-
Neuropsychopharmacology : Official... Feb 2022A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic...
A critical brain area implicated in nicotine dependence is the interpeduncular nucleus (IPN) located in the ventral midbrain and consisting primarily of GABAergic neurons. Previous studies indicate that IPN GABAergic neurons contribute to expression of somatic symptoms of nicotine withdrawal; however, whether IPN neurons are dynamically regulated during withdrawal in vivo and how this may contribute to both somatic and affective withdrawal behavior is unknown. To bridge this gap in knowledge, we expressed GCaMP in IPN GABAergic neurons and used in vivo fiber photometry to record changes in fluorescence, as a proxy for neuronal activity, in male mice during nicotine withdrawal. Mecamylamine-precipitated withdrawal significantly increased activity of IPN GABAergic neurons in nicotine-dependent, but not nicotine-naive mice. Analysis of GCaMP signals time-locked with somatic symptoms including grooming and scratching revealed reduced IPN GABAergic activity during these behaviors, specifically in mice undergoing withdrawal. In the elevated plus maze, used to measure anxiety-like behavior, an affective withdrawal symptom, IPN GABAergic neuron activity was increased during open-arm versus closed-arm exploration in nicotine-withdrawn, but not non-withdrawn mice. Optogenetic silencing IPN GABAergic neurons during withdrawal significantly reduced withdrawal-induced increases in somatic behavior and increased open-arm exploration. Together, our data indicate that IPN GABAergic neurons are dynamically regulated during nicotine withdrawal, leading to increased anxiety-like symptoms and somatic behavior, which inherently decrease IPN GABAergic neuron activity as a withdrawal-coping mechanism. These results provide a neuronal basis underlying the role of the IPN in the expression of somatic and affective behaviors of nicotine withdrawal.
Topics: Animals; GABAergic Neurons; Interpeduncular Nucleus; Male; Mecamylamine; Mice; Nicotine; Substance Withdrawal Syndrome
PubMed: 34326477
DOI: 10.1038/s41386-021-01107-1 -
TheScientificWorldJournal 2012An important new area of antidepressant drug development involves targeting the nicotinic acetylcholine receptor (nAChR). This receptor, which is distributed widely in... (Review)
Review
An important new area of antidepressant drug development involves targeting the nicotinic acetylcholine receptor (nAChR). This receptor, which is distributed widely in regions of the brain associated with depression, is also implicated in other important processes that are relevant to depression, such as stress and inflammation. The two classes of drugs that target nAChRs can be broadly divided into mecamylamine- and cytisine-based compounds. These drugs probably exert their effects via antagonism at α4β2 nAChRs, and strong preclinical data support the antidepressant efficacy of both classes when used in conjunction with other primary antidepressants (e.g., monoamine reuptake inhibitors). Although clinical data remain limited, preliminary results in this area constitute a compelling argument for further evaluation of the nAChR as a target for future antidepressant drug development.
Topics: Alkaloids; Antidepressive Agents; Azocines; Humans; Mecamylamine; Nicotine; Nicotinic Agonists; Quinolizines; Receptors, Nicotinic
PubMed: 22619570
DOI: 10.1100/2012/104105 -
Neuropharmacology Sep 2009Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to be critically involved in ethanol-related behaviors as well as in neurochemical responses to ethanol....
Neuronal nicotinic acetylcholine receptors (nAChRs) are believed to be critically involved in ethanol-related behaviors as well as in neurochemical responses to ethanol. However, discernment of nAChR contribution to ethanol reinforcement and consumption remains incomplete. The current studies examined the influence of the nAChR antagonist mecamylamine (MEC) on operant ethanol self-administration using a procedure that independently assessed appetitive and consumptive processes, and compared these findings to effects of MEC on sucrose self-administration. Male C57BL/6J (B6) mice were trained to respond for 30-min access to a retractable drinking tube containing either 10% v/v ethanol (10E) or 5% w/v sucrose (5S). Once trained, mice were habituated to saline injection and then treated with a series of MEC doses (0-8 mg/kg; i.p.) in a within-subject design. In a separate cohort, MEC was evaluated for its influence on locomotor activity. MEC dose-dependently reduced 10E and 5S self-administration. The suppression in ethanol intake was attributable to a reduction in bout frequency, whereas the attenuation in sucrose intake was due to a decrease in bout size. Doses of MEC (6-8 mg/kg) that altered drinking patterns were also found to impair locomotor activity. Although MEC non-selectively reduced 10E and 5S intakes in mice, there was some specificity in alterations of the underlying drinking pattern for each reinforcer. Assessment of drinking topography within an operant self-administration procedure may provide useful insights regarding the role of nAChR function in the regulation of ethanol consumption.
