enhance endogenous systems (e.g., cytokines, dopamine, and glutamate) that facilitate psychostimulant addiction. Therefore, using mouse locomotor, conditioned place preference (CPP), and intracranial self-stimulation (ICSS) assays, we tested the hypothesis that methamphetamine (METH) reward and acute locomotor activation requires P2X7 receptor activity. We also investigated effects of P2X7 blockade on METH-induced changes in cytokine levels in brain reward regions. A438079 (5, 10, 50 mg/kg), a P2X7 antagonist, did not affect spontaneous locomotor activity but reduced hyperlocomotion caused by acute METH (1 mg/kg) exposure. A438079 (10 mg/kg) also prevented expression of METH CPP without causing aversive or rewarding effects. For ICSS experiments, METH (1 mg/kg) facilitated brain reward function as interpreted from reductions in baseline threshold. In the presence of A438079 (50 mg/kg), METH-induced facilitation of ICSS was reduced. Repeated METH exposure (1 mg/kg × 7 d) caused enhancement of IL-17A levels in the prefrontal cortex (PFC) that was normalized by A438070 (10 mg/kg × 7 d). The present data suggest that P2X7 receptor activity contributes to rewarding and locomotor-stimulant effects of METH through a potential mechanism involving IL-17A, which has recently been implicated in anxiety.

Astrocyte-derived lactate/NADH alters methamphetamine-induced memory consolidation and retrieval by regulating neuronal synaptic plasticity in the dorsal hippocampus.

Drug memory is associated with drug-taking experience and environmental cues, which mainly contribute to addiction. Recent studies report that glycogenolysis-derived lactate from astrocyte transport to neurons is necessary for long-term potentiation and memory formation instead of its function as an energy substrate. However, the role of astrocyte-neuron lactate transfer in neuronal plasticity and methamphetamine (METH)-induced addiction memory consolidation and retrieval, especially the underlying mechanisms, are not clear. C57BL/6J mice trained for METH-induced conditioned place preference (CPP) were stereotaxically injected with the glycogen phosphorylaseinhibitor 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) into the dorsal hippocampus (dHPC) 15 minbeforetraining. The CPP score was recorded, and neuronal synaptic plasticity was detected with Golgi staining. The neuronal Ca2+ levels were examined using AAV-GCaMP6 injection. Moreover, monocarboxylate transporters (MCT1, MCT2, MCT4) were inhibited with oligodeoxynucleotides in the dHPC to further prove the METH appetitive memory changes. The data showed that inhibiting lactate transport by microinjection with DAB or monocarboxylate transporter oligodeoxynucleotides in the dHPC completely destroyed METH-induced CPP, reduced Npas4 and other plasticity-associated gene expression and decreased neuronal Ca2+ levels and neuronal arborization and spine density, all of which were fully rescued by L-lactate coadministration except for MCT2-ODN administration. Furthermore, the downstream signaling molecule NADH could mimic lactate's effects and trigger METH CPP by influencing the redox state of neurons and regulating NMDA receptor activity. Collectively, these findings indicate that astrocyte-neuron lactate transfer is crucial for METH-induced memory consolidation and retrieval.

Examining Sex Differences in Conditioned Place Preference or Aversion to Methamphetamine in Adolescent and Adult Mice.

Adolescence marks a particularly vulnerable period to developing substance use disorders. Human and rodent studies suggest that hypersensitivity to reward may contribute towards such vulnerability when adolescents are exposed to casual drug use. Methamphetamine is a popular illicit substance used by male and female youths. However, age- and sex-specific research in methamphetamine is scarce. The present study therefore aimed to examine potential sex differences in methamphetamine-conditioned place preference in adolescent and adult mice. Mice (n = 16–24/group) were conditioned to methamphetamine (0.1 mg/kg). We observed that regardless of age, females were more hyperactive compared to males. Individually normalized score against baseline preference indicated that on average, adolescents formed stronger preference compared to adults in both sexes. This suggests that adolescents are more sensitive to the rewarding effects of methamphetamine compared to adults. Surprisingly, individual data showed that some mice formed a conditioned place aversion instead of preference, with females less likely to form an aversion compared to males. These results suggest that adolescents may be hypersensitive to methamphetamine’s rewarding effects. In addition, female resistance to the aversive effects of methamphetamine may relate to the sex-specific findings in humans, including quicker transition to regular methamphetamine use observed in females compared to males.

