Oral administration of bacterial probiotics improves Helicobacter pylori-induced memory impairment in rats: Insights from behavioral and biochemical investigations.

There are numerous evidence supporting the association between Helicobacter pylori (H. pylori) infection and the occurrence of cognitive deficits in humans. In this regard, treatment of H. pylori infection has been suggested as an effective strategy to decelerate the neurodegenerative processes of memory deficits in AD patients. Numerous studies support the beneficial effects of probiotics on various pathological conditions, particularly cognitive deficits, however, this concern has not been addressed in relation to the memory impairment induced by H. pylori infection. In the present study, we aimed to reveal whether oral administration of two bacterial probiotics (including Lactobacillus rhamnosus and Lactobacillus plantarum), could ameliorate H. pylori-induced memory deficits at behavioral level in rats. Besides, cellular mechanisms were investigated by biochemical methods to find out how probiotic effects are mediated in hippocampal circuitry. Male Wistar rats were infected by H. pylori for 3 consecutive days, then probiotic treatment was done for the next 3 days and after a drug-free period (12 days), animals were assessed by Morris Water Maze and Novel Object Recognition tests. Finally, rats were euthanized by CO2 and hippocampal tissues were excised for biochemical measurements. Results indicated that H. pylori infection markedly impairs memory function in rats which is associated with alterations of oxidative, inflammatory, neurotrophic, and cholinergic markers. Interestingly, treatment with either of the probiotics alone or in combination, significantly improved the H. pylori-induced memory deficits and this was associated with restoration of balance in biochemical factors within the hippocampal neurons.

Omega-3 fatty acids prevent nicotine withdrawal-induced impairment of learning and memory via affecting oxidative status, inflammatory response, cholinergic activity, BDNF and amyloid-B in rat hippocampal tissues.

In the present study, the main objective was to reveal whether treatment by Omega-3 fatty acids could prevent the adverse effects of adolescent nicotine withdrawal on spatial and avoidance memory in male rats. For this purpose, Morris water maze and passive avoidance tests were performed on male Wistar rats and the hippocampal levels of oxidative stress markers, inflammatory indices, brain-derived neurotrophic factor, nitrite, amyloid-B and acetylcholinesterase (AChE) were measured. Moreover, density of dark neurons were assessed in CA1 and CA3 regions. Results showed that adolescent nicotine exposure followed by a period of drug cessation exacerbates the behavioral indices of learning and memory through affecting a variety of biochemical markers within the hippocampal tissues. These changes lead to elevation of oxidative and inflammatory markers, reduction of neurotrophic capacity and increased AChE activity in hippocampal tissues. In addition, it was observed that co-administration of nicotine with Omega-3 fatty acids significantly prevents nicotine withdrawal-induced adverse effects through restoration of the mentioned biochemical disturbances. Therefore, we suggest administration of Omega-3 fatty acids as a safe, inexpensive and effective therapeutic strategy for prevention of memory dysfunctions associated with nicotine abstinence during adolescence.

Preparation and Evaluation of the In situ Gel-forming Chitosan Hydrogels for Nasal Delivery of Morphine in a Single Unit dose in Rats to Enhance the Analgesic Responses.