Topics: Alcohol Drinking; Analysis of Variance; Animals; Choice Behavior; Conditioning, Operant; Dose-Response Relationship, Drug; Drinking Behavior; Ethanol; Male; Mecamylamine; Mice; Mice, Inbred C57BL; Motor Activity; Nicotinic Antagonists; Reinforcement, Psychology; Saccharin; Self Administration; Sucrose; Time Factors
PubMed: 19501109
DOI: 10.1016/j.neuropharm.2009.05.012 -
The Pharmacogenomics Journal Aug 2011The histidine triad nucleotide-binding protein-1 gene (HINT1) is implicated in schizophrenia and in the behavioral effects of morphine and amphetamine. Because nicotine...
The histidine triad nucleotide-binding protein-1 gene (HINT1) is implicated in schizophrenia and in the behavioral effects of morphine and amphetamine. Because nicotine dependence (ND) is highly comorbid with schizophrenia and other substance abuse, we examined the association of HINT1 with ND. Association analyses from two independent samples show that HINT1 gene variants are associated with ND phenotypes. Furthermore, human postmortem mRNA expression shows that smoking status and genotype influence HINT1 expression in the brain. In animal studies, western blot analyses show an increase of HINT1 protein level in the mouse nucleus accumbens (NAc) after chronic nicotine exposure. This increase was reduced after treatment with the nicotinic-receptor antagonist mecamylamine, and 24 and 72 h after cessation of nicotine treatment. These results indicate a genetic association between HINT1 variants and ND, and indicate that nicotine-induced modulation of HINT1 level may be involved in mechanisms of excess smoking.
Topics: Adolescent; Adult; Aged; Animals; Autopsy; Brain; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Haplotypes; Humans; Linear Models; Logistic Models; Male; Mecamylamine; Mice; Mice, 129 Strain; Middle Aged; Nerve Tissue Proteins; Nicotinic Agonists; Nicotinic Antagonists; Phenotype; RNA, Messenger; Smoking; Time Factors; Tobacco Use Disorder; Virginia; Young Adult
PubMed: 20514075
DOI: 10.1038/tpj.2010.41 -
Behavioural Brain Research Sep 2015The mesolimbic dopamine (DA) system is known to play a role in cue-mediated reward-seeking for natural rewards and drugs of abuse. Specifically, cholinergic and...
The mesolimbic dopamine (DA) system is known to play a role in cue-mediated reward-seeking for natural rewards and drugs of abuse. Specifically, cholinergic and glutamatergic receptors in the ventral tegmental area (VTA) have been shown to regulate cue-induced drug-seeking. However, the potential role of these VTA receptors in regulating cue-induced reward seeking for natural rewards is unknown. Here, we examined whether blockade of VTA acetylcholine receptors (AChRs) and N-methyl-d-aspartate receptors (NMDARs) would alter cue-induced sucrose seeking in male Sprague-Dawley rats. Subjects underwent 10 days of sucrose self-administration training (fixed ratio 1 schedule) followed by 7 days of forced abstinence. On withdrawal day 7, rats received bilateral VTA infusion of vehicle, the muscarinic AChR antagonist scopolamine (2.4 or 24 μg/side), the nicotinic AChR antagonist mecamylamine (3 or 30 μg/side), or the NMDAR antagonist AP-5 (0.1 or 1 μg/side) immediately prior to examination of cue-induced sucrose-seeking. Scopolamine infusion led to robust attenuation, but did not completely block, sucrose-seeking behavior. In contrast, VTA administration of mecamylamine or AP-5 did not alter cue-induced sucrose-seeking. Together, the data suggest that VTA muscarinic AChRs, but not nicotinic AChRs nor NMDARs, facilitate the ability of food-associated cues to drive seeking behavior for a food reward.
