Publications by authors named "Panayotis K Thanos"

117 Publications

Chronic neuroleptic treatment combined with a high fat diet elevated [3H] flunitrazepam binding in the cerebellum.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jul 25;112:110407. Epub 2021 Jul 25.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; Department of Psychology, University at Buffalo, Buffalo, NY, USA. Electronic address:

Clinical and preclinical studies have shown dysfunctions in genetic expression and neurotransmission of γ-Aminobutyric acid (GABA), GABA receptor subunits, and GABA-synthesizing enzymes GAD and GAD in schizophrenia. It is well documented that there is significant weight gain after chronic neuroleptic treatment in humans. While there are limited studies on the effects of diet on GABA signaling directly, a change in diet has been used clinically as an adjunct to treatment for schizophrenic relief. In this study, rats chronically consumed either a chow diet (CD) or a 60% high-fat diet (HFD) and drank from bottles that contained one of the following solutions: water, haloperidol (1.5 mg/kg), or olanzapine (10 mg/kg) for four weeks. Rats were then euthanized and their brains were processed for GABA in-vitro receptor autoradiography using [H] flunitrazepam. A chronic HFD treatment yielded significantly increased [H] flunitrazepam binding in the rat cerebellum independent of neuroleptic treatment. The desynchronization between the prefrontal cortex and the cerebellum is associated with major cognitive and motor dysfunctions commonly found in schizophrenic symptomatology, such as slowed reaction time, motor dyscoordination, and prefrontal activations related to speech fluency and cognitive alertness. These data support the notion that there is a dietary effect on GABA signaling within the cerebellum, as well as the importance of considering nutritional intervention methods as an adjunct treatment for patients chronically treated with neuroleptics. Finally, we indicate that future studies involving the analysis of individual patient's genetic profiles will further assist towards a precision medicine approach to the treatment of schizophrenia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2021.110407DOI Listing
July 2021

Fluoxetine Potentiates Oral Methylphenidate-Induced Gene Regulation in the Rat Striatum.

Mol Neurobiol 2021 Jul 2. Epub 2021 Jul 2.

Stanson Toshok Center for Brain Function and Repair, Rosalind Franklin University of Medicine and Science, North Chicago, IL, 60064, USA.

Methylphenidate (MP) is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (FLX) to treat various disorders. MP, a dopamine reuptake inhibitor, helps manage attention-deficit hyperactivity disorder (ADHD) and is abused as a cognitive enhancer; it has a reduced addiction liability. We showed that combining FLX (serotonin) with MP potentiates MP-induced gene regulation in the striatum. These studies used intraperitoneal drug administration, which is relevant for MP abuse. Clinically, MP and FLX are taken orally (slower bioavailability). Here, we investigated whether chronic oral administration of MP and FLX also altered striatal gene regulation. MP (30/60 mg/kg/day), FLX (20 mg/kg/day), and MP + FLX were administered in rats' drinking water for 8 h/day over 4 weeks. We assessed the expression of dynorphin and substance P (both markers for striatal direct pathway neurons) and enkephalin (indirect pathway) by in situ hybridization histochemistry. Chronic oral MP alone produced a tendency for increased dynorphin and substance P expression and no changes in enkephalin expression. Oral FLX alone did not increase gene expression. In contrast, when given together, FLX greatly enhanced MP-induced expression of dynorphin and substance P and to a lesser degree enkephalin. Thus, FLX potentiated oral MP-induced gene regulation predominantly in direct pathway neurons, mimicking cocaine effects. The three functional domains of the striatum were differentially affected. MP + SSRI concomitant therapies are indicated in ADHD/depression comorbidity and co-exposure occurs with MP misuse as a cognitive enhancer by patients on SSRIs. Our findings indicate that MP + SSRI combinations, even given orally, may enhance addiction-related gene regulation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-021-02466-yDOI Listing
July 2021

A high-fat diet, but not haloperidol or olanzapine administration, increases activated microglial expression in the rat brain.

Neurosci Lett 2021 07 21;757:135976. Epub 2021 May 21.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, United States; Department of Psychology, State University at Buffalo, Buffalo, NY, United States. Electronic address:

This study examined the effects of chronic treatment of the antipsychotic drugs, haloperidol and olanzapine, on microglial activation in the brain. In addition, we explored the interaction of these antipsychotic drugs with normal and high-fat diet. In order to measure activated microglial expression, we used [H] PK11195 in vitro autoradiography. Male Sprague Dawley rats were given a diet of either regular chow diet or a high-fat diet, and assigned either water, haloperidol drinking solution (1.5 mg/kg), or olanzapine drinking solution (10 mg/kg) for four weeks. Following treatment, rats were euthanized and brains extracted for [H] PK11195 autoradiography. Rats on 4 weeks of a high-fat diet showed increased [H] PK11195 binding compared to rats on a normal diet in the temporal association cortex (19 %), ectorhinal cortex (17 %), entorhinal cortex (18 %), and perirhinal cortex (18 %), irrespective of drug treatment. These are regions associated with memory, sensory, and visual processing. Rats treated with either haloperidol or olanzapine showed no differences in [H] PK11195 binding compared to the control group. However, there were differences between the 2 different antipsychotic medications themselves. Haloperidol increased [H] PK11195 binding in the amygdala (23 %), ectorhinal cortex (24 %), and perihinal cortex (29 %), compared to olanzapine. These results corroborate a known role of a high-fat diet and central inflammatory changes but suggest no role of these antipsychotic drugs in promoting neuroinflammation across 4 weeks compared to normal control rats.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neulet.2021.135976DOI Listing
July 2021

A Novel Precision Approach to Overcome the "Addiction Pandemic" by Incorporating Genetic Addiction Risk Severity (GARS) and Dopamine Homeostasis Restoration.