Ameliorative effects of alkaloid extract from Mitragyna speciosa (Korth.) Havil. Leaves on methamphetamine conditioned place preference in mice

Ethnopharmacological relevanceMitragyna speciosa (Korth.) Havil., popularly known as Kratom (KT), is a medicinal plant used for pain suppression in Southeast Asia. It has been claimed to assist drug users withdraw from methamphetamine (METH) dependence. However, its use was controversial and not approved yet. Aim of the studyThis study was conducted to characterize local field potential (LFP) patterns in the nucleus accumbens (NAc) and the hippocampus (HP) in mice with METH conditioned place preference (CPP) that were treated with KT alkaloid extract. Materials and methodsMale Swiss albino ICR mice were implanted with intracraneal electrodes into the NAc and HP. To induce METH CPP, animals were injected intraperitoneally once a day with METH (1 mg/kg) and saline (0.9% w/v) alternately and put into METH/saline compartments to experience the associations between drug/saline injection and the unique environmental contexts for 10 sessions. Control group received saline injection paired with both saline/saline compartments. On post-conditioning day, effects of 40 (KT40), 80 (KT80) mg/kg KT alkaloid extract and 20 mg/kg bupropion (BP) on CPP scores and LFP powers and NAc-HP coherence were tested. ResultsTwo-way ANOVA revealed significant induction of CPP by METH sessions (P < 0.01). Multiple comparisons indicated that METH CPP was completely abolished by KT80 (P < 0.001). NAc gamma I (30.0–44.9 Hz) and HP delta (1.0–3.9 Hz) powers were significantly increased in mice with METH CPP (P < 0.01). The elevated NAc gamma I was significantly suppressed by KT80 (P < 0.05) and the increased HP delta was significantly reversed by KT40 (P < 0.01) and KT80 (P < 0.001). In addition, NAc-HP coherence was also significantly increased in gamma I (30.0–44.9 Hz) frequency range (P < 0.05) but it was reversed by KT80 (P < 0.05). Treatment with BP did not produce significant effect on these parameters. ConclusionsThese findings demonstrated that KT alkaloid extract significantly reversed CPP scores and LFP patterns induced by METH administration. The ameliorative effects of the extract might be beneficial for treatment of METH craving and addiction.

Repeated oxytocin treatment during abstinence inhibited context- or restraint stress-induced reinstatement of methamphetamine-conditioned place preference and promoted adult hippocampal neurogenesis in mice

Propensity to relapse, even after long-term abstinence, is a crucial feature of methamphetamine (METH) abuse. We and other laboratories have reported that acute treatment of oxytocin (OXT), a hormone and neuropeptide, could inhibit reinstatement of METH seeking in animal studies. However, the effects of repeated OXT treatment on METH reinstatement as well as underlying mechanisms are still unclear. In the present study, the effects of repeated OXT treatment during abstinence on context- or restraint stress-induced reinstatement were investigated using the mice conditioned place preference (CPP) paradigm. After three intermittent injections of METH (2 mg/kg, i.p.) to induce CPP, mice received a daily bilateral intra-hippocampus injection of OXT (0.625, 1.25 or 2.5 μg) for 8 consecutive days before the context- or restraint stress-induced reinstatement test. Meanwhile, adult hippocampal neurogenesis (AHN) level was detected using immunostaining. To further clarify the role of AHN underlying OXT's effects on METH-CPP reinstatement, temozolomide (TMZ, 25 mg/kg, i.p.) was employed to deplete AHN prior to OXT treatment. The data showed that repeated OXT treatment (1.25 and 2.5 μg, intra-hippocampus) significantly inhibited both context- and restraint stress-induced METH-CPP reinstatement and concomitantly promoted AHN in a dose-dependent manner. Notably, TMZ pre-treatment markedly abolished all the above-mentioned effects of OXT, suggesting that AHN was closely involved in OXT's inhibition on reinstatement induced by both triggers. Taken together, the present study indicated that repeated OXT treatment during abstinence could inhibit both context- and restraint stress-induced METH-CPP reinstatement possibly by promoting AHN in mice, which provided a better understanding for OXT's beneficial effects on METH addiction.

Hippocampal neurogenesis interferes with extinction and reinstatement of methamphetamine-associated reward memory in mice