Topics: Animals; Appetitive Behavior; Cohort Studies; Conditioning, Operant; Cues; Dietary Sucrose; Dose-Response Relationship, Drug; Feeding Behavior; Male; Mecamylamine; Motivation; Muscarinic Antagonists; Neuropsychological Tests; Nicotinic Antagonists; Rats, Sprague-Dawley; Receptors, Muscarinic; Receptors, Nicotinic; Reward; Scopolamine; Self Administration; Ventral Tegmental Area
PubMed: 26026787
DOI: 10.1016/j.bbr.2015.05.036 -
The International Journal of... Nov 2009Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three... (Comparative Study)
Comparative Study Randomized Controlled Trial
Cholinergic neurotransmission has been implicated in memory and attention. We investigated the effect of the non-competitive nicotinic antagonist mecamylamine on three components of attention processes (i.e. alerting, orienting and executive control) in 12 healthy male subjects whilst performing the Attention Network Task (ANT) in a magnetic resonance imaging (MRI) scanner. Participants received 15 mg mecamylamine in a single blind and placebo- controlled randomized procedure 90 min prior to obtaining functional MRI data. Our results confirm previous reports of beneficial effects of cueing (alerting and orienting) and detrimental effects of conflict (executive control) on reaction times when performing the ANT. The functional MRI data confirmed distinct neural networks associated with each of the three attention components. Alerting was associated with increased left temporal lobe activation while orienting increased bilateral prefrontal, right precuneus and left caudate activation. Executive control activated anterior cingulate and precuneus. Mecamylamine slowed overall response time and down-regulated brain activation associated with orienting and to some extent brain activation associated with executive control when compared to placebo. These findings are consistent with nicotinic modulation of orienting attention by cueing and executive control when responding to conflicting information. The latter nicotine antagonist effect may be mediated via cholinergic modulation of dopamine neurotransmission in mesolimbic pathways.
Topics: Adult; Attention; Cross-Over Studies; Humans; Male; Mecamylamine; Nerve Net; Nicotinic Antagonists; Psychomotor Performance; Reaction Time; Single-Blind Method; Young Adult
PubMed: 19737441
DOI: 10.1017/S1461145709990551 -
Neuroscience Letters Apr 2023Pentobarbital-induced anesthesia is believed to be mediated by enhancement of the inhibitory action of γ-aminobutyric acid (GABA)ergic neurons in the central nervous...
Pentobarbital-induced anesthesia is believed to be mediated by enhancement of the inhibitory action of γ-aminobutyric acid (GABA)ergic neurons in the central nervous system. However, it is unclear whether all components of anesthesia induced by pentobarbital, such as muscle relaxation, unconsciousness, and immobility in response to noxious stimuli, are mediated only through GABAergic neurons. Thus, we examined whether the indirect GABA and glycine receptor agonists gabaculine and sarcosine, respectively, the neuronal nicotinic acetylcholine receptor antagonist mecamylamine, or the N-methyl-d-aspartate receptor channel blocker MK-801 could enhance pentobarbital-induced components of anesthesia. Muscle relaxation, unconsciousness, and immobility were evaluated by grip strength, the righting reflex, and loss of movement in response to nociceptive tail clamping, respectively, in mice. Pentobarbital reduced grip strength, impaired the righting reflex, and induced immobility in a dose-dependent manner. The change in each behavior induced by pentobarbital was roughly consistent with that in electroencephalographic power. A low dose of gabaculine, which significantly increased endogenous GABA levels in the central nervous system but had no effect on behaviors alone, potentiated muscle relaxation, unconsciousness, and immobility induced by low pentobarbital doses. A low dose of MK-801 augmented only the masked muscle-relaxing effects of pentobarbital among these components. Sarcosine enhanced only pentobarbital-induced immobility. Conversely, mecamylamine had no effect on any behavior. These findings suggest that each component of anesthesia induced by pentobarbital is mediated through GABAergic neurons and that pentobarbital-induced muscle relaxation and immobility may partially be associated with N-methyl-d-aspartate receptor antagonism and glycinergic neuron activation, respectively.
Topics: Mice; Animals; Receptors, N-Methyl-D-Aspartate; Pentobarbital; Dizocilpine Maleate; Sarcosine; Mecamylamine; gamma-Aminobutyric Acid; Unconsciousness
PubMed: 36907265
DOI: 10.1016/j.neulet.2023.137175 -
British Journal of Pharmacology Feb 19781 The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal...
1 The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal homovanillic acid (HVA) concentration and on the alpha-methyl-p-tyrosine (AMPT)-induced depletion of striatal or mesolimbic dopamine content in the brain of rats. 2 Mecamylamine (2 mg/kg) alone did not alter the striatal HVA concentration, but it reduced the probenecid-induced accumulation of HVA. Mecamylamine pretreatment reduced the morphine- and haloperidol-induced elevation of striatal HVA concentrations. Hexamethonium did not alter the striatal HVA concentration when given alone or in probenecid- or morphine-treated rats, whereas pempidine (8 mg/kg) clearly reduced the probenecid-induced accumulation of HVA in the striatum. 3 Mecamylamine (2 and 8 mg/kg) slowed the rate of AMPT-induced depletion of dopamine from the striatum and mesolimbic area both in the brain of control rats treated with morphine or haloperidol. 4 Mecamylamine slightly prolonged the cataleptic effect of morphine. 5 The results indicate that mecamylamine inhibits the release of dopamine both from the striatal and mesolimbic dopaminergic neurones.