J Pers Med 2021 Mar 16;11(3). Epub 2021 Mar 16.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA.

This article describes a unique therapeutic precision intervention, a formulation of enkephalinase inhibitors, enkephalin, and dopamine-releasing neuronutrients, to induce dopamine homeostasis for detoxification and treatment of individuals genetically predisposed to developing reward deficiency syndrome (RDS). The formulations are based on the results of the addiction risk severity (GARS) test. Based on both neurogenetic and epigenetic evidence, the test evaluates the presence of reward genes and risk alleles. Existing evidence demonstrates that the novel genetic risk testing system can successfully stratify the potential for developing opioid use disorder (OUD) related risks or before initiating opioid analgesic therapy and RDS risk for people in recovery. In the case of opioid use disorders, long-term maintenance agonist treatments like methadone and buprenorphine may create RDS, or RDS may have been in existence, but not recognized. The test will also assess the potential for benefit from medication-assisted treatment with dopamine augmentation. RDS methodology holds a strong promise for reducing the burden of addictive disorders for individuals, their families, and society as a whole by guiding the restoration of dopamine homeostasisthrough anti-reward allostatic neuroadaptations. WC 175.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11030212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002215PMC
March 2021

High Genetic Addiction Risk Score (GARS) in Chronically Prescribed Severe Chronic Opioid Probands Attending Multi-pain Clinics: an Open Clinical Pilot Trial.

Mol Neurobiol 2021 Jul 8;58(7):3335-3346. Epub 2021 Mar 8.

Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.

Millions of Americans experience pain daily. In 2017, opioid overdose claimed 64,000 lives increasing to 84,000 lives in 2020, resulting in a decrease in national life expectancy. Chronic opioid use results in dependency, drug tolerance, neuroadaptation, hyperalgesia, potential addictive behaviors, or Reward Deficiency Syndrome (RDS) caused by a hypodopaminergia. Evaluation of pain clinic patients with the Genetic Addiction Risk Score (GARS) test and the Addiction Severity Index (ASI- Media Version V) revealed that GARS scores equal to or greater than 4 and 7 alleles significantly predicted drug and alcohol severity, respectively. We utilized RT-PCR for SNP genotyping and multiplex PCR/capillary electrophoresis for fragment analysis of the role of eleven alleles in a ten-reward gene panel, reflecting the activity of brain reward circuitry in 121 chronic opioid users. The study consisted of 55 males and 66 females averaging ages 54 and 53 years of age, respectively. The patients included Caucasians, African Americans, Hispanics, and Asians. Inclusion criteria mandated that the Morphine Milligram Equivalent (MME) was 30-600 mg/day (males) and 20 to 180 mg/day (females) for treatment of chronic pain over 12 months. Ninety-six percent carried four or more risk alleles, and 73% carried seven or more risk alleles, suggesting a high predictive risk for opioid and alcohol dependence, respectively. These data indicate that chronic, legally prescribed opioid users attending a pain clinic possess high genetic risk for drug and alcohol addiction. Early identification of genetic risk, using the GARS test upon entry to treatment, may prevent iatrogenic induced opioid dependence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12035-021-02312-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257535PMC
July 2021

Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

J Syst Integr Neurosci 2020 Aug 19;6(2). Epub 2019 Dec 19.

Department of Psychiatry, Ichan School of Medicine at Mount Sinai, New York, NY., USA.

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of cases and controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15761/JSIN.1000221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891477PMC
August 2020

Chronic oral methylphenidate treatment in adolescent rats promotes dose-dependent effects on NMDA receptor binding.

Life Sci 2021 Jan 10;264:118708. Epub 2020 Nov 10.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; Department of Psychology, University at Buffalo, Buffalo, NY, USA. Electronic address:

Aim: Examine the effects of chronic oral Methylphenidate (MP) treatment on the N-Methyl-D-aspartic acid (NMDA) glutamate receptor binding in the rat brain using a previously established drinking paradigm that has been shown to deliver MP with similar pharmacokinetic profile as observed clinically.

Main Methods: Briefly, rats were divided into three treatment groups of water, low dose MP (LD; 4/10 mg/kg), or high dose MP (HD; 30/60 mg/kg). Following a 3-month treatment period, some rats were sacrificed while others went through an additional 1-month abstinence period before they were sacrificed. In vitro autoradiography (ARG) was carried out using [H] MK801 to examine NMDA receptor binding in the brain.

Key Findings: The dose-dependent effects of MP following 13 weeks of treatment on [H] MK-801 binding were seen across the brain in the following regions: prelimbic, insular, secondary motor, primary motor, retrosplenial, rhinal, piriform, auditory, visual, dorsolateral striatum, nucleus accumbens core, hippocampus, amygdala, and thalamic regions. No differences were observed in [H] MK-801 binding levels in animals that underwent the same treatment followed by a 4 week abstinence.

