Region-specific alterations in the expression and phosphorylation of NMDA receptor subunits in the rat prefrontal cortex and dorsal striatum accompanying behavioral sensitization induced by cocaine and ethanol.

Behavioral sensitization is defined as the enhanced behavioral response to drugs of abuse after repeated exposure, which can serve as a behavioral model of addiction. Our previous study demonstrated that behavioral cross-sensitization occurs between cocaine and ethanol, suggesting commonalities between these drugs. N-methyl-d-aspartate (NMDA) receptors play important roles in synaptic plasticity, learning, memory, and addiction-associated behaviors. However, little is known about whether NMDA receptor-mediated signaling regulation is a common feature following behavioral sensitizations induced by cocaine and ethanol. Thus, the present study examined the expression of phospho-S896-NR1, NR2A, and NR2B subunits in the prefrontal cortex and dorsal striatum following reciprocal cross-sensitization between cocaine and ethanol. We also examined the mRNA expression of the NR2A and NR2B subunits. In the ethanol-sensitized state, phosphorylation of NR1 and expression of NR2A and NR2B subunits were increased in both the prefrontal cortex and dorsal striatum. In the cocaine-sensitized state, phosphorylation of NR1 and expression of the NR2A and NR2B subunits were increased in the prefrontal cortex but not in the dorsal striatum. Corresponding changes in mRNA expression were observed in the ethanol-sensitized state but not in the cocaine-sensitized state. Acute treatment with either cocaine or ethanol had no effect on the phosphorylation and expression of NMDA receptor subunits in either the prefrontal cortex or dorsal striatum, regardless of the sensitization state. These results indicate a partially overlapping neural mechanism for cocaine and ethanol that may induce the development of behavioral sensitization.

Behavioral and transcriptional effects of repeated electroconvulsive seizures in the neonatal MK-801-treated rat model of schizophrenia.

RATIONALE: Electroconvulsive therapy (ECT) is an effective treatment modality for schizophrenia. However, its antipsychotic-like mechanism remains unclear. OBJECTIVES: To gain insight into the antipsychotic-like actions of ECT, this study investigated how repeated treatments of electroconvulsive seizure (ECS), an animal model for ECT, affect the behavioral and transcriptomic profile of a neurodevelopmental animal model of schizophrenia. METHODS: Two injections of MK-801 or saline were administered to rats on postnatal day 7 (PN7), and either repeated ECS treatments (E10X) or sham shock was conducted daily from PN50 to PN59. Ultimately, the rats were divided into vehicle/sham (V/S), MK-801/sham (M/S), vehicle/ECS (V/E), and MK-801/ECS (M/E) groups. On PN59, prepulse inhibition and locomotor activity were tested. Prefrontal cortex transcriptomes were analyzed with mRNA sequencing and network and pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) analyses were subsequently conducted. RESULTS: Prepulse inhibition deficit was induced by MK-801 and normalized by E10X. In M/S vs. M/E model, Egr1, Mmp9, and S100a6 were identified as center genes, and interleukin-17 (IL-17), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF) signaling pathways were identified as the three most relevant pathways. In the V/E vs. V/S model, mitophagy, NF-κB, and receptor for advanced glycation end products (RAGE) pathways were identified. qPCR analyses demonstrated that Igfbp6, Btf3, Cox6a2, and H2az1 were downregulated in M/S and upregulated in M/E. CONCLUSIONS: E10X reverses the behavioral changes induced by MK-801 and produces transcriptional changes in inflammatory, insulin, and mitophagy pathways, which provide mechanistic insight into the antipsychotic-like mechanism of ECT.

Characteristics of MK-801-induced locomotor sensitization.

Repeated administration of drugs of abuse leads to progressively greater behavioral responses; this phenomenon is referred to as behavioral sensitization. MK-801 blocks the N-methyl-d-aspartate (NMDA) receptor and elicits behavioral sensitization. Ketamine and phencyclidine, are also NMDA antagonists and have well-documented abuse potential. This study investigated the characteristics of MK-801-induced behavioral sensitization and found that it induced sensitization rapidly; only five consecutive treatments were required. The optimal dose for robust sensitization was also identified, which corresponded to the typical doses of abused NMDA antagonists (i.e., between the doses inducing antidepressant and anesthetic effects). Following MK-801-induced behavioral sensitization, changes were observed in the expression and/or phosphorylation of NMDA receptor subunits. While the expression of early growth response protein 1, which serves as a marker of neuronal activation, was affected by MK-801 sensitization, extracellular signal-regulated kinase phosphorylation was not associated with MK-801 treatment.