Topics: Animals; Catalepsy; Corpus Striatum; Dopamine; Drug Interactions; Haloperidol; Homovanillic Acid; Humans; Limbic System; Male; Mecamylamine; Methyltyrosines; Morphine; Rats
PubMed: 564219
DOI: 10.1111/j.1476-5381.1978.tb08448.x -
Neuropharmacology Jun 2014The effects of addictive drugs most commonly occur via interactions with target receptors. The same is true of nicotine and its multiple receptors in a variety of cell...
The effects of addictive drugs most commonly occur via interactions with target receptors. The same is true of nicotine and its multiple receptors in a variety of cell types. However, there are also side effects for given substances that can dramatically change cellular, tissue, organ, and organism functions. In this study, we present evidence that nicotine possesses such properties, and modulates neuronal excitability. We recorded whole-cell voltages and currents in neurons situated in the dorsal portion of the lateral septum in acute coronal brain slices of adult rats. Our experiments in the lateral septum revealed that nicotine directly affects HCN - hyperpolarization-activated cyclic nucleotide gated non-selective cation channels. We demonstrate that nicotine effects persist despite the concurrent application of nicotinic acetylcholine receptors' antagonists - mecamylamine, methyllycaconitine, and dihydro-β-erythroidine. These results are novel in regard to HCN channels in the septum, in general, and in their sensitivity to nicotine, in particular.
Topics: Action Potentials; Animals; Biophysical Phenomena; Biophysics; Cyclic Nucleotide-Gated Cation Channels; Dihydro-beta-Erythroidine; Electric Stimulation; In Vitro Techniques; Mecamylamine; Neurons; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Septal Nuclei
PubMed: 24582613
DOI: 10.1016/j.neuropharm.2014.02.012 -
Neurobiology of Learning and Memory Jan 2017The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the...
The present study was aimed at establishing whether the mTOR pathway and its downstream effector p70S6K in CA3 pyramidal neurons are under the modulation of the cholinergic input to trigger the formation of long term memories, similar to what we demonstrated in CA1 hippocampus. We performed in vivo behavioral experiments using the step down inhibitory avoidance test in adult Wistar rats to evaluate memory formation under different conditions. We examined the effects of rapamycin, an inhibitor of mTORC1 formation, scopolamine, a muscarinic receptor antagonist or mecamylamine, a nicotinic receptor antagonist, on short and long term memory formation and on the functionality of the mTOR pathway. Acquisition was conducted 30min after i.c.v. injection of rapamycin. Recall testing was performed 1h, 4h or 24h after acquisition. We found that (1) mTOR and p70S6K activation in CA3 pyramidal neurons were involved in long term memory formation; (2) rapamycin significantly inhibited mTOR and of p70S6K activation at 4h, and long term memory impairment 24h after acquisition; (3) scopolamine impaired short but not long term memory, with an early increase of mTOR/p70S6K activation at 1h followed by stabilization at longer times; (4) mecamylamine and scopolamine co-administration impaired short term memory at 1h and 4h and reduced the scopolamine-induced increase of mTOR/p70S6K activation at 1h and 4h; (5) mecamylamine and scopolamine treatment did not impair long term memory formation; (6) unexpectedly, rapamycin increased mTORC2 activation in microglial cells. Our results demonstrate that in CA3 pyramidal neurons the mTOR/p70S6K pathway is under the modulation of the cholinergic system and is involved in long-term memory encoding, and are consistent with the hypothesis that the CA3 region of the hippocampus is involved in memory mechanisms based on rapid, one-trial object-place learning and recall. Furthermore, our results are in accordance with previous reports that selective molecular mechanisms underlie either short term memory, long term memory, or both. Furthermore, our discovery that administration of rapamycin increased the activation of mTORC2 in microglial cells supports a reappraisal of the beneficial/adverse effects of rapamycin administration.
Topics: Animals; Avoidance Learning; CA3 Region, Hippocampal; Male; Mecamylamine; Memory, Long-Term; Memory, Short-Term; Muscarinic Antagonists; Nicotinic Antagonists; Phosphorylation; Rats; Rats, Wistar; Ribosomal Protein S6 Kinases, 70-kDa; Scopolamine; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 27838442
DOI: 10.1016/j.nlm.2016.11.006