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Behavioural Brain Research Feb 2023Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events....
Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2 µg/µl/side, and rapamycin, an mTOR inhibitor (0.02 µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6 µg/µl/side) and muscarine (0.02 µg/µl/side), respectively, had no effect, while the higher doses (6 and 2 µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.
Topics: Animals; Male; Rats; Avoidance Learning; Fear; Hippocampus; Muscarine; Muscarinic Antagonists; Nicotine; Rats, Wistar; Receptors, Cholinergic; Sirolimus; TOR Serine-Threonine Kinases; Extinction, Psychological; Memory
PubMed: 36179804
DOI: 10.1016/j.bbr.2022.114129 -
BMC Complementary Medicine and Therapies Jan 2022Rubus occidentalis, also known as black raspberry, contains several bioactive components that vary depending on the maturity of the fruit. The goal of this study was to...
BACKGROUND
Rubus occidentalis, also known as black raspberry, contains several bioactive components that vary depending on the maturity of the fruit. The goal of this study was to evaluate the efficacy of immature Rubus occidentalis extract(iROE) on acid-induced hyperalgesia, investigate the mechanism involved, and compare the antihyperalgesic effect of immature and mature ROEs.
METHODS
In adult male Sprague-Dawley rats, chronic muscle pain was induced via two injections of acidic saline into one gastrocnemius muscle. To evaluate the dose response, the rats were injected intraperitoneally with 0.9% saline or iROE (10, 30, 100, or 300 mg/kg) following hyperalgesia development. To evaluate the mechanism underlying iROE-induced analgesia, the rats were injected intraperitoneally with saline, yohimbine 2 mg/kg, dexmedetomidine 50 μg/kg, prazosin 1 mg/kg, atropine 5 mg/kg, mecamylamine 1 mg/kg, or naloxone 5 mg/kg 24 h after hyperalgesia development, followed by iROE 300 mg/kg administration. To compare immature versus mature ROE, the rats were injected with mature ROE 300 mg/kg and immature ROE 300 mg/kg after hyperalgesia development. For all experiments, the mechanical withdrawal threshold(MWT) was evaluated using von Frey filaments before the first acidic saline injection, 24 h after the second injection, and at various time points after drug administration. Data were analysed using multivariate analysis of variance(MANOVA) and the linear mixed-effects model(LMEM). We compared the MWT at each time point using analysis of variance with the Bonferroni correction.
RESULTS
The iROE 300 mg/kg injection resulted in a significant increase in MWT compared with the control, iROE 30 mg/kg, and iROE 100 mg/kg injections at ipsilateral and contralateral sites. The iROE injection together with yohimbine, mecamylamine, or naloxone significantly decreased the MWT compared with iROE alone, whereas ROE together with dexmedetomidine significantly increased the MWT. According to MANOVA, the effects of immature and mature ROEs were not significantly different; however, the LMEM presented a significant difference between the two groups.
CONCLUSIONS
Immature R. occidentalis showed antihyperalgesic activity against acid-induced chronic muscle pain, which may be mediated by the α-adrenergic, nicotinic cholinergic, and opioid receptors. The iROE displayed superior tendency regarding analgesic effect compared to mature ROE.
Topics: Animals; Behavior, Animal; Hyperalgesia; Male; Musculoskeletal Pain; Phytotherapy; Plant Preparations; Plant Senescence; Rats; Rats, Sprague-Dawley; Rubus; Saline Solution
PubMed: 35016667
DOI: 10.1186/s12906-021-03491-z -
Drug and Alcohol Dependence Mar 2017Although both men and women use e-cigarettes, most preclinical nicotine research has focused on its effects in male rodents following injection. The goals of the present...
BACKGROUND
Although both men and women use e-cigarettes, most preclinical nicotine research has focused on its effects in male rodents following injection. The goals of the present study were to develop an effective e-cigarette nicotine delivery system, to compare results to those obtained after subcutaneous (s.c.) injection, and to examine sex differences in the model.