Significance: These results demonstrate that chronic MP treatment altered NMDA receptor expression throughout the brain, which in turn may impact an individual's drug-seeking behavior, fear memory formation and overall activity. However, these effects of chronic MP were eliminated following cessation of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2020.118708DOI Listing
January 2021

Roux-en-Y gastric bypass increases GABA-A receptor levels in regions of the rat brain involved in object recognition memory and perceptual acuity.

Physiol Behav 2020 10 6;224:113053. Epub 2020 Jul 6.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA; Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address:

Roux-en-Y gastric bypass surgery (RYGB), one of the most common and successful procedures for combatting obesity, is associated with post-surgery substance use disorder (SUD) and other addictive behaviors in a subset of patients. We investigated the effects of RYGB on GABA-A receptor levels in the rat brain to identify potential mechanisms of this behavior. The GABAergic system is affected in addiction and has been implicated in the pathology of obesity. We assigned male Sprague-Dawley rats to four groups: standard, low fat diet with sham surgery (control), ad libitum HFD with sham surgery (Sham), calorie restricted HFD with sham surgery (Sham-FR), or HFD with RYGB surgery. Surgery was performed after 8 weeks on the control or HFD diet. Rats maintained their respective diets for 9 weeks post-surgery, then were sacrificed for GABA-A receptor autoradiography using the [H] Flunitrazepam ligand. We identified increased GABA-A binding in the perirhinal cortex of ad-libitum HFD fed rats compared to normal diet controls. RYGB surgery increased GABA-A in the ectorhinal cortex compared to normal diet controls, and increased binding in the jaw region of the primary somatosensory cortex compared to food-restricted rats that received sham surgery. Hypothalamus GABA-A was also negatively correlated with body weight in the RYGB group, where GABA signaling may play a role in obesity regulation. These results suggest that HFD and RYGB modulate GABA signaling in regions important for object recognition memory, and that increased GABA-A levels in the jaw's perceptual field cortex arise from the surgery itself, independent of caloric restriction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.physbeh.2020.113053DOI Listing
October 2020

Chronic aerobic exercise: Autoradiographic assessment of GABA(a) and mu-opioid receptor binding in adult rats.

Pharmacol Biochem Behav 2020 09 25;196:172980. Epub 2020 Jun 25.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, United States of America; Department of Psychology, University at Buffalo, Buffalo, NY 14203, United States of America. Electronic address:

Exercise programs have shown great potential for both the prevention and treatment of substance use disorder (SUD). As exercise has been shown to have potent effects on physical and psychological health, it is reasonable to examine the mechanism of how exercise can be used as an adjunct treatment for addiction. The present study examined the effects of chronic aerobic (treadmill) exercise on both GABA(a) and mu-opioid receptor levels in the brains of male and female rats. GABA(a) receptor binding, measured by [H] Flunitrazepam, was increased in the cingulate cortex following exercise, but only in females. Mu-opioid receptor expression, measured by [H] ([D-Ala, N-MePhe, Gly-ol]-enkephalin) (DAMGO), showed no effect of exercise while showing an effect of sex, with increased [H] DAMGO binding in the brains of sedentary males compared to that of sedentary females. Our findings support the potential role for GABA(a) signaling in the cingulate cortex as part of the mechanism of action of aerobic exercise. These data, along with prior reports, aid our understanding of the neurochemical impact and mechanism of chronic aerobic exercise on neuropsychiatric disease, particularly regarding addiction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2020.172980DOI Listing
September 2020

The functional networks of a novel environment: Neural activity mapping in awake unrestrained rats using positron emission tomography.

Brain Behav 2020 08 20;10(8):e01646. Epub 2020 Jun 20.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA.

Introduction: Novel environment stimulation is thought to have an important role in cognitive development and has been shown to encourage exploratory behavior in rats. However, psychopathology or perceived danger or stress can impede this exploratory drive. The balance between brain circuits controlling the exploratory drive elicited by a novel environment, and the avoidance response to stressors, is not well understood.

Methods: Using positron emission tomography (PET) and the glucose analog [ F]fluorodeoxyglucose (18F-FDG), we assessed awake brain glucose metabolism (BGluM) in rats while in a novel environment (cage of an unfamiliar male rat) and non-novel environment (the animal's home cage).

Results: Exposure to the novel environment increased BGluM in regions associated with vision (visual cortex), motor function and motivated behavior (striatum and motor cortex), and anxiety (stria terminalis), and decreased BGluM in regions associated with auditory processing (auditory cortex, insular cortex, inferior colliculus), locomotor activity (globus pallidus, striatum, motor cortex, ventral thalamic nucleus), spatial navigation (retrosplenial cortex), and working memory (hippocampus, cingulate cortex, prelimbic cortex, orbitofrontal cortex).

Conclusion: These results suggest that the novel cage is a stressful environment that inhibits activity in brain regions associated with exploratory behavior. Patterns of inhibition in the novel cage also support the proposed rat default mode network, indicating that animals are more cognitively engaged in this environment. Additionally, these data support the unique capability of combining FDG-PET with psychopharmacology experiments to examine novelty seeking and brain activation in the context of decision making, risk taking, and cognitive function more generally, along with response to environmental or stress challenges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/brb3.1646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428510PMC
August 2020

The therapeutic potential of exercise for neuropsychiatric diseases: A review.