Corrigendum: Problematic Use of Alcohol and Online Gaming as Coping Strategies During the COVID-19 Pandemic: A Mini Review.

[This corrects the article DOI: 10.3389/fpsyt.2021.685964.].

Electroconvulsive seizure inhibits the mTOR signaling pathway via AMPK in the rat frontal cortex.

RATIONALE: Accumulating evidence indicates critical involvement of mammalian target of rapamycin (mTOR) in the treatment of depressive disorders, epilepsy, and neurodegenerative disorders through its signal transduction mechanisms related to protein translation, autophagy, and synaptic remodeling. Electroconvulsive seizure (ECS) treatment is a potent antidepressive, anti-convulsive, and neuroprotective therapeutic modality; however, its effects on mTOR signaling have not yet been clarified. METHODS: The effect of ECS on the mTOR complex 1 (mTORC1) pathway was investigated in the rat frontal cortex. ECS or sham treatment was administered once per day for 10 days (E10X or sham), and compound C was administered through the intracerebroventricular cannula. Changes in mTORC1-associated signaling molecules and their interactions were analyzed. RESULTS: E10X reduced phosphorylation of mTOR downstream substrates, including p70S6K, S6, and 4E-BP1, and increased inhibitory phosphorylation of mTOR at Thr2446 compared to the sham group in the rat frontal cortex, indicating E10X-induced inhibition of mTORC1 activity. Akt and ERK1/2, upstream kinases that activate mTORC1, were not inhibited; however, AMPK, which can inhibit mTORC1, was activated. AMPK-responsive phosphorylation of Raptor at Ser792 and TSC2 at Ser1387 inhibiting mTORC1 was increased by E10X. Moreover, intrabrain inhibition of AMPK restored E10X-induced changes in the phosphorylation of S6, Raptor, and TSC2, indicating mediation of AMPK in E10X-induced mTOR inhibition. CONCLUSIONS: Repeated ECS treatments inhibit mTORC1 signaling by interactive crosstalk between mTOR and AMPK pathways, which could play important roles in the action of ECS via autophagy induction.

Relationship between Resting-State Alpha Coherence and Cognitive Control in Individuals with Internet Gaming Disorder: A Multimodal Approach Based on Resting-State Electroencephalography and Event-Related Potentials.

The human brain is constantly active, even at rest. Alpha coherence is an electroencephalography (EEG) rhythm that regulates functional connectivity between different brain regions. However, the relationships between resting-state alpha coherence and N2/P3 components associated with response inhibition and cognitive processes have not been investigated in addictive disorders. The present study investigated the relationships between alpha coherence during the resting state and N2/P3 components of event-related potentials during the Go/Nogo task in healthy controls (HCs) and patients with Internet gaming disorder (IGD). A total of 64 young adults (HC: n = 31; IGD: n = 33) participated in this study. Alpha coherence values at left fronto-central and bilateral centro-temporal electrode sites were significantly correlated with P3 latency in HCs, whereas inverse correlations were observed in patients with IGD. Furthermore, significant differences were observed in the correlation values between the groups. Our results suggest that patients with IGD lack dynamic interactions of functional connectivity between the fronto-centro-temporal regions during the resting state and the event-related potential (ERP) index during cognitive tasks. The findings of this study may have important implications for understanding the neurophysiological mechanisms linking resting-state EEG and task-related ERPs underlying IGD.

Problematic Use of Alcohol and Online Gaming as Coping Strategies During the COVID-19 Pandemic: A Mini Review.

The COVID-19 (coronavirus disease 2019) pandemic has dramatically changed our daily lives and activities, including those originally intended to serve for leisure and pleasure. Drinking and online gaming became coping behaviors used to rescue ourselves from the stress and restricted lifestyle during the COVID-19 pandemic. However, frequent drinking and gaming can result in the pathological consequences of addiction. Those affected use the stimuli not to obtain pleasure, but rather to avoid the displeasure induced by stress and previous use, often unsuccessfully. This review aims to provide an overview of recent longitudinal cohort studies on alcohol and gaming use during the COVID-19 pandemic, as well as to analyze how the pandemic has affected alcohol and gaming use. There was a substantial risk of alcohol and online gaming overuse during the lockdown, which may depend on the pandemic's duration or overuse patterns. Previous studies have shown that increased alcohol consumption and online gaming are associated with heightened stress and anxiety levels caused by social isolation/quarantine. Over time, frequent or excessive alcohol consumption and gaming could lead to an increased risk of more serious mental health problems. Every effort should be made to mitigate mental health problems and ensure adequate adaptation to these exceptional circumstances. Therefore, it would be helpful to encourage physical activity, social interaction, and collaboration to facilitate psychological and physical health.