METHODS
Hypothermia and locomotor suppression were assessed following aerosol exposure or s.c. injection with nicotine in female and male mice. Subsequently, plasma and brain concentrations of nicotine and cotinine were measured.
RESULTS
Passive exposure to nicotine aerosol produced concentration-dependent and mecamylamine reversible hypothermic and locomotor suppressant effects in female and male mice, as did s.c. nicotine injection. In plasma and brain, nicotine and cotinine concentrations showed dose/concentration-dependent increases in both sexes following each route of administration. Sex differences in nicotine-induced hypothermia were dependent upon route of administration, with females showing greater hypothermia following aerosol exposure and males showing greater hypothermia following injection. In contrast, when they occurred, sex differences in nicotine and cotinine levels in brain and plasma consistently showed greater concentrations in females than males, regardless of route of administration.
DISCUSSION
In summary, the e-cigarette exposure device described herein was used successfully to deliver pharmacologically active doses of nicotine to female and male mice. Further, plasma nicotine concentrations following exposure were similar to those after s.c. injection with nicotine and within the range observed in human smokers. Future research on vaped products can be strengthened by inclusion of translationally relevant routes of administration.
Topics: Aerosols; Animals; Brain; Cotinine; Dose-Response Relationship, Drug; Drug Delivery Systems; Electronic Nicotine Delivery Systems; Female; Injections, Subcutaneous; Male; Mecamylamine; Mice; Mice, Inbred ICR; Motor Activity; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Sex Characteristics
PubMed: 28157590
DOI: 10.1016/j.drugalcdep.2016.12.004 -
Genes, Brain, and Behavior Apr 2023Nicotine is the reinforcing ingredient in tobacco. Following chronic exposure, sudden cessation of nicotine use produces negative symptoms of withdrawal that contribute...
Nicotine is the reinforcing ingredient in tobacco. Following chronic exposure, sudden cessation of nicotine use produces negative symptoms of withdrawal that contribute to dependence. The molecular mechanisms underlying nicotine withdrawal behaviors, however, are poorly understood. Using recombinant inbred mice, chronic nicotine was delivered by minipump and withdrawal induced using mecamylamine. Somatic signs of withdrawal, and anxiety-like behavior using elevated plus maze, were then assessed. Interval mapping was used to identify associations between genetic variation and withdrawal behaviors, and with basal gene expression. Differential gene expression following nicotine exposure and withdrawal was also assessed in progenitor mice using microarrays. Quantitative trait loci mapping identified chromosome intervals with significant genetic associations to somatic signs of withdrawal or withdrawal-induced anxiety-like behavior. Using bioinformatics, and association with basal gene expression in nucleus accumbens, we implicated Rb1, Bnip3l, Pnma2, Itm2b, and Kif13b as candidate genes for somatic signs of withdrawal, and Galr1, which showed trans-regulation from a region of chromosome 14 that was associated with somatic signs of withdrawal. Candidate genes within the chromosome 9 region associated with anxiety-like withdrawal behavior included Dixdc1, Ncam1, and Sorl1. Bioinformatics identified six genes that were also significantly associated with nicotine or alcohol traits in recent human genome-wide association studies. Withdrawal-associated somatic signs and anxiety-like behavior had strong non-overlapping genetic associations, respectively, with regions of chromosome 14 and chromosome 9. Genetic, behavioral and gene expression correlations, and bioinformatics analysis identified several candidate genes that may represent novel molecular targets for modulating nicotine withdrawal symptoms.
Topics: Mice; Animals; Humans; Nicotine; Mice, Inbred DBA; Genome-Wide Association Study; Mice, Inbred C57BL; Substance Withdrawal Syndrome; LDL-Receptor Related Proteins; Membrane Transport Proteins; Kinesins; Intracellular Signaling Peptides and Proteins; Membrane Proteins
PubMed: 36781202
DOI: 10.1111/gbb.12844 -
Neuroscience Letters Jan 2022Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock...