INTRODUCTION: In this study, an in situ gel-forming chitosan hydrogel was prepared with the use of glutamate salt of chitosan (Ch-Ga), ß-glycerophosphate (Gp), and morphine (Mor). The paper is focused on in vitro physicochemical properties and in-vivo analgesic effects of the prepared chitosan hydrogel. METHOD: The thermosensitive properties of prepared chitosan hydrogel were evaluated during the different temperatures and times. The physicochemical properties of chitosan hydrogel were investigated by infrared (IR) spectroscopy and X-ray diffraction analysis (XRD). Also, its cell cytotoxicity effects were evaluated in murine NIH/3T3 normal cells. Subsequently, the distribution of chitosan hydrogel in the nasal cavity of rats and its analgesic responses were evaluated. The prepared chitosan hydrogel showed that it could be gelled at the temperature of 34 °C before leaving the nose in the shortest possible time of 30 s. RESULT: The analgesic responses of the intranasal (IN) injection of chitosan hydrogel (IN-chitosan hydrogel, 10 mg Mor/kg) in a single unit dose in rat relative to the placebo and intranasal or intraperitoneal (IP) injection of free morphine solution (IN-Free Mor or IP-Free Mor, 10 mg Mor/kg) via the hot plate test, reveal that the IN-chitosan hydrogel could induce fast analgesic effects of morphine with maximum possible effect (MPE) of 93% after 5 min compare to the IN-Free Mor and IP-Free Mor with MPE of 80% after 15 min and 66% after 30 min, respectively. Also, prolonged analgesic effects with MPE of 78 % after 6 h of injection were only seen in the IN-chitosan hydrogel injected group. The obtained fluorescent images of rat's brain injected with IN-chitosan hydrogel containing doxorubicine (Dox) as a fluorescent agent showed that the mucosal adhesive and absorption enhancer properties of IN-chitosan hydrogel resulting in longer presence of them in the nasal cavity of rats followed by more absorption of Dox from the blood vessels of olfactory bulbs with a 74% color intensity compared to the IN-Free Mor and IN-Free Dox with 15%. CONCLUSION: These data reveal that the IN-chitosan hydrogel could induce fast and prolonged analgesic effects of morphine compare to the IN/IP-Free Mor, which could be considered as an in situ gel-forming thermosensitive chitosan hydrogel for nasal delivery of wide ranges of therapeutic agents.

Effects of Ocimum basilicum L. Extract on Hippocampal Oxidative Stress, Inflammation, and BDNF Expression in Amnesic Aged Rats.

The present study was conducted to investigate the effects of Ocimum basilicum L. (OB) extract on learning and memory impairment in aged rats. Male rats were divided into the following experimental groups: Group 1 (control): including 2 months old rats, Group 2 (aged) including 2 years old rats, Groups 3-5 (aged-OB): including 2 years old rats received 50, 100, and 150 mg/kg OB for 8 weeks by oral gavage. Aging increased the delay to find the platform but, however, decreased the time spent in the target quadrant when tested by Morris water maze (MWM). Aging also reduced the latency to enter the dark chamber in the passive avoidance (PA) test compared to the control group. Moreover, interleukin-6 (IL-6) and malondialdehyde (MDA) levels were raised in the hippocampus and cortex of aged rats. In contrast, thiol levels and enzymatic activity of superoxide dismutase (SOD) and catalase (CAT) significantly reduced. In addition, aging significantly reduced BDNF expression. Finally, OB administration reversed the mentioned effects. The current research showed that OB administration improves learning/memory impairment induced by aging. It also found that this plant extract protects the brain tissues from oxidative damage and neuroinflammation.

Omega-3 fatty acids prevent nicotine withdrawal-induced exacerbation of anxiety and depression by affecting oxidative stress balance, inflammatory response, BDNF and serotonin metabolism in rats.

Adolescents are known to be more vulnerable than adults to the adverse effects of nicotine dependence. In the present study, we aimed to investigate whether adolescent nicotine exposure, followed by a period of abstinence, could affect the anxiety- and depressive-like behaviors in rats. For this purpose, behavioral assessments were carried out using open field test, elevated plus maze and forced swimming test in male rats received chronic nicotine intake during adolescence followed by a period of abstinence in adulthood, compared to their control counterparts. In addition, O3 pre-treatment was done at three different doses to reveal whether it could prevent nicotine withdrawal effects. Then, animals were euthanized and the cortical concentrations of oxidative stress markers, inflammatory indices, brain-derived neurotrophic factor, serotonin and the enzymatic activity of monoamine oxidase-A were measured. Results indicated that nicotine withdrawal exacerbates the behavioral signs of anxiety through alteration of the brain oxidative stress balance, inflammatory response and serotonin metabolism. Moreover, we found that omega 3 pre-treatment significantly prevents the nicotine withdrawal-induced complications by restoration of changes in the mentioned biochemical indices. Moreover, the improving effects of O3 fatty acids were found to be dose-dependent in all experiments. Taken together, we would like to suggest the O3 fatty acids supplementation as a safe, inexpensive and effective strategy for prevention or amelioration of detrimental effects induced by nicotine withdrawal at cellular and behavioral levels.

Comparative investigation of analgesic tolerance to taurine, sodium salicylate and morphine: Involvement of peripheral muscarinic receptors.