J Neurol Sci 2020 05 4;412:116763. Epub 2020 Mar 4.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, USA; Department of Psychology, State University of New York at Buffalo, Buffalo, NY, USA. Electronic address:

Exercise is known to have a myriad of health benefits. There is much to be learned from the effects of exercise and its potential for prevention, attenuation and treatment of multiple neuropsychiatric diseases and behavioral disorders. Furthermore, recent data and research on exercise benefits with respect to major health crises, such as, that of opioid and general substance use disorders, make it very important to better understand and review the mechanisms of exercise and how it could be utilized for effective treatments or adjunct treatments for these diseases. In addition, mechanisms, epigenetics and sex differences are examined and discussed in terms of future research implications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2020.116763DOI Listing
May 2020

Hypodopaminergia and "Precision Behavioral Management" (PBM): It is a Generational Family Affair.

Curr Pharm Biotechnol 2020 ;21(6):528-541

Department of Precision Addiction Management, Geneus Health, LLC., San Antonio, TX, United States.

Background/aims: This case series presents the novel Genetic Addiction Risk Score (GARS®) coupled with a customized pro-dopamine regulator matched to polymorphic reward genes having a hypodopaminergic risk.

Methods: The proband is a female with a history of drug abuse and alcoholism. She experienced a car accident under the influence and voluntarily entered treatment. Following an assessment, she was genotyped using the GARS, and started a neuronutrient with a KB220 base indicated by the identified polymorphisms. She began taking it in April 2018 and continues.

Results: She had success in recovery from Substance Use Disorder (SUD) and improvement in socialization, family, economic status, well-being, and attenuation of Major Depression. She tested negative over the first two months in treatment and a recent screening. After approximately two months, her parents also decided to take the GARS and started taking the recommended variants. The proband's father (a binge drinker) and mother (no SUD) both showed improvement in various behavioral issues. Finally, the proband's biological children were also GARS tested, showing a high risk for SUD.

Conclusion: This three-generation case series represents an example of the impact of genetic information coupled with an appropriate DNA guided "Pro-Dopamine Regulator" in recovery and enhancement of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2174/1389201021666191210112108DOI Listing
July 2020

Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects.

Dev Psychobiol 2020 03 27;62(2):170-180. Epub 2019 Aug 27.

Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA.

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dev.21902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028498PMC
March 2020

Roux-en-Y gastric bypass in rat reduces mu-opioid receptor levels in brain regions associated with stress and energy regulation.

PLoS One 2019 20;14(6):e0218680. Epub 2019 Jun 20.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Clinical Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, State University of New York at Buffalo, Buffalo, NY, United States of America.

Roux-en-Y gastric bypass surgery (RYGB) is the most common and effective weight loss procedure for severe obesity. However, a significant increase in addictive behaviors and new-onset substance use disorder (SUD) are sometimes observed post-surgery. The endogenous opioid system is known to play a major role in motivated behavior and reward, as well as the abuse of substances, including alcohol, tobacco, opioids and highly palatable foods. Here, we examined the effects of RYGB on mu-opioid receptor levels in the brain. Male Sprague-Dawley rats were assigned to one of four groups: standard diet with sham surgery (control), ad libitum high-energy high-fat (HF) diet with sham surgery, calorie restricted HF diet with sham surgery (Sham-FR), or HF diet with RYGB surgery. Control and HF groups were fed their respective diets for 8 weeks, with surgery performed on the eighth week. After 9 weeks on their respective diets post-surgery, animals were sacrificed for mu-opioid receptor autoradiography using the [3H] [D-Ala2,N-Me-Phe4-Gly5-ol]- enkephalin (DAMGO) ligand. Rats with RYGB showed reduced DAMGO binding in the central amygdala compared to sham-operated HF diet controls, and in the hypothalamus compared to high-fat fed Sham-FR. Diet alone did not change [3H] DAMGO binding in any region. These findings show that RYGB surgery, independent of diet or caloric restriction, decreases mu opioid signaling in specific regions important for stress and energy regulation. Thus, RYGB surgery may lead to greater stress sensitivity via downregulated mu opioid signaling in the central amygdala, which may contribute to the observed increased risk in some subjects for addictive behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0218680PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6586324PMC
February 2020

Chronic aerobic exercise: Lack of effect on brain CB1 receptor levels in adult rats.

Life Sci 2019 Aug 22;230:84-88. Epub 2019 May 22.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, United States of America; Department of Psychology, University at Buffalo, Buffalo, NY, 1403, United States of America. Electronic address:

Introduction: Exercise programs have been shown to be effective for both reducing risk for, and intervention following, substance abuse behaviors in both clinical and preclinical studies. Less is known, however, regarding the underlying neurobiological substrates involved in these changes in drug seeking behavior. In this study, we assessed cannabinoid receptor (CB1) levels throughout the brain which are key in endocannabinoid signaling following chronic aerobic exercise.

Methods: Male and female Lewis young adult rats were grouped into exercise and sedentary groups at 8 weeks of age. Exercise rats ran on a treadmill at 10 m/min, 5 days/week, for 6 weeks, whereas sedentary rats remained in their home cage. Rats were euthanized after 6 weeks, and in vitro receptor autoradiography was performed using [H] SR141716A to quantify CB1 receptors throughout the brain.