Event-related brain response to visual cues in individuals with Internet gaming disorder: relevance to attentional bias and decision-making.

This study investigated attentional bias toward game-related cues in Internet gaming disorder (IGD) using electrophysiological markers of late positive potential (LPP) and identifying the sources of LPP. In addition, the association between LPP and decision-making ability was investigated. The IGD (n = 40) and healthy control (HC; n = 39) participants viewed a series of game-related and neutral pictures, while their event-related potentials (ERPs) were recorded. LPPs were calculated as the mean amplitudes between 400 and 700 ms at the centro-parietal (CP3, CP1, Cpz, CP2, and CP4) and parietal (P3, P1, Pz, P2, and P4) electrode sites. The source activations of LPP were estimated using standardized low-resolution brain electromagnetic tomography (sLORETA). In addition, decision-making ability was evaluated by the Cambridge Gambling Task. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HC group. sLORETA showed that the IGD group was more active in the superior and middle temporal gyri, which are involved in social perception, than in the HC group, whereas it was less active in the frontal area. Individuals with IGD have deficits in decision-making ability. In addition, in the HC group, the lower the LPP when looking at the game-related stimuli, the better the quality of decision-making, but not in the IGD group. Enhanced LPP amplitudes are associated with emotional arousal to gaming cues and decision-making deficits in IGD. In addition, source activities suggest that patients with IGD perceive game-related cues as social stimuli. LPP can be used as a neurophysiological marker of IGD.

Comparison of the sensitizing effects of cocaine and ethanol on histone deacetylase isoforms in the rat brain.

Behavioral sensitization, an animal model of drug addiction, persists for a prolonged period after repeated exposure to drugs of abuse. The persistence of an addiction behavioral phenotype suggests long-lasting changes in gene regulation at the epigenetic level. We measured the expression of histone deacetylases (HDACs) isoforms in the prefrontal cortex and dorsal striatum following the development of sensitization to cocaine (15 mg/kg, administered five times) and ethanol (0.5 g/kg, administered 15 times) to investigate the epigenetic changes that mediate sensitization. Animals sensitized to ethanol exhibited augmented locomotor activity in response to the cocaine challenge. Similarly, those sensitized to cocaine exhibited increased locomotor activity in response to an ethanol challenge. These findings indicate cross-sensitization between ethanol and cocaine and suggest that a common molecular mechanism underlying the cross-sensitization. In animals sensitized to cocaine or ethanol, mRNA levels of class II HDACs (HDAC4 and HDAC5) were decreased in the prefrontal cortex and dorsal striatum, whereas acute treatments with either drug had no effect on the expression of class II HDACs. By contrast, class I HDACs (HDAC1 and HDAC2) responded to the acute cocaine challenge, whereas sensitization itself did not have a consistent effect on class I HDAC levels. These findings support the hypothesis of a common epigenetic mechanism underlying persistent behavioral sensitization induced by different drugs, which may be mediated by the altered expression of class II HDACs.

Electroconvulsive Seizures Induce Autophagy by Activating the AMPK Signaling Pathway in the Rat Frontal Cortex.

BACKGROUND: It is uncertain how electroconvulsive therapy-induced generalized seizures exert their potent therapeutic effects on various neuropsychiatric disorders. Adenosine monophosphate-activated protein kinase (AMPK) plays a major role in maintaining metabolic homeostasis and activates autophagic processes via unc-51-like kinase (ULK1). Evidence supports the involvement of autophagy system in the action mechanisms of antidepressants and antipsychotics. The effect of electroconvulsive therapy on autophagy-related signaling requires further clarification. METHODS: The effect of electroconvulsive seizure on autophagy and its association with the AMPK signaling pathway were investigated in the rat frontal cortex. Electroconvulsive seizure was provided once per day for 10 days (E10X), and compound C or 3-methyadenine was administered through an intracerebroventricular cannula. Molecular changes were analyzed with immunoblot, immunohistochemistry, and transmission electron microscopy analyses. RESULTS: E10X increased p-Thr172-AMPKα immunoreactivity in rat frontal cortex neurons. E10X increased phosphorylation of upstream effectors of AMPK, such as LKB1, CaMKK, and TAK1, and of its substrates, ACC, HMGR, and GABABR2. E10X also increased p-Ser317-ULK1 immunoreactivity. At the same time, LC3-II and ATG5-ATG12 conjugate immunoreactivity increased, indicating activation of autophagy. An intracerebroventricular injection of the AMPK inhibitor compound C attenuated the electroconvulsive seizure-induced increase in ULK1 phosphorylation as well as the protein levels of LC3-II and Atg5-Atg12 conjugate. Transmission electron microscopy clearly showed an increased number of autophagosomes in the rat frontal cortex after E10X, which was reduced by intracerebroventricular treatment with the autophagy inhibitor 3-methyadenine and compound C. CONCLUSIONS: Repeated electroconvulsive seizure treatments activated in vivo autophagy in the rat frontal cortex through the AMPK signaling pathway.