Psychological stress has been demonstrated to increase reports of pain in humans with pelvic pain of urologic origin. In rodent models, conditioning with acute footshock (AFS) has been demonstrated to increase measures of stress/anxiety as well as bladder hypersensitivity. The spinal neurochemical mechanisms of this pro-nociceptive process are unknown and so the present study administered antagonists for multiple receptors that have been associated with facilitatory mechanisms into the spinal intrathecal space. Bladder hypersensitivity was induced through use of an AFS paradigm in which female Sprague-Dawley rats received a 15-min intermittent shock treatment. Visceromotor responses (VMRs; abdominal muscle contractions) to air pressure-controlled urinary bladder distension (UBD) were used as nociceptive endpoints. Immediately following AFS treatments, rats were anesthetized (inhaled isoflurane, IP urethane) and surgically prepared. Pharmacological antagonists were administered via an intrathecal (IT) catheter onto the lumbosacral spinal cord and VMRs to graded UBD determined 15 min later. Administration of IT naloxone hydrochloride (10 μg) and IT phentolamine hydrochloride (10 μg) resulted in VMRs that were more robust than VMRs in rats that received AFS and IT normal saline whereas there was no significant effect of these drugs on VMRs in rats which underwent non-footshock procedures. In contrast, a low dose of the NMDA-receptor antagonist, MK-801 (30 μg), significantly reduced VMRs in rats made hypersensitive to UBD by AFS, but had no significant effect on rats that underwent non-footshock procedures. This study suggests that pro-nociceptive effects of AFS in otherwise healthy rats involve a spinal NMDA-linked mechanism. The effects of IT naloxone and IT phentolamine suggest the presence of inhibitory influences that are opioidergic and/or alpha-adrenergic and that are masked by the pro-nociceptive mechanisms. Other agents with no statistically significant effect on VMRs include methysergide (30 μg), ondansetron (10 μg), mecamylamine (50 μg), antalarmin (24 μg), aSVG30 (12 μg), and SSR149415 (50 μg).
Topics: Animals; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Hyperalgesia; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Spinal Cord; Stress, Physiological; Urinary Bladder
PubMed: 34929317
DOI: 10.1016/j.neulet.2021.136401 -
Psychopharmacology May 2017It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal.
RATIONALE
It is presently unclear whether diabetic rats experience greater rewarding effects of nicotine and/or negative affective states produced by nicotine withdrawal.
OBJECTIVE
The present study utilized a rodent model of diabetes to examine the rewarding effects of nicotine and negative affective states and physical signs produced by withdrawal.
METHODS
Separate groups of rats received systemic administration of either vehicle or streptozotocin (STZ), which destroys insulin-producing beta cells in the pancreas and elevates glucose levels. Place conditioning procedures were utilized to compare the rewarding effects of nicotine (conditioned place preference; CPP) and negative affective states produced by withdrawal (conditioned place aversion; CPA) in vehicle- and STZ-treated rats. CPA and physical signs of withdrawal were compared after administration of the nicotinic receptor antagonist mecamylamine to precipitate withdrawal in nicotine-dependent rats. A subsequent study utilized elevated plus maze (EPM) procedures to compare anxiety-like behavior produced by nicotine withdrawal in vehicle- and STZ-treated rats.
RESULTS
STZ-treated rats displayed greater rewarding effects of nicotine and a larger magnitude of aversive effects and physical signs produced by withdrawal as compared to vehicle-treated controls. STZ-treated rats also displayed higher levels of anxiety-like behavior on the EPM during nicotine withdrawal as compared to controls.
CONCLUSION
The finding that both nicotine reward and withdrawal are enhanced in a rodent model of diabetes implies that the strong behavioral effects of nicotine promote tobacco use in persons with metabolic disorders, such as diabetes.