Results: Exercise rats did not show significantly different [H] SR141716A binding levels as compared to sedentary rats; however, an overall sex effect was found, where males had 29% higher [H] SR141716A binding within the pyramidal layer of the hippocampus when compared to females. The chronic aerobic exercise regimen did not produce any changes in CB1 receptor levels.

Conclusions: The present study found that chronic exercise during young adulthood did not alter cannabinoid CB1 receptor levels in the brain. Therefore, previously reported decreased cocaine preference in parallel treated cohorts did not involve exercise induced changes in CB1 levels which is key for endocannabinoid signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.lfs.2019.05.058DOI Listing
August 2019

Dopamine D4 receptor gene expression plays important role in extinction and reinstatement of cocaine-seeking behavior in mice.

Behav Brain Res 2019 06 21;365:1-6. Epub 2019 Feb 21.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; Department of Psychology, University at Buffalo, Buffalo, NY, USA. Electronic address:

Dopamine D4 receptor (DRD4) dysregulation is associated with a variety of behaviors including novelty-seeking, approach avoidance, and ADHD. DRD4 has also been shown to interact with the environment to produce changes in behavior and longevity. The present study sought to examine the role of DRD4 on cocaine-seeking behavior in the conditioned place preference (CPP) test and determine its effects on extinction and reinstatement in adult wild-type (WT), heterozygous (HT), and knockout (KO) mice. Results revealed that all mice, regardless of sex or genotype, developed a similar acquisition for a cocaine place preference. Female DRD4 KO mice failed to extinguish their preference for the cocaine-paired chamber following the extinction period. Male DRD4 KO mice failed to reinstate their preference after a priming dose following successful extinction. No differences in locomotor activity were observed within drug treatment conditions due to genotype, and female mice displayed reduced locomotor activity during CPP conditioning compared to male mice. The observed effects illustrate the role DRD4 gene expression has on extinction and reinstatement, but not acquisition, of cocaine-seeking behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2019.02.036DOI Listing
June 2019

Analysis of Evidence for the Combination of Pro-dopamine Regulator (KB220PAM) and Naltrexone to Prevent Opioid Use Disorder Relapse.

EC Psychol Psychiatr 2018 Aug 30;7(8):564-579. Epub 2018 Jul 30.

Department of Psychiatry, Washington University, School of Medicine, St. Louis, MO, USA.

Blum's laboratory first showed the benefits of naloxone or narcotic antagonists in the treatment of alcohol dependence. This seminal work published in Nature in the early 70's, in conjunction with many other studies, later served as the basis for the development of the narcotic antagonist (NTX) now used to treat both alcohol and opioid dependence. In 2006 an extended-release injectable of Naltrexone (XR-NTX) was approved by the FDA. Naltrexone is a relatively weak antagonist of κ- and δ-receptors and is also a potent μ-receptor antagonist. Dosages of naltrexone that effectively reduce opioid and alcohol consumption also actively block μ-receptors, but chronically down-regulate mesolimbic dopamine release. While studies show benefit especially in the short term, there is ongoing evidence that the retention and compliance with NTX are not sufficient to characterize adherence as high. However, extended-release NTX opioid treatment is associated with superior outcomes including less likely relapse (defined as daily use), and much longer time to relapse despite higher rates of concurrent non-opioid substance use like cocaine. Regarding long-term extended-release injectable (XR-NTX) for opioid dependence; there was higher compliance with Opioid Use Disorder (OUD) than for Alcohol Use Disorder (AUD.). Consideration of modalities in combination with XR-NTX is imperative. Research by Blum., showed that a combination of Naltrexone and a pro-dopamine regulator neuro-nutrient (KB220) significantly prevented opioid relapse. Thus, early identification of addiction vulnerability with the Genetic Addiction Risk Score (GARS™) a panel of polymorphic risk alleles from ten reward circuitry genes will provide valuable information especially as it relates to genetically guided therapy with the KB220 neuro nutrient termed 'Precision Addiction Management".
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226033PMC
August 2018

Chronic oral methylphenidate treatment increases microglial activation in rats.

J Neural Transm (Vienna) 2018 12 20;125(12):1867-1875. Epub 2018 Sep 20.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, 1021 Main St., Buffalo, NY, USA.

Methylphenidate (MP) is a widely prescribed psychostimulant used to treat attention deficit hyperactivity disorder. Previously, we established a drinking paradigm to deliver MP to rats at doses that result in pharmacokinetic profiles similar to treated patients. In the present study, adolescent male rats were assigned to one of three groups: control (water), low-dose MP (LD; 4/10 mg/kg), and high dose MP (HD; 30/60 mg/kg). Following 3 months of treatment, half of the rats in each group were euthanized, and the remaining rats received only water throughout a 1-month-long abstinence phase. In vitro autoradiography using [H] PK 11195 was performed to measure microglial activation. HD MP rats showed increased [H] PK 11195 binding compared to control rats in several cerebral cortical areas: primary somatosensory cortex including jaw (68.6%), upper lip (80.1%), barrel field (88.9%), and trunk (78%) regions, forelimb sensorimotor area (87.3%), secondary somatosensory cortex (72.5%), motor cortices 1 (73.2%) and 2 (69.3%), insular cortex (59.9%); as well as subcortical regions including the thalamus (62.9%), globus pallidus (79.4%) and substantia nigra (22.7%). Additionally, HD MP rats showed greater binding compared to LD MP rats in the hippocampus (60.6%), thalamus (59.6%), substantia nigra (38.5%), and motor 2 cortex (55.3%). Following abstinence, HD MP rats showed no significant differences compared to water controls; however, LD MP rats showed increased binding in pre-limbic cortex (78.1%) and ventromedial caudate putamen (113.8%). These findings indicate that chronic MP results in widespread microglial activation immediately after treatment and following the cessation of treatment in some brain regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00702-018-1931-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526704PMC
December 2018

