Where is nicotinic receptors found

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The authors would like to thank Robert Beech and Diann Stedman for critical reading of the manuscript. Marina R Picciotto Ph. D, Barbara J Caldarone Ph. D, Sarah L King Ph. You can also search for this author in PubMed Google Scholar. Reprints and Permissions. Few studies have reported the effects of ethanol on nAChRs in these areas. One study reported that co-administration of ethanol i. Taken together, nAChRs in the amygdala and hippocampus play a prominent role in not only learning and memory but also reward-related learning.

From an anatomical prospective, the hippocampus is integrally linked to brain circuits involved in addiction, receiving direct dopaminergic input from midbrain neurons and providing extensive efferent connections to the ventral striatum, amygdala, and PFC Kelley, Therefore, alterations in structure or function in the hippocampus may be translated by other brain regions that drive maladaptive behaviors associated with addiction. Most studies investigating the involvement of nAChRs in synaptic plasticity have been conducted in the hippocampus.

Figure 3. Schematic representation of nAChR subtypes and circuit function in the hippocampus and amygdala. B In the amygdala, cholinergic inputs from the basal forebrain synapse in proximity to pre-synaptic nAChRs that modulate both excitatory and inhibitory synaptic transmission.

Nicotinic receptors exert a temporally- and spatially-dependent bidirectional control over synaptic plasticity, both in vitro and in vivo Table 2. Additionally, activation of nAChRs on hippocampal interneurons can induce LTP or LTD depending on the exact timing of agonist application in respect to the pre-synaptic stimulation Ji et al. In the CA3 region of hippocampal slices, bath application of nicotine can drive the pyramidal cells above threshold in the absence of an action potential by activating pre-synaptic nAChRs located on glutamatergic terminals.

In the developing brain, long-lasting changes in synaptic transmission were observed following a single exposure to nicotine in the hippocampus. Together these findings strongly imply that the timing and location of nAChR activity are important determinants for synaptic plasticity in the hippocampus. The amygdala is another essential brain region implicated in memory processing, particularly for encoding the emotional and motivational significance of environmental stimuli as well as initiating innate unconditioned responses to aversive situations.

It is a central region for integrating sensory and cognitive information through its extensive connections to other limbic structures, the cortex, hippocampus, and thalamus LeDoux, In addition, experimental evidence strongly suggests drugs of abuse act on this system and can modify synaptic events, especially during periods of withdrawal McCool et al.

Reciprocal connections between the amygdala, hypothalamus and parabrachial nucleus are known to regulate the hypothalamic-pituitary-adrenal axis and autonomic responses to conditioned fear Takeuchi et al.

The amygdala also participates in stress- and reward-related behaviors through its connections to the PFC and NAc, respectively Simpson et al.

The basolateral nucleus of the amygdala is densely innervated by cholinergic projections arising from the basal forebrain Sah et al. Different pathways reside within the amygdala and are responsible for various functions regarding the acquisition, expression, and retrieval of fear memories as well as unconditioned behaviors LeDoux, In the amygdala Table 2 , nicotine has been shown to facilitate LTP in a pathway-specific manner.

Robust LTP in amygdala slices from mice that received nicotine treatment for 7 days compared to controls and persisted 72 h after nicotine cessation. Even just one day of nicotine exposure significantly enhanced LTP. At this time, little is known about nicotinic receptor-mediated plasticity in the amygdala. Ethanol is capable of modulating synaptic changes in this circuit but it has yet to be elucidated if and how nicotinic receptors are involved. A primary mechanism underlying long-lasting synaptic plasticity is a change in the number or expression of membrane-bound receptors.

Long-term exposure to nicotine induces an up-regulation of specific subtypes of nAChRs and increases the number of high-affinity nicotinic binding sites across multiple brain regions in the brains of postmortem human smokers Perry et al. The concept of up-regulation of nAChRs is somewhat unexpected and contradictory to what the homeostatic model would predict. Following chronic drug use, receptors are usually down regulated in response to excessive stimulation as an adaptive mechanism to adjust the neural network to a pre-exposure point.

Evidence suggests that nicotine causes a rapid desensitization of nAChRs, and this loss in receptor function would promote up-regulation to compensate for the diminished signaling of inactivated receptors over prolonged periods of time Fenster et al. These changes result in higher sensitivity to nicotine and have been correlated with nicotine addiction [see review, Govind et al.

Several mechanisms have been proposed for nicotine-induced up-regulation of nAChRs and it is quite likely that more than one mechanism is responsible for this phenomenon.