Repeated ethanol exposure influences key enzymes in cholesterol and lipid homeostasis via the AMPK pathway in the rat prefrontal cortex.

Cholesterol homeostasis has been proposed to be implicated in the development of addiction. However, the effects of ethanol on cholesterol homeostasis within the brain are not well understood. One of the most important regulators of cholesterol homeostasis is HMG-CoA reductase (HMG-CoAR), the rate-limiting enzyme of cholesterol biosynthesis. We examined the phosphorylation of HMG-CoAR and the other key regulator of lipid synthesis, acetyl-CoA carboxylase (ACC), following acute or chronic treatment with ethanol (0.5, 1, or 2 g/kg) in the rat prefrontal cortex. The phosphorylation of AMP-activated protein kinase (AMPK), which regulates the HMG-CoAR activity, and its well-known upstream regulators, was also studied. The phosphorylation of HMG-CoAR and ACC were transiently increased by ethanol treatment only in animals previously treated chronically with ethanol. Acute administration to naïve animals did not induce the phosphorylation, regardless of dosage. Similarly, the phosphorylation of AMPK and the upstream regulators, LKB1 and CaMK4, were transiently increased only in chronically ethanol-treated animals. In naïve animals, a high dose (2 g/kg) of ethanol decreased phosphorylation. The phosphorylation of TAK1, another upstream kinase of AMPK, was increased only from 30 min to 24 h after the chronic treatment with ethanol. Together, these results indicate that repeated exposure is required for the activating effect of ethanol on HMG-CoAR and ACC. This effect seems to be mediated by the AMPK system, and may contribute to the long-lasting neuroadaptation involved in the development of alcohol dependence.

Behavioral cross-sensitization between cocaine and ethanol is accompanied by parallel changes in the activity of AMPK system.

Behavioral sensitization is thought to be relevant to the psychopathology of drug addiction. A previous study from our research group demonstrated cross-sensitization between cocaine and ethanol. Although these findings suggest a common mechanism of action between these two drugs, little is known about the molecular or cellular aspects of this commonality. The AMPK pathway functions as an intracellular energy sensor and plays a critical role in maintaining cellular energy homeostasis. Thus, the present study examined AMPK signaling following reciprocal cross-sensitization between cocaine and ethanol in the rat prefrontal cortex and dorsal striatum. Male Sprague-Dawley rats were repeatedly treated with either cocaine (15 mg/kg, 5 times) or ethanol (0.5 g/kg, 15 times) and then challenged reciprocally with the other drug. When sensitized to either cocaine or ethanol, the phosphorylation in response to additional challenges with the same drug was enhanced, indicating the development of sensitization. However, responses to the cocaine challenge were enhanced in the ethanol-sensitized state, whereas the responses to the ethanol challenge were not apparently enhanced in the cocaine-sensitized state. This was likely due to the ceiling effect of cocaine sensitization, which suggested that cocaine had more robust effects than ethanol. Although the same changes were found for two upstream kinases of AMPK (LKB1 and CaMK4), TAK1 responded differently and was not affected by acute challenges from either cocaine or ethanol. In the prefrontal cortex, there was an increase in activity, whereas there was a decrease in activity in the dorsal striatum. This difference might be due to dopamine D1 receptor dominance in the prefrontal cortex and D2 receptor dominance in the dorsal striatum. Taken together, these results suggest that both cocaine and ethanol may share overlapping molecular pathways in the process of behavioral sensitization. However, the action of cocaine was stronger than that of ethanol.

Reduction in Alpha Peak Frequency and Coherence on Quantitative Electroencephalography in Patients with Schizophrenia.