Weekday-only chronic oral methylphenidate self-administration in male rats: Reversibility of the behavioral and physiological effects.

Behav Brain Res 2019 01 24;356:189-196. Epub 2018 Aug 24.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, Buffalo, NY, USA. Electronic address:

Methylphenidate (MP) is a commonly prescribed psychostimulant for Attention Deficit Hyperactivity Disorder (ADHD). We recently reported behavioral and developmental effects of chronic MP use in healthy rats. The current study investigated how interrupting chronic MP treatment with weekend abstinence altered the behavioral and physiological consequences of chronic MP treatment, and if prolonged abstinence would reverse the observed effects. Male Sprague Dawley rats were assigned to one of three treatment groups: water (W); low dose (LD) MP; and high dose (HD) MP. For 13 weeks, rats had access to drink from a bottle containing 4 mg/kg MP (LD), 30 mg/kg MP (HD) or water (W) for 1 h, and 10 mg/kg MP (LD), 60 mg/kg MP (HD) or water (W) for the next 7 h, each week day. During weekends, all animals received only water as well as throughout the 5-week-long abstinence phase, which immediately followed the treatment phase. Throughout the treatment phase, regardless of weekend abstinence, chronic MP resulted in significant decreased food and fluid intake and body weight. Also, HD MP exposure resulted in the following behavioral effects: increased open field and circadian locomotor activity; increased latency to immobility and decreased time spent immobile in the forced swim test; increased center activity in the open field and percent of time spent in an open arm of the elevated-plus-maze; and increased social affiliation and memory in the Crawley's three chamber sociability test. During the prolonged (5-week) abstinence phase, all these effects were reversed while HD treated rats increased their fluid intake. These results indicated that intermittent brief abstinence periods (weekend's off-treatment) produced the same behavioral and developmental effects as those previously reported with chronic (7 days/week) MP treatment, but were reversible following a prolonged abstinence period (5 weeks).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2018.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6317517PMC
January 2019

Chronic forced exercise inhibits stress-induced reinstatement of cocaine conditioned place preference.

Behav Brain Res 2018 11 20;353:176-184. Epub 2018 Jul 20.

University at Buffalo, Research Institute on Addictions, Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, 1021 Main Street, Buffalo, NY, 14203-1016, USA. Electronic address:

Stress increases the likelihood of cocaine relapse in humans and animals, even following a prolonged extinction/abstinence period. Exercise has previously been shown to reduce stress and decrease the likelihood of drug dependence, while also reducing cravings in humans and inhibiting relapse behaviors due to other risk factors in rodents. The present study evaluated the efficacy of exercise to reduce stress-induced relapse to cocaine in a rodent model. Young adult female Sprague Dawley rats were tested for cocaine conditioned place preference (CPP), then split into sedentary or exercise (six weeks of one-hour daily treadmill running, five days per week) groups. Following cocaine CPP, rats were tested for extinction behavior, and then tested for stress-primed reinstatement (15 min immobilization) following the six-week intervention period. Exercise inhibited stress-induced reinstatement of cocaine CPP despite increasing serum corticosterone levels following 15 min of immobilization, suggesting that chronic aerobic exercise intervention may result in adaptations of stress pathways. These findings suggest that exercise may help prevent stress-induced drug relapse, adding to a growing body of evidence supporting the utility of exercise to combat substance abuse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbr.2018.07.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319952PMC
November 2018

Recovery from behavior and developmental effects of chronic oral methylphenidate following an abstinence period.

Pharmacol Biochem Behav 2018 09 18;172:22-32. Epub 2018 Jul 18.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, Department of Pharmacology & Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, Buffalo, NY, USA. Electronic address:

Chronic oral methylphenidate (MP) exposure in rats is associated with numerous developmental and behavioral consequences. The present study investigated the persistence of the effects of chronic oral MP exposure after abstinence from MP use. Male and female rats were exposed to daily orally self-administered water, low dose MP (LD), or high dose (HD) MP for 13 weeks, followed by a 4-week abstinence period. Fluid, food consumption and bodyweights were monitored and animals were tested for locomotor activity, anxiety- and depressive-like symptoms, learning and memory, and social behavior during both the treatment and abstinence phases of the experiment. During treatment, MP attenuated bodyweight regardless of sex, but increased food and fluid consumption in females and males by 20.7% and 30.1%, respectively. MP also increased locomotor activity in both males and females observed as increased distance travelled in an open field. (59.1% and 95.9%, respectively) and increased locomotor activity in the home cage over a 24-hour circadian cycle (45.5% and 63.0%). Additionally, MP exerted an anxiolytic effect observed as increased time spent in the open arms of an elevated plus maze (31.1% in HD males, 59.2% in HD females), and an increased latency to immobility in a forced swim test (330% in HD males, 418% in HD females). The effects of MP (bodyweight, consumption, locomotion, anxiolytic, and anti-depressive) were, almost without exception, eliminated during the abstinence period. MP had no impact on learning and memory performance as measured by a T-maze, or social behavior during treatment. These findings suggest that the behavioral consequences of chronic oral MP treatment in our preclinical model are reversible in rats following an abstinence period from use of the drug.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pbb.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319957PMC
September 2018

Roux-en-Y gastric bypass surgery normalizes dopamine D1, D2, and DAT levels.