Drugs of abuse, including morphine and cocaine, can reduce hippocampal neurogenesis (HN). Whereas promotion of HN is being increasingly recognized as a promising strategy for treating morphine and cocaine addiction. The present study is focused on exploring the changes of HN during methamphetamine (METH) administration and further clarify if HN is involved in METH-associated reward memory. After successfully establishing the conditioned place preference (CPP) paradigm to simulate the METH-associated reward memory in C57BL/6 mice, we observed that HN was significantly inhibited during METH (2 mg/kg, i. p.) administration and returned to normal after the extinction of METH CPP, as indicated by the immunostaining of bromodeoxyuridine (BrdU) and doublecortin (DCX) in the hippocampus. To promote/inhibit HN levels, 7,8-dihydroxyflavone (DHF), a small tyrosine kinase receptor B (TrkB) agonist and temozolomide (TMZ), an alkylating agent, were administered intraperitoneally (i.p.), respectively. The data showed that either DHF (5 mg/kg, i. p.) or TMZ (25 mg/kg, i. p.) pre-treatment before METH administration could significantly prolong extinction and enhance reinstatement of the reward memory. Notably, DHF treatment after METH administration significantly facilitated extinction and inhibited METH reinstatement, while TMZ treatment resulted in opposite effects. The present study indicated that METH administration could induce a temporal inhibitory effect on HN. More importantly, promotion of HN after the acquisition of METH-associated reward memory, but not inhibition of HN or promotion of HN before the acquisition of reward memory, could facilitate METH extinction and inhibit METH reinstatement, indicating the beneficial effect of HN on METH addiction by erasing the according reward memory.

Ginsenoside Rb1 attenuates methamphetamine (METH)-induced neurotoxicity through the NR2B/ERK/CREB/BDNF signalings in vitro and in vivo models

AimThis study investigates the effects of ginsenoside Rb1 (GsRb1) on methamphetamine (METH)-induced toxicity in SH-SY5Y neuroblastoma cells and METH-induced conditioned place preference (CPP) in adult Sprague-Dawley rats. It also examines whether GsRb1 can regulate these effects through the NR2B/ERK/CREB/BDNF signaling pathways. MethodsSH-SY5Y cells were pretreated with GsRb1 (20 μM and 40 μM) for 1 h, followed by METH treatment (2 mM) for 24 h. Rats were treated with METH (2 mg/kg) or saline on alternating days for 10 days to allow CPP to be examined. GsRb1 (5, 10, and 20 mg/kg) was injected intraperitoneally 1 h before METH or saline. Western blot was used to examine the protein expression of NR2B, ERK, P-ERK, CREB, P-CREB, and BDNF in the SH-SY5Y cells and the rats' hippocampus, nucleus accumbens (NAc), and prefrontal cortex (PFC). ResultsMETH dose-dependently reduced the viability of SH-SY5Y cells. Pretreatment of cells with 40 μM of GsRb1 increased cell viability and reduced the expression of METH-induced NR2B, p-ERK, p-CREB and BDNF. GsRb1 also attenuated the expression of METH CPP in a dose-dependent manner in rats. Further, GsRb1 dose-dependently reduced the expression of METH-induced NR2B, p-ERK, p-CREB, and BDNF in the PFC, hippocampus, and NAc of rats. ConclusionGsRb1 regulated METH-induced neurotoxicity in vitro and METH-induced CPP through the NR2B/ERK/CREB/BDNF regulatory pathway. GsRb1 could be a therapeutic target for treating METH-induced neurotoxicity or METH addiction.

Effects of the GluN2B-selective antagonist Ro 63-1908 on acquisition and expression of methamphetamine conditioned place preference in male and female rats

BackgroundMethamphetamine abuse has increased significantly in recent years. Currently, there are no FDA-approved pharmacotherapies for the treatment of methamphetamine use disorder. The goal of the current study was to determine if the N-methyl-d-aspartate (NMDA) GluN2B-selective antagonist Ro 63-1908 can block the conditioned rewarding effects of methamphetamine as assessed in conditioned place preference (CPP). MethodsTwo main experiments were conducted. In the first experiment, male (n = 24) and female (n = 24) rats received either vehicle or Ro 63-1908 (1.0–10.0 mg/kg) 30 min prior to the posttest to determine if blocking the GluN2B subunit attenuates expression of methamphetamine CPP. In the second experiment, male (n = 18) and female (n = 18) rats received either vehicle or Ro 63-1908 (1.0 or 3.0 mg/kg) 30 min prior to each conditioning session to determine if blocking the GluN2B subunit attenuates acquisition of methamphetamine CPP. ResultsRo 63-1908 (3.0 mg/kg) blocked acquisition of methamphetamine CPP in male rats, but only attenuated CPP in female rats. Ro 63-1908 did not alter expression of CPP in either sex. Increasing the dose of Ro 63-1908 (10.0 mg/kg) failed to block acquisition of CPP in an additional group of female rats (n = 6). A control experiment showed that Ro 63-1908 (3.0 mg/kg) did not produce CPP or conditioned place aversion in male rats (n = 6) or in female rats (n = 6). ConclusionsThe results of this study show that Ro 63-1908 is able to decrease the conditioned rewarding effects of methamphetamine.