BACKGROUND: The aim of the study was to examine the characteristics of alpha wave peak frequency, power, and coherence in patients with schizophrenia. METHODS: Thirty-one patients with schizophrenia and age- and sex-matched subjects with no psychopathology were enrolled. All study participants underwent quantitative electroencephalography (QEEG). Alpha-related values, including peak frequency, power, and coherence, were evaluated. RESULTS: Alpha peak frequency on the Oz area was slower in the schizophrenia group than that in the control group. However, no differences in absolute or relative power were observed between the two groups. Significant reductions in absolute and relative coherence were observed at the C3-C4 and T3-T4 nodes in the patients with schizophrenia. Relative coherence was reduced at the P3-P4 nodes. CONCLUSION: This study focused on alpha variables detected in QEEG as intrinsic values to distinguish schizophrenia from a healthy control. The results suggest decreased alpha peak frequency of the occipital lobe and decreased coherence between the two hemispheres in patients with schizophrenia. A further study could elucidate the causal relationship and biological meaning of the variations in alpha waves in patients with schizophrenia.

Electroconvulsive Seizure Alters the Expression and Daily Oscillation of Circadian Genes in the Rat Frontal Cortex.

OBJECTIVE: Electroconvulsive therapy (ECT) is the most effective treatment for mood disorders. Accumulating evidence has suggested the important role of circadian genes in mood disorders. However, the effects of ECT on circadian genes have not been systemically investigated. METHODS: We examined the expression and daily oscillation of major circadian genes in the rat frontal cortex after electroconvulsive seizure (ECS). RESULTS: Firstly, mRNA and protein level were investigated at 24 hr after single ECS (E1X) and repeated ECS treatements for 10 days (E10X), which showed more remarkable changes after E10X than E1X. mRNA expression of Rorα, Bmal1, Clock, Per1, and Cry1 was decreased, while Rev-erbα expression was increased at 24 hr after E10X compared to sham. The proteins showed similar pattern of changes. Next, the effects on oscillation and rhythm properties (mesor, amplitude, and acrophase) were examined, which also showed more prominent changes after E10X than E1X. After E10X, mesor of Rorα, Bmal1, and Cry1 was reduced, and that of Rev-erbα was increased. Five genes, Rev-erbα, Bmal1, Per1, Per2, and Cry2, showed earlier acrophase after E10X. CONCLUSION: The findings suggest that repeated ECS induces reduced expression and phase advance of major circadian genes in the in vivo rat frontal cortex.

Long-Term Evolution of Metabolic Status in Patients with Schizophrenia Stably Maintained on Second-Generation Antipsychotics.

OBJECTIVE: Second-generation antipsychotics (SGAs) increase the risk of metabolic syndrome (MetS). Despite the risk of MetS, SGAs may have to be continued with change in some patients. The aim of this study was to trace the evolution of MetS in these patients. METHODS: Patients with schizophrenia who had been maintained on a fixed SGA regimen for more than a year were followed-up without changing the regimen. Metabolic indicators were evaluated at baseline and at follow-up. Prevalence, incidence and spontaneous normalization rate of MetS were estimated. Risk factors that might have influenced the evolution were scrutinized. RESULTS: A total of 151 subjects were included. During the mean observation period of 389.9±162.4 days, the prevalence of MetS was increased from 35.1 to 45.0%. The incidence rate was 29.6%, while the normalization rate was 26.4%, risk factors affecting incidence were age (OR=1.09, 95% CI: 1.03-1.17), baseline continuous values of metabolic syndrome risk scores (cMetS, OR=1.77, 95% CI:1.29-2.55) and baseline body weight (OR=1.06, 95% CI: 1.01-1.13). Normalization was influenced by age (OR=0.74, 95% CI: 0.57-0.89) and baseline body weight (OR=0.85, 95% CI: 0.72-0.95). CONCLUSION: The prevalence of MetS steadily increased with the continuous use of SGAs. However, individual difference was extensive and about a quarter of the patients were able to recover naturally without specific measurements.

Characteristics of ethanol-induced behavioral sensitization in rats: Molecular mediators and cross-sensitization between ethanol and cocaine.