Synapse 2018 Jul 10. Epub 2018 Jul 10.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, Department of Pharmacology and Toxicology, Jacobs School of Medicine and Biosciences, University at Buffalo, Buffalo, New York.

Roux-en-Y gastric bypass surgery (RYGB) is one of the most effective treatments for morbid obesity. However, increased substance abuse following RYGB has been observed clinically. This study examined the effects of RYGB on the dopamine system to elucidate these observed changes in reward-related behavior. Rats were assigned to four groups: normal diet with sham surgery, ad libitum high fat (HF) diet with sham surgery, restricted HF diet with sham surgery, and HF diet with RYGB surgery. Following surgeries, rats were kept on their respective diets for 9 weeks before they were sacrificed. [ H]SCH 23390, [ H]Spiperone, and [ H]WIN35 428 autoradiography was performed to quantify the effects of diet and RYGB surgery on dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter (DAT) binding. Rats on a chronic HF diet became obese with reduced D1R-like binding within the ventrolateral striatum and the nucleus accumbens core, reduced D2R-like binding in all areas of the striatum and nucleus accumbens core and shell, and reduced DAT binding in the dorsomedial striatum. Restricted HF diet rats showed similar reductions in D1R-like and D2-R-like binding as the obese rats, and reduced DAT binding within all areas of the striatum. Both RYGB and restricted HF diet rats showed similar weight reductions, with RYGB rats showing no difference in binding compared to controls. The observed changes in binding between non-treated obese rats and RYGB rats demonstrates that HF dietary effects on the dopamine system were reversed by RYGB.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/syn.22058DOI Listing
July 2018

Striatal Rgs4 regulates feeding and susceptibility to diet-induced obesity.

Mol Psychiatry 2020 09 28;25(9):2058-2069. Epub 2018 Jun 28.

Departments of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.

Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41380-018-0120-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310669PMC
September 2020

Exercise Reduces Dopamine D1R and Increases D2R in Rats: Implications for Addiction.

Med Sci Sports Exerc 2018 08;50(8):1596-1602

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions (BNNLA), Research Institute on Addictions, University at Buffalo, Buffalo, NY.

Introduction: Exercise has been shown to be effective for preventing and treating substance abuse in both clinical and preclinical studies. Less is known, however, regarding the underlying neurobiological mechanisms driving these changes in drug-seeking behavior. One possibility is that exercise may alter the mesolimbic dopamine pathway in such a way that makes drugs of abuse less salient and/or rewarding.

Methods: To examine possible exercise-induced changes in dopamine signaling, male and female Lewis rats were split into exercise and sedentary groups at 8 wk of age. Exercise rats were run on a treadmill at 10 m·min, 5 d·wk, for 6 wk, whereas sedentary rats remained in their home cage. Rats were killed after the 6 wk of treatment, and their brains were used for in vitro autoradiography using [H]SCH 23,390, [H]Spiperone, and [H]WIN55,428 ligands to quantify dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter binding, respectively.

Results: Exercised rats had 18% and 21% lower D1R-like binding levels compared to sedentary rats within the olfactory tubercle and nucleus accumbens shell, respectively. In addition, male and female exercise rats showed greater D2R-like binding levels within the dorsomedial caudate putamen (30%), ventrolateral caudate putamen (24%), and ventromedial caudate putamen (27%), as well as the olfactory tubercle (19%). Greater D2R-like binding in the nucleus accumbens core (24%) and shell (25%) of exercised rats compared with sedentary rats approached significance. No effects were found for dopamine transporter binding.

Conclusions: These findings support the hypothesis that aerobic exercise results in changes in the mesolimbic pathway that could mediate exercise-induced attenuation of drug-seeking behavior.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1249/MSS.0000000000001627DOI Listing
August 2018

Fatty acid-binding proteins 5 and 7 gene deletion increases sucrose consumption and diminishes forced swim immobility time.

Behav Pharmacol 2018 09;29(6):503-508

Research Institute on Addictions, University at Buffalo, Buffalo.