Involvement of Hippocampal D1-Like Dopamine Receptors in the Inhibitory Effect of Cannabidiol on Acquisition and Expression of Methamphetamine-Induced Conditioned Place Preference.

Cannabidiol (CBD) is a non-psychotomimetic compound with strong potential to decrease the psychostimulant's rewarding effect with unclear receptors. Furthermore, as a part of the reward circuit, the hippocampus plays a crucial role in regulating the reward properties of drugs as determined by conditioned place preference (CPP). In the current research, CPP was used to evaluate the role of intra-CA1 microinjection of D1-like dopamine receptor antagonists in CBD's inhibitory effect on the acquisition and expression phases of methamphetamine (METH). Animals were treated by METH (1 mg/kg; sc) in a five-day schedule to induce CPP. To find out the impact of D1-like dopamine receptor antagonist, SCH23390, in the CA1 on the inhibitory influence of CBD on the acquisition of METH, the rats received intra-CA1 administration of SCH23390 (0.25, 1, and 4 µg/0.5 µl) following ICV treatment of CBD (10 µg/5 µl) over conditioning phase of METH. Furthermore, animals were given SCH23390 in the CA1 ensuing ICV microinjection of CBD (50 µg/5 µl) in the expression phase of METH to rule out the influence of SCH23390 on the suppressive effect of CBD on the expression of METH CPP. Intra-CA1 microinjection of SCH23390 abolished CBD's suppressive impact on both METH-induced CPP phases without any side effect on the locomotion. The current research disclosed that CBD inhibited the rewarding characteristic of METH via D1-like dopamine receptors in the CA1 region of the hippocampus.

Spectral power and theta-gamma coupling in the basolateral amygdala related with methamphetamine conditioned place preference in mice

The basolateral amygdala (BLA) plays a crucial role in conditioned place preference (CPP) for addictive drugs. However, neural signaling associated with methamphetamine (METH) craving and seeking remained to be investigated. This study characterized local field potential (LFP) oscillatory patterns in the BLA and conditioned place preference induced by METH-related context. Male Swiss albino ICR mice were deeply anesthetized for LFP intracranial electrode implantation in the BLA. Control and METH groups received sessions to learn to associate saline-paired and METH-paired compartments of the CPP apparatus with saline and METH injections, respectively, for 10 days. LFP signals and exploring behavior were recorded simultaneously during pre- and post-conditioning phases. Time spent in METH-paired compartment was normalized and expressed as CPP scores. Fast Fourier Transform (FFT) algorithm was used to analyze LFP powers of 8 discrete frequency ranges (delta, theta, alpha, beta, gamma I-IV). During post-conditioning phase of METH CPP with METH cues, statistical analysis revealed that METH group significantly increased time spent in METH-paired compartment. Significant suppressions of theta and alpha powers were observed. Phase-amplitude cross frequency coupling analyses confirmed significant increases in maximal modulation index (MI), frequency for phase of slow wave and MI of theta-gamma II coupling. Taken together, LFP oscillation in the BLA was sensitive in association with METH CPP. These research findings might suggest the underlying mechanisms of drug reward learning and adaptive changes in the BLA in acquisition of METH CPP and dependence.

Assessing the Effect of Diazepam on Methamphetamine-Induced Seeking Behavior in Rats

Background: Relapse is a common problem in substance-use disorders. Accumulating evidence has shown that diazepam can reduce the abuse potential of some drugs. Objectives: We investigated the effects of diazepam during and after the withdrawal period on the reinstatement of conditioned place preference (CPP) induced by a single dose of methamphetamine in male Wistar rats. Methods: Three groups of rats were trained to acquire methamphetamine CPP. The rats in the control group received, respectively, saline and methamphetamine (1 mg/kg, daily, ip) in the extinction and priming phases. Two other groups (one and two) had a similar process, but the rats in group one received diazepam (3 mg/kg, daily, ip) in the extinction phase and those in group 2 received a single dose of diazepam just before the priming phase. The CPP was checked daily during all processes. Results: We showed that a 3-day period injection of methamphetamine (1 mg/kg) resulted in a positive conditioning score on the first day after conditioning. Also, 3 mg/kg of diazepam daily in the extinction period shortened the withdrawal period for one day and extinction happened on the 9th and 10th days. Diazepam also reduced the conditioning score at the reinstatement phase (P &lt; 0.01). Furthermore, diazepam injection (3 mg/kg) before the methamphetamine priming dose did not have any significant effect on the reinstatement of drug-seeking. Conclusions: This study demonstrated that administration of diazepam during the extinction period was associated with reduced maintenance and reinstatement of methamphetamine-induced CPP, while the single dose of diazepam could not prevent the reinstatement of methamphetamine.