Topics: Animals; Conditioning, Psychological; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Male; Mecamylamine; Nicotine; Nicotinic Antagonists; Rats; Rats, Wistar; Reward; Rodentia; Substance Withdrawal Syndrome; Tobacco Use Disorder
PubMed: 28342091
DOI: 10.1007/s00213-017-4592-y -
Translational Neuroscience 2015To investigate the effect of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase (Trk) on potassium chloride cotransporter 2 (KCC2) in rats following...
PURPOSE
To investigate the effect of brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase (Trk) on potassium chloride cotransporter 2 (KCC2) in rats following nicotine withdrawal and the roles played by BDNF/Trk/KCC2 pathway in nicotine withdrawal-induced hyperalgesia.
METHODS
Seventy-eight rats were randomly assigned to five groups: control group (n = 12) without any treatment, normal saline group (NS group, n = 12) and nicotine withdrawal group (NW group, n = 30) receiving a subcutaneous injection of saline or nicotine for 7 days, respectively. The NW + dimethyl sulfoxide (DMSO) (n = 12) and NW+ Trk antagonist K252a groups (n = 12) received an intrathecal injection of DMSO (10 μl) and K252a (10 μg/10 μl) for 3 days after nicotine withdrawal, respectively. Nicotine withdrawal was precipitated by subcutaneous injection of nonselective and noncompetitive antagonist of nicotinic acetylcholine receptors mecamylamine. Pain was tested using thermal withdrawal latency (TWL). A Western blot was used to examine the expression of BDNF and KCC2.
RESULTS
The TWL was significantly decreased in NW group relative to control and NS groups ( < 0.01). Compared with the NW group, the NW+K252a group manifested a significantly higher latency ( < 0.01). The BDNF expression was increased and KCC2 was decreased in NW group compared with the control group ( < 0.01). K252a reduced KCC2 downregulation.
CONCLUSION
BDNF/Trk signaling may contribute to nicotine withdrawal-induced hyperalgesia via downregulation of KCC2.
PubMed: 28123805
DOI: 10.1515/tnsci-2015-0022 -
Brain and Behavior Apr 2020There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement)...
OBJECTIVES
There is a long-standing interest in developing nicotinic acetylcholine receptor (nAChR) antagonists for concomitant use with nAChR agonists (e.g., nicotine replacement) as complementary smoking cessation aids. Previous studies demonstrate that daily nicotine treatment confers tolerance to some effects of nicotine, as well as cross-tolerance to other nAChR agonists. The current study assessed the extent to which antagonism of nicotine varies as a function of daily nicotine treatment.
METHODS
Schedule-controlled responding and hypothermia were selected for study because they have been previously used to examine the pharmacology of nicotine, and both are sensitive to the development nicotine tolerance. The rate-decreasing and hypothermic effects of nicotine, as well as antagonism of those effects, were examined in C57BL/6J mice before, during treatment with, and after discontinuation of three daily injections of 1.78 mg/kg nicotine. The nonselective nAChR antagonist mecamylamine and the β2 nAChR antagonist dihydro-β-erythroidine (DHβE) were studied in combination with nicotine.
RESULTS
The ED values of nicotine to produce rate-decreasing and hypothermic effects were, respectively, 0.44 and 0.82 mg/kg prior, 1.6 and 3.2 mg/kg during, and 0.74 and 1.1 mg/kg after discontinuation of daily nicotine treatment. Prior to daily nicotine treatment, mecamylamine decreased response rate and rectal temperature. However, during daily nicotine, mecamylamine (up to 5.6 mg/kg) only decreased rectal temperature. DHβE (up to 5.6 mg/kg) when studied prior to daily nicotine decreased rectal temperature, but that decrease was abolished during chronic nicotine treatment. Mecamylamine and DHβE antagonized the rate-decreasing and hypothermic effects of nicotine before and after daily nicotine; however, during daily nicotine, mecamylamine and DHβE antagonized only the hypothermic effects of nicotine.