Nowadays various analgesic medications are used for the management of acute and chronic pain. Among these opioid and non-steroidal anti-inflammatory drugs stand in the first line of therapy, however, prolonged administration of these substance is generally challenged by development of analgesic tolerance in patients. Therefore, it is highly valuable to find new pharmacological strategies for prolonged therapeutic procedures. In this respect, Taurine, a free amino acid, has been shown to induce significant analgesia at both spinal and peripheral levels through cholinergic mechanisms. In the present study, we used hot-plate analgesic test to investigate how taurine either as a single medication or in combination with sodium salicylate and morphine may affect both acute response to pain and development of analgesic tolerance. The effect of taurine was also tested on morphine withdrawal syndrome. Hyoscine butyl bromide was used to assess the role of muscarinic receptors in taurine-mediated effects. Finally, biochemical assay was done to reveal how the activity of brain acetylcholinesterase may change in relation with muscarinic receptor activity. Results indicated that acute administration of taurine-sodium salicylate combination causes more potent analgesia compared to the use of tau (but not SS alone) and this seems to be mediated via activity of muscarinic receptors in peripheral nervous system. Furthermore, the effect of this combination undergoes less analgesic tolerance during time. Combination of taurine and morphine is an effective strategy to attenuate both morphine analgesic tolerance and dependence and this also seems to depend on activity of muscarinic receptors, however through differential cellular mechanisms.

A history of ethanol intake accelerates the development of morphine analgesic tolerance: A protective potential for omega-3 fatty acids.

Adolescence is a critical life period during which significant neurodevelopmental changes occur within the central nervous system. Consistently, substance abuse in this stage has been found to induce persistent changes in brain responsiveness to future drug challenges. Nowadays, heavy episodic alcohol consumption during adolescence, also known as binge-drinking behavior, is a growing concern in modern societies. On the other hand, alcohol is well known to act as a gateway drug, that is, it promotes the individual's craving for consumption of other drugs of abuse. With this in mind, we aimed to assess whether adolescent ethanol exposure could alter the development of tolerance and dependence to morphine, as an available common opioid drug. Tail flick test was used to measure thermal nociceptive changes in adult male Wistar rats undergone ethanol/vehicle exposure during adolescence. Furthermore, morphine withdrawal syndrome was induced by naloxone injection, and behavioral signs were recorded for 20 min. It was found that adolescent ethanol intake facilitates morphine analgesic tolerance and decreases baseline latency; however, the severity of dependence is not significantly altered. Moreover, we found that 15 days of treatment with omega-3 fatty acids (O3) prevents the mentioned ethanol-induced changes suggesting a therapeutic potential for this compound. O3 supplementation, as an inexpensive and noninvasive method, may assist the clinicians to reverse the adverse effect of alcohol binge drinking on adolescents' brains and to reduce the vulnerability to drug exposure in adulthood. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Vitamin B12 administration prevents ethanol-induced learning and memory impairment through re-establishment of the brain oxidant/antioxidant balance, enhancement of BDNF and suppression of GFAP.

There are growing evidence indicating that the adolescent brain is persistently affected by the use of psychostimulant agents. In this regard, alcohol drinking has become rather common among the adolescents in many societies during the last decade. It is currently well known that long-term ethanol exposure deteriorates various cognitive functions such as learning and memory. Mechanistically, these adverse effects have been shown to be mediated by oxidative damage to central nervous system. On the other hand, Vit-B12 is known to improve cognitive performance by suppression of oxidative parameters. Thus, in the present study we aimed to test whether treatment by Vit-B12 could prevent ethanol-induced complications in mice using behavioral and biochemical methods. Different groups of male Syrian mice received ethanol, ethanol+Vit-B12, Vit-B12 alone, or saline during adolescence and then learning and memory functions were assessed by Morris water maze (MWM) and Passive Avoidance (PA) tests. Finally, mice were sacrificed for measurement of biochemical factors. Results indicated that, adolescent ethanol intake impairs learning and memory function through exacerbation of oxidative stress and Vit-B12 treatment improves these complications by re-establishment of oxidant/anti-oxidant balance in CNS. Moreover, we found that Vit-B12 prevents ethanol-induced reduction of BDNF and enhancement of GFAP and acetylcholinesterase (AChE) activity. In conclusion, it seems that Vit-B12 supplementation could be used as an effective therapeutic strategy to prevent learning and memory defects induced by chronic alcohol intake during adolescence.

Environmental health risk factors and cutaneous leishmaniasis (CL): A case-control study in northeastern Iran.

Background & objectives: Cutaneous leishmaniasis (CL) is one of the main causes of vector-born diseases in younger population. To evaluate the association of environmental health factors on the odds of CL incidence, a case-control study was conducted in northeastern Iran. Methods: This study was conducted within 2020-2021 based on individual and household data from a tertiary referral center. Cases were patients diagnosed with CL by PCR method; controls were selected among the patients' relatives, and information was obtained from a health registry system. Demographic and socioeconomic data of 1871 subjects, included age, sex, household information and environmental health factors. Multivariable models with environmental factors in various conditions and CL were separately fit by univariate and mixed multiple unconditional logistic regression. Results: Participants included 617 cases (mean [SD] age, 13.62[13.72] years; 58.20% male) and 1264 controls (mean [SD] age, 16.45[15.44] years; 50.40% male). Results revealed that the use of well-water sources compared to surface water is significantly associated with CL (odds ratio [OR]=0.204; 95%CI, 0.13-0.33;P<0.001). Muddy houses, ruined buildings or wastelands and stagnant water, canals and rivers near the houses were also associated with CL (OR=3.85; 95%CI, 1.66-8.89; P=.002; OR=2.47; 95%CI, 1.76-3.47; P<.001). Besides, existence of pine tree was found to be a risk factor (OR=3.25; 95%CI, 2.12-4.99; P<.001) and similarly for the use of waste collection system (OR=4.43; 95%CI, 3.32-7.51; P<.001). Interpretation & conclusion: Environmental factors related to houses were significantly associated with CL and may represent the modifiable risk factors of CL disease.

Experimental data on lithium salts: From neuroprotection to multi-organ complications.

Lithium-salts stand on the first line of therapy for the management of specific psychiatric conditions, mainly bipolar mood disorder. It is also known to protect the brain against neurodegenerative processes such as Alzheimer's disease. Despite the mentioned merits, recent studies have revealed that high dose or prolonged lithium intake deteriorate the function of multiple key organs including heart, ovaries, thyroid gland and kidneys. Mechanistically, both positive and negative effects of lithium are mediated through methylation of ß-catenin nuclear-binding proteins which is potentiated by lithium-induced inhibition of GSK-3 or inositol monophosphatase. The current study briefly reviews the recent experimental data on lithium therapy considering both positive (i.e., neuroprotective) and negative aspects. In this regard, the question is that whether doses of lithium administered in experimental research are comparable with the therapeutic doses, as currently prescribed in clinical practice. It should be noted that the experimental data on animal studies, as widely reviewed here, could not be directly generalized to clinic. This is mainly because lithium doses applied in animal models are usually higher than therapeutic doses, however, there are evidence indicating that even animal to human translated doses of lithium, cause serious complications and this has been reported by meta-analyses on human studies. Therefore, we suggest the clinicians to use lithium-salts with precaution particularly in pregnancy and precisely adjust lithium concentration considering the patient's general health status to avoid lithium toxicity. Indeed, alternative approaches are recommended when the subject is pregnant, prolonged therapy is required or specific organ dysfunction is diagnosed.

COVID-19, body mass index and cholesterol: an ecological study using global data.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is now globally considered a serious economic, social and health threat. A wide range of health related factors including Body Mass Index (BMI) is reported to be associated with the disease. In the present study, we analyzed global databases to assess the correlation of BMI and cholesterol with the risk of COVID-19. METHODS: In this ecological study, we used age-standardized BMI and cholesterol levels as well as the incidence and mortality ratio of COVID-19 at the national-levels obtained from the publicly available databases such as the World Health Organization (WHO) and NCD Risk Factor Collaboration (NCD-RisC). Bivariate correlation analysis was applied to assess the correlations between the study variables. Mean differences (standard deviation: SD) of BMI and cholesterol levels of different groups were tested using independent sample t-test or Mann-Whitney rank test as appropriate. Multivariable linear regression analysis was performed to identify variables affecting the incidence and mortality ratio of COVID-19. RESULTS: Incidence and mortality ratio of COVID-19 were significantly higher in developed (29,639.85 ± 20,210.79 for cases and 503.24 ± 414.65 for deaths) rather than developing (8153.76 ± 11,626.36 for cases and 169.95 ± 265.78 for deaths) countries (P < 0.01). Results indicated that the correlations of BMI and cholesterol level with COVID-19 are stronger in countries with younger population. In general, the BMI and cholesterol level were positively correlated with COVID-19 incidence ratio (ß = 2396.81 and ß = 30,932.80, p < 0.01,| respectively) and mortality ratio (ß = 38.18 and ß = 417.52, p < 0.05,| respectively) after adjusting for socioeconomic and demographic factors. CONCLUSION: Countries with higher BMI or cholesterol at aggregate levels had a higher ratios of COVID-19 incidence and mortality. The aggregated level of cholesterol and BMI are important risk factors for COVID-19 major outcomes, especially in developing countries with younger populations. We recommend monitoring and promotion of health indicices to better prevent morbidity and mortality of COVID-19.

Prolonged morphine exposure during adolescence alters the responses of lateral paragigantocellularis neurons to naloxone in adult morphine dependent rats.

INTRODUCTION: Adolescence is a critical period in brain development, and it is characterized by persistent maturational alterations in the function of central nervous system. In this respect, many studies show the non-medical use of opioid drugs by adolescents. Although this issue has rather widely been addressed during the last decade, cellular mechanisms through which adolescent opioid exposure may induce long-lasting effects are not duly understood. The present study examined the effect of adolescent morphine exposure on neuronal responses of lateral paragigantocellularis nucleus to naloxone in adult morphine-dependent rats. METHODS: Adolescent male Wistar rats (31 days old) received increasing doses of morphine (from 2.5 to 25 mg/kg, twice daily, s.c.) for 10 days. Control subjects were injected saline with the same protocol. After a drug-free interval (20 days), animals were rendered dependent on morphine during 10 days (10 mg/kg, s.c., twice daily). Then, extracellular single-unit recording was performed to investigate neural response of LPGi to naloxone in adult morphine-dependent rats. RESULTS: Results indicated that adolescent morphine treatment increases the number of excitatory responses to naloxone, enhances the baseline activity and alters the pattern of firing in neurons with excitatory responses in adult morphine-dependent rats. Moreover, the intensity of excitatory responses is reduced following the early life drug intake. CONCLUSION: It seems that prolonged opioid exposure during adolescence induces long-lasting neurobiological changes in LPGi responsiveness to future opioid withdrawal challenges.

Vitamin D3 administration prevents memory deficit and alteration of biochemical parameters induced by unpredictable chronic mild stress in rats.

The present study aimed to investigate the effects of vitamin D3 (Vit D) administration on memory function, hippocampal level of amyloid-beta (Aß), brain-derived neurotrophic factor (BDNF) and oxidative stress status in a rat model of unpredictable chronic mild stress (UCMS). Vit D was intraperitoneally administered at doses of 100, 1000, and 10,000 IU/kg. Animals were subjected to UCMS for a total period of 4 weeks. Memory function was assessed using morris water maze (MWM) and passive avoidance (PA) tests. Biochemical markers were measured to reveal the status of oxidative stress and antioxidant defense system. In addition, the levels of Aß and BDNF were measured in hippocampal region. In the UCMS group, latency to find the platform was greater and the time spent in target quadrant (MWM test) as well as the latency to enter the dark compartment (PA test), were less than the vehicle group. Hippocampal malondialdehyde (MDA) and Aß concentrations in the UCMS group were higher than the vehicle group. Hippocampal level of thiol and BDNF plus the activities of catalase and superoxide dismutase (SOD) were reduced in UCMS group compared to the control subjects (i.e. vehicle group). Interestingly, Vit D treatment supplementation reversed the mentioned effects of UCMS. Our findings indicated that Vit D administration improves UCMS-induced impairment of learning and memory through prevention of adverse effects on Aß, BDNF and oxidative stress parameters.

Adolescent Substance Abuse, Transgenerational Consequences and Epigenetics.