There is controversy surrounding how this up-regulation of surface receptors occurs but it does not appear to be due to a change in subunit mRNA transcript levels Marks et al. Another possible mechanism is an increase in receptor trafficking to the cell surface upon long exposures to nicotine Harkness and Millar, Additionally, nicotine can reportedly facilitate receptor maturation by acting as a chaperone in the endoplasmic reticulum Nashmi et al. However, membrane-impermanent ligands can also induce up-regulation of surface receptors; therefore, second messengers must exist that are sufficient to drive this response Whiteaker et al.

In order for nicotine-induced up-regulation to occur, nAChRs must pass through the secretory pathway before being inserted into the membrane Darsow et al. The up-regulation of nAChRs varies with subunit composition, cell type and brain region. There are a limited number of studies that have investigated ethanol-induced changes in expression of nAChRs and therefore it is certainly an area of research which should be expounded upon.

In vitro experiments demonstrated nAChRs are directly affected by ethanol and after long-term exposure these receptors may undergo anatomical and functional changes, possibly by altering receptor expression or composition Dohrman and Reiter, In M10 cells, ethanol modulates the number of nAChRs by initially blunting the expression during short exposure 6—72 h but increasing it with longer incubation periods 96 h. In a different study, long-term consumption of ethanol 5 months by rats increased the levels of [ 3 H]-nicotinic binding in the hypothalamus and thalamus, and decreased the levels in the hippocampus Yoshida et al.

In ethanol-treated 6 months mice, small changes in [ 3 H]-nicotinic binding were found only in the thalamus and in just one of the mice strains tested, leading the authors to conclude this effect is brain region specific and genetic factors may influence this response Booker and Collins, These effects were not seen in mouse brains following short-term 1—2 weeks ethanol treatment Burch et al.

Finally, receptor up-regulation should enhance neuronal excitability and favor induction of drug-induced LTP. One behavioral correlate of synaptic plasticity is the manifestation of locomotor sensitization, which is defined as an enhanced locomotor response after repeated exposures to a drug compared to the activity measured during the first drug administration.

Increased locomotor response to prolonged nicotine, ethanol, cocaine, amphetamine, and methamphetamine has been extensively studied in rodent animal models and is thought to have relevance to drug seeking and relapse in humans Steketee and Kalivas, Data suggests repeated administration of a drug causes altered dopaminergic and glutamatergic transmission in the mesocorticolimbic system Vanderschuren and Kalivas, ; Pascual et al.

Up-regulation of receptors may not be the sole cause of drug-induced locomotor sensitization, since the timing of these events don't necessarily correlate, but likely plays a role in the development of this behavioral response Vezina, Long-lasting behavioral sensitization has been shown to correlate well with LTP, reflecting persistent adaptations in neural mechanisms such as the modulation of synaptic strengths, change in neurotransmitter release, alterations in gene expression and formation of new connections between synapses.

In the next section, we will focus on nicotine and ethanol's effect on behavioral sensitization. Several studies have shown nicotine induces locomotor sensitization in mice and rats by a range of nicotine doses 0. Typically, the first nicotine injection produces locomotor depression which is rapidly overcome by subsequent nicotine exposure and is associated with the development of tolerance to the drug's acute depressant effect Morrison and Stephenson, This enhanced locomotor activity in response to repeated nicotine administration is long-lasting Miller et al.

While nicotine—induced sensitization has been widely studied, motor stimulant effects of ethanol have generally received less attention. The development of sensitization to ethanol is predominantly shown in mice. Similar to nicotine-induced locomotor activity, mice were pre-treated with ethanol injections 1. Following this exposure, they were challenged with a single injection of ethanol after a period of withdrawal 7—30 days. Results indicated the mice were significantly more sensitive to the locomotor stimulating effects of ethanol during this challenge session and this effect lasted up to 29 days following termination of ethanol administration Lessov and Phillips, ; Itzhak and Martin, ; Fish et al.

Under similar circumstances, stimulation of locomotor activity by ethanol consuming rats has also been reported Hoshaw and Lewis, There is a substantial amount of evidence supporting the idea that activation of the DAergic system is required for the emergence of the sensitized locomotor response, with induction of sensitization attributed to the VTA and the expression to the NAc Mao and McGehee, Through actions on nAChRs in this system, both nicotine and ethanol influence neuronal activity firing rate Mereu et al.

For example, intracranial injections of nicotine directly into the VTA results in locomotor sensitization Reavill and Stolerman, ; Kita et al. For these reasons, behavioral sensitization induced by nicotine and ethanol can be partially attributed to their actions on nAChRs in the midbrain reward pathway. While repeated exposure to a single drug can produce behavioral sensitization, sometimes cross-sensitization between drugs