Repeated exposure to drugs of abuse can induce a progressive increase in locomotor activity, known as behavioral sensitization. However, little is known about behavioral sensitization to ethanol. We examined whether ethanol could induce behavioral sensitization and investigated several molecular changes accompanying sensitization. We also assessed whether "cross-sensitization" occurred between ethanol and cocaine, another abused drug. Ethanol-induced sensitization was examined in rats after ethanol treatment (0.5 or 2g/kg) for 15days. The biochemical effects of low- or high-dose ethanol were examined in terms of N-methyl-d-aspartate (NMDA) receptor subunit phosphorylation or expression. Neuronal activity after ethanol treatment was assessed by measuring the level of early growth response (Egr-1) expression. Ethanol-induced behavioral sensitization was observed at the low dose (0.5g/kg) but not the high dose (2g/kg). Although acute treatment with the sensitizing dose of ethanol robustly increased Egr-1 protein and mRNA levels, the expression and phosphorylation of NMDA receptor subunits were not affected. The biochemical responses to ethanol seemed to be enhanced in ethanol-sensitized animals. Cross-sensitization between ethanol and cocaine was observed, which supports the hypothesis that there are commonalities among substances in the pathophysiology of substance dependence.

Clinical Usefulness of Long-term Application of Fentanyl Matrix in Chronic Non-Cancer Pain: Improvement of Pain and Physical and Emotional Functions.

BACKGROUND: Opioids are recently recommended for those who do not gain adequate pain relief from the use of acetaminophen or nonsteroidal anti-inflammatory drugs. Medical opioids are administered in various routes, and transdermal opioid products that can make up for the weaknesses of the oral or intravenous products have been developed. This study is to evaluate the clinical usefulness of fentanyl matrix in terms of the long-term improvement in pain and physical and mental functions. METHODS: This was a multicenter, open, prospective, observational study that was conducted in 54 institutions in Korea. Patients with non-cancerous chronic pain completed questionnaires, and investigators also completed questionnaires. A total of 1,355 subjects participated in this study, and 639 subjects completed the study. Subjects received transdermal fentanyl matrix (12 µg/hr, 25 µg/hr, or 50 µg/hr depending on the patient's response and demand). Subjects visited at 29 ± 7 days, 85 ± 14 days, and 169 ± 14 days after administration, respectively, to receive drug titration and fill out the questionnaires. The results were analyzed using the intention-to-treat (ITT) analysis, full analysis set (FAS), and per-protocol (PP) analysis. The FAS analysis included only 451 participants; the PP analysis, 160 participants; and the ITT analysis, 1,355 participants. RESULTS: The intensity of pain measured by the Numeric Rating Scale decreased from 7.07 ± 1.78 to 4.93 ± 2.42. The physical assessment score and mental assessment score of the Short-Form Health Survey 12 improved from 28.94 ± 7.23 to 35.90 ± 10.25 and from 35.80 ± 11.76 to 42.52 ± 10.58, respectively. These differences were significant, and all the other indicators also showed improvement. Adverse events with an incidence of ≥ 1% were nausea, dizziness, vomiting, and pruritus. CONCLUSIONS: The long-term administration of fentanyl matrix in patients with non-cancerous pain can reduce the intensity of pain and significantly improves activities of daily living and physical and mental capabilities.

Region-specific activation of the AMPK system by cocaine: The role of D1 and D2 receptors.

The 5' adenosine monophosphate-activated protein kinase (AMPK) functions as an intracellular energy sensor that regulates and maintains energy balance. The psychostimulant drug cocaine has profound effects on behavior that are accentuated with repeated use, which is a process termed sensitization. Thus, the present study examined whether the sensitizing effects of cocaine could be observed in the AMPK system and aimed to determine whether these effects were mediated by dopamine (DA) D1 or D2 receptors. In the first set of experiments, rats were injected daily for 5days with either cocaine (15mg/kg, intraperitoneal [IP]) or saline. On the day 6, each group was divided into two subgroups and given either cocaine or saline. In the second set of experiments, rats were pretreated with SCH23390 (0.5mg/kg, IP), haloperidol (1mg/kg, IP), or both agents in combination, followed by cocaine or saline treatment. In the drug-naïve state, acute treatment with cocaine produced an increase in locomotor activity and increased AMPK phosphorylation in the frontal cortex but decreased it in the dorsal striatum. In the drug-sensitized state (following repeated treatment), the behavioral responsiveness to cocaine was augmented and accompanied by alterations in AMPK activity. The phosphorylation levels of the upstream kinases Ser-431-LKB1 and Thr-196-CaMK4 were congruent with the changes in AMPK activity. Thr-184/187-TAK1 was phosphorylated after chronic cocaine treatment in the dorsal striatum but not in the frontal cortex. The opposite effects induced by cocaine in the AMPK system in the dorsal striatum and frontal cortex may be explained by the differential activations of DA D1 and D2 receptors in these brain regions.