CONCLUSIONS
The differential antagonism of rate-decreasing and hypothermic effects implicates differential involvement of nAChR subtypes. The decreased capacity of mecamylamine and DHβE to antagonize nicotine during chronic nicotine treatment may indicate that their effectiveness as smoking cessations might vary as a function of nicotine tolerance and dependence.
Topics: Animals; Dihydro-beta-Erythroidine; Dose-Response Relationship, Drug; Drug Tolerance; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Smoking Cessation
PubMed: 32092237
DOI: 10.1002/brb3.1581 -
Neurobiology of Learning and Memory Oct 2021Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2...
Acetylcholine plays a pivotal neuromodulatory role in the brain, influencing neuronal activity and cognitive function. Nicotinic receptors, particularly α7 and α4β2 receptors, modulate firing of dorsolateral prefrontal (dlPFC) excitatory networks that underlie successful working memory function. Minimal work however has been done examining working memory following systemic blockade of nicotinic receptor systems in nonhuman primates, limiting the ability to explore interactions of other neuromodulatory influences with working memory impairment caused by nicotinic antagonism. In this study, we investigated working memory performance after administering three nicotinic antagonists, mecamylamine, methyllycaconitine, and dihydro-β-erythroidine, in rhesus macaques tested in a spatial delayed response task. Surprisingly, we found that no nicotinic antagonist significantly impaired delayed response performance compared to vehicle. In contrast, the muscarinic antagonist scopolamine reliably impaired delayed response performance in all monkeys tested. These findings suggest there are some limitations on using systemic nicotinic antagonists to probe the involvement of nicotinic receptors in aspects of dlPFC-dependent working memory function, necessitating alternative strategies to understand the role of this system in cognitive deficits seen in aging and neurodegenerative disease.
Topics: Aconitine; Animals; Conditioning, Operant; Dihydro-beta-Erythroidine; Female; Macaca mulatta; Male; Mecamylamine; Memory, Short-Term; Muscarinic Antagonists; Nicotinic Antagonists; Scopolamine
PubMed: 34425219
DOI: 10.1016/j.nlm.2021.107505 -
Psychoneuroendocrinology Jul 2021Clozapine is a second generation antipsychotic drug that has proven to be helpful in the management of patients with psychotic disorders that are resistant to other...
Clozapine is a second generation antipsychotic drug that has proven to be helpful in the management of patients with psychotic disorders that are resistant to other medications. Unfortunately, the majority of patients treated with clozapine develop metabolic dysregulation, including weight gain and insulin resistance. There are few treatments available to effectively counter these side-effects. The goal of the present study was to use an established animal model to better understand the nature of these metabolic side-effects and determine whether existing drugs could be used to alleviate metabolic changes. Adult female rats were treated with a range of doses of clozapine (2, 10 and 20 mg/kg) and subjected to the hyperinsulinemic-euglycemic clamp, to measure whole-body insulin resistance. Clozapine dose-dependently decreased the glucose infusion rate, reflecting pronounced insulin resistance. To reverse the insulin resistance, rats were co-treated with the ganglionic blocker mecamylamine (0.1, 1.0 and 5.0 mg/kg) which dose-dependently reversed the effects of 10 mg/kg clozapine. A 1.0 mg/kg dose of mecamylamine independently reversed the large increase in peripheral epinephrine caused by treatment with clozapine. To study the influence of specific adrenoceptors, rats were treated with multiple doses of α (prazosin), α (idazoxan), β (atenolol) and β (butoxamine) adrenoceptor antagonists after the onset of clozapine-induced insulin resistance. Both beta blockers were effective in attenuating the effects of clozapine, while idazoxan had a smaller effect; no change was seen with prazosin. The current results indicate that peripheral catecholamines may play a role in clozapine's metabolic effects and be a target for future treatments.
Topics: Adrenergic Antagonists; Animals; Antipsychotic Agents; Clozapine; Drug Interactions; Female; Ganglionic Blockers; Insulin Resistance; Mecamylamine; Rats
PubMed: 34023734
DOI: 10.1016/j.psyneuen.2021.105257