Adolescence is the transitional period between childhood and adulthood and a critical period in brain development. Adolescence in humans is also associated with increased expression of risk-taking behaviors. Epidemiological and clinical studies, for example, show a surge of drug abuse and raise the hypothesis that the adolescent brain undergoes critical changes resulting in diminished control. Determining how substance abuse during this critical period might cause longterm neurobiological changes in cognition and behavior is therefore critically important. The present work aims to provide an evaluation of the transgenerational and multi-generational phenotypes derived from parent animals exposed to drugs of abuse only during their adolescence. Specifically, we will consider changes found following the administration of cannabinoids, nicotine, alcohol and opiates. In addition, epigenetic modifications of the genome following drug exposure will be discussed as emerging evidence of the underlying adverse transgenerational effects. Notwithstanding, much of the new data discussed here is from animal models, indicating that future clinical studies are much needed to better understand the neurobiological consequences and mechanisms of drug actions on the human brains' development and maturation.

Intermittent REM sleep deprivation attenuates the development of morphine tolerance and dependence in male rats.

Opioid agonists are used in clinic for pain management, however this application is challenged by development of tolerance and dependence following prolonged exposure. Various approaches have been suggested to address this concern, however, there is still no consensus among the researchers. Neural processing of sleep and nociception are co-regulated through shared brain regions having bidirectional interplays. Thus, we aimed to investigate whether application of REM sleep deprivation (REM-SD) could affect morphine analgesic tolerance and dependence. To this end, adult male rats underwent sleep deprivation during light and dark phases (LSD and DSD, respectively) using the inverted flower pot method and then tolerance and dependence was induced by repeated injection of morphine for 7 days (10 mg/kg, daily, i.p.). Results indicated that REM-SD delays the development of tolerance to morphine during both phases; however this effect was more potent following LSD. Moreover, LSD decreased the baseline thermal threshold and total withdrawal score. One possible hypothesis for our observations is REM-SD-induced attenuation of orexin system which is still controversial among the researchers. Other stronger possibilities might be down-regulation of opioid receptors in response to sleep loss experience. Finally, it seems that modification of sleep periods may assist to decrease the severity of opioid tolerance and dependence.

Coregulation of sleep-pain physiological interplay by orexin system: An unprecedented review.

Accumulating evidence support the critical role of endogenous orexin system in modulation of various physiological functions. Among these, regulation of pain and wakefulness have extensively been investigated, however, by independent series of studies each focusing a distinct side. It is now well established that orexins induce potent analgesic effect via affecting their receptors within several specific brain structures. These mainly include locus coeruleus (LC), lateral paragigantocellularis (LPGi), ventral tegmental area (VTA), dorsal raphe nucleus (DRN), periaquiductal gray (PAG) and tuberomammillary nuclei (TMN). On the other hand, increased activity of orexinergic neurons enhances general wakefulness. Interestingly, a review of literature reveals that brain regions underlying orexin-mediated analgesia are most probably the site of action for orexin wake-promoting effects as well. The present study first pieces together the existing evidence supporting the rationale for the possibility of sleep-pain coregulation by orexin system and then suggests several shared mechanisms through which orexin can control the two mentioned processes. Furthermore, this study explains how imbalanced orexinergic transmission can cause progressive dysregulation of sleep-pain processing.

Adolescent drug exposure: A review of evidence for the development of persistent changes in brain function.

Over the past decade, many studies have indicated that adolescence is a critical period of brain development and maturation. The refinement and maturation of the central nervous system over this prolonged period, however, makes the adolescent brain highly susceptible to perturbations from acute and chronic drug exposure. Here we review the preclinical literature addressing the long-term consequences of adolescent exposure to common recreational drugs and drugs-of-abuse. These studies on adolescent exposure to alcohol, nicotine, opioids, cannabinoids and psychostimulant drugs, such as cocaine and amphetamine, reveal a variety of long-lasting behavioral and neurobiological consequences. These agents can affect development of the prefrontal cortex and mesolimbic dopamine pathways and modify the reward systems, socio-emotional processing and cognition. Other consequences include disruption in working memory, anxiety disorders and an increased risk of subsequent drug abuse in adult life. Although preventive and control policies are a valuable approach to reduce the detrimental effects of drugs-of-abuse on the adolescent brain, a more profound understanding of their neurobiological impact can lead to improved strategies for the treatment and attenuation of the detrimental neuropsychiatric sequelae.

Adolescent nicotine challenge promotes the future vulnerability to opioid addiction: Involvement of lateral paragigantocellularis neurons.

Tobacco smoking is recognized as a life-threatening risk factor worldwide. Initiation of smoking primarily occurs during adolescence which is a critical developmental phase characterized by specific neurobehavioral alterations. The effect of adolescent nicotine exposure on vulnerability to opioid addiction has not been previously addressed. Furthermore, lateral paragigantocellularis (LPGi) is a key modulator of opiate effects. In this study we investigated the effect of adolescent nicotine treatment on development of morphine tolerance and dependence as well as LPGi neuronal responses to morphine during adulthood. Male Wistar rats received subcutaneous injections of either nicotine or saline during adolescence and then development of morphine tolerance and dependence was assessed during adulthood by tail-flick and withdrawal tests, respectively. In vivo single-unit recording was performed to examine the LPGi neuronal activities. Results indicated that adolescent nicotine exposure significantly facilitates the development of tolerance to analgesic effect of morphine and increases the expression of morphine withdrawal signs in adulthood. Also, it was observed that following adolescent nicotine treatment, the extent of morphine-induced excitation is attenuated in LPGi neurons of adult rats. Moreover, the onset of morphine-induced inhibition was increased in these animals. Neither the baseline, nor the regularity of firing was affected in our observations. It could be concluded that nicotine challenge during adolescence may enhance the future vulnerability to opioid addiction through induction of persistent neuroadaptations in LPGi neurons.

Synergistic effect of orexin-glutamate co-administration on spontaneous discharge rate of locus coeruleus neurons in morphine-dependent rats.

Various intrinsic and extrinsic factors can increase the spontaneous discharge rate of locus coeruleus (LC) neurons. Among the extrinsic ones, orexinergic neurons of the lateral hypothalamus (LH) send widespread projections to LC region. Accumulating evidence support the involvement of glutamate in mediating the excitatory effect of orexin-A on LC neurons. In addition, both orexinergic and glutamatergic systems have been shown to play critical roles in molecular changes underlying the development of morphine dependence. The present study was designed to investigate the interaction between orexin-A and glutamate in modulating the firing rate of LC neurons. Regarding the role of both orexinergic and glutamatergic systems in morphine dependence, this effect was also investigated in morphine dependent rats. For this purpose, spontaneous discharge rate of LC neurons was recorded using the whole-cell patch clamp recording method in presence of orexin-A, glutamate or orexin-A plus glutamate in acutely prepared brain slices. Results indicated that superfusion of either orexin-A or glutamate enhances the firing rate of LC neurons in both dependent and non-dependent rats. However, co-application of orexin-A and glutamate elicited a significant synergism in enhancement of firing rate only in morphine dependent animals. In conclusion, it seems that development of morphine dependence promotes adaptations in locus coeruleus neurons that potentiate the orexin-glutamate interaction.

Acute morphine administration alters the power of local field potentials in mesolimbic pathway of freely moving rats: Involvement of dopamine receptors.

Increasing number of evidence support the role of ventral tegmental area (VTA) and nucleus accumbens (NAc) in mediating the opiate effects as the two critical components of brain reward pathway. It is believed that VTA to NAC dopaminergic projections mediate the reinforcing effects induced by opioid drugs. Although numerous studies have investigated mechanisms of reward processing in these brain regions, alterations of local field potentials (LFPs), as an index of total synaptic currents, has not been previously addressed. In the present study, thin metal electrodes were implanted in both VTA and shell sub-region of NAc to simultaneously record the spontaneous LFPs in freely moving rats. After one week recovery period, a single dose of morphine was systemically administered and the LFP recording was performed 15, 30, 45 and 60 post-injection. Also, in order to assess the role of dopamine system, two groups of animals were pre-treated by selective antagonists of dopamine type-1 and type-2 receptors 15 min prior to morphine injection. The obtained results indicated that in VTA, acute morphine administration potentiates the power of all LFP frequency bands (i.e. delta, theta, alpha, beta and gamma). However, in NAc shell, theta wave was significantly attenuated by morphine and other components were not affected. In addition, pre-treatment with both antagonists prevented the observed effect of morphine on LFP power suggesting the involvement of dopamine receptors in this process. Future studies should address mechanisms of dopamine-morphine interactions. It is also valuable to focus on acute and chronic effects of morphine on LFP power and assessment of the observed effects following naloxone challenge.