Inhibition and genetic deletion of fatty acid-binding proteins (FABPs) 5 and 7 have been shown to increase the levels of the endocannabinoid anandamide as well as the related N-acylethanolamine's palmitoylethanolamide and oleoylethanolamide. This study examined the role of these FABPs on forced-swim (FS) behavior and on sucrose consumption in two experiments: (experiment 1) using wild-type (WT) mice treated with the FABP inhibitor SBFI26 or vehicle and (experiment 2) using WT and FABP5/7 deficient mice. Results from experiment 1 showed that acute treatment with SBFI26 did not have any effect on sucrose intake or FS behavior in mice. In experiment 2, male and female FABP5/7 deficient mice showed significant increases in sucrose consumption (25 and 21%, respectively) compared with their WT counterparts. In addition, immobility time during the FS was decreased by 27% in both male and female FABP5/7 knockout mice compared with their WT counterparts. The fact that such differences were seen between the acute pharmacological approach and the genetic approach (gene deletion) of FABP needs to be further investigated. The function of FABPs and their specific effects on endocannabinoid anandamide, oleoylethanolamide, and palmitoylethanolamide may play an important role in the development of reward and mood behaviors and could provide opportunities for potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FBP.0000000000000402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642700PMC
September 2018

Fatty-acid-binding protein 5 controls retrograde endocannabinoid signaling at central glutamate synapses.

Proc Natl Acad Sci U S A 2018 03 12;115(13):3482-3487. Epub 2018 Mar 12.

Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794.

Endocannabinoids (eCBs) are lipid-signaling molecules involved in the regulation of numerous behaviors and physiological functions. Released by postsynaptic neurons, eCBs mediate retrograde modulation of synaptic transmission and plasticity by activating presynaptic cannabinoid receptors. While the cellular mechanisms by which eCBs control synaptic function have been well characterized, the mechanisms controlling their retrograde synaptic transport remain unknown. Here, we demonstrate that fatty-acid-binding protein 5 (FABP5), a canonical intracellular carrier of eCBs, is indispensable for retrograde eCB transport in the dorsal raphe nucleus (DRn). Thus, pharmacological inhibition or genetic deletion of FABP5 abolishes both phasic and tonic eCB-mediated control of excitatory synaptic transmission in the DRn. The blockade of retrograde eCB signaling induced by FABP5 inhibition is not mediated by impaired cannabinoid receptor function or reduced eCB synthesis. These findings indicate that FABP5 is essential for retrograde eCB signaling and may serve as a synaptic carrier of eCBs at central synapses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1721339115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879704PMC
March 2018

Fatty acid binding protein deletion prevents stress-induced preference for cocaine and dampens stress-induced corticosterone levels.

Synapse 2018 06 19;72(6):e22031. Epub 2018 Feb 19.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, New York.

Genetic and pharmacological manipulation of endocannabinoid (eCB) signaling has previously been shown to have an important role on the rewarding properties of drugs of abuse, including cocaine. Recently, fatty acid binding proteins (FABPs) have been proposed as intracellular transporters of the endocannabinoid anandamide (AEA) as well as other bioactive lipids to their catabolic enzyme, fatty acid amide hydrolase (FAAH). The role of these transporters in modulating the brains reward system has yet to be investigated. This study examined the effects of genetic deletion of FABP 5/7 on cocaine preference, as assessed by the Conditioned Place Preference (CPP) paradigm. Male and female wild type (WT) and FABP 5/7 KO mice showed similar acquisition of cocaine CPP, with no differences found in overall locomotor activity. In addition, while male and female WT mice showed stress-induced CPP for cocaine, male and female FABP 5/7 KO mice failed to show a stress-induced preference for the cocaine-paired chamber. Additionally, serum corticosterone levels were analyzed to explore any potential differences in stress response that may be responsible for the lack of stress-induced preference for cocaine. Serum samples were obtained in animals under basal conditions as well as following a 30-min tube restraint stress. Male and female FABP 5/7 KO mice showed reduced corticosterone levels under stress compared to their WT counterparts. The reduction in corticosterone response under stress may mediate that lack of a stress-induced preference for cocaine in the FABP 5/7 KO mice. Thus, the role of FABPs may play an important role in drug-seeking behavior under stressful conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/syn.22031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6341999PMC
June 2018

Pharmacological Inhibition of Brain Fatty Acid Binding Protein Reduces Ethanol Consumption in Mice.

J Reward Defic Syndr Addict Sci 2017 31;3(2):21-27. Epub 2017 Oct 31.

Behavioral Neuropharmacology and Neuroimaging Laboratory on Addictions, Research Institute on Addictions, University at Buffalo, Buffalo, NY, USA.

The endocannabinoid (eCB) system is involved in a wide range of behavioral disorders including alcoholism. Inhibition of fatty acid amide hydrolase (FAAH), the principal enzyme that degrades the eCB anandamide (AEA), which enhances AEA levels in the brain, significantly increases ethanol consumption and preference. In the present study, we examined whether pharmacological inhibition of fatty acid binding proteins (FABPs) 5 and 7, which blocks the transport of AEA to FAAH, and increase AEA levels also alters ethanol consumption and preference. Using a limited access two-bottle choice paradigm, we evaluated ethanol consumption in both male and female C57Bl/6 mice. Results showed a significant decrease in ethanol consumption in both males and females treated with SBFI26, an inhibitor of FABPs. Specifically, male and female mice treated with SBFI26 consumed 24% and 42% less compared to mice receiving no injections, respectively. Subsequently, corticosterone was examined to evaluate the effects FABP5/7 inhibition upon the stress response. We observed a significant elevation in corticosterone levels following restraint stress in SBFI26 treated females, with a weak effect seen in males as compared to vehicle. Based on our results, targeting of FABPs appears to play an important role in ethanol consumption that is differentially regulated in males and females, which is mediated by the stress response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777574PMC
October 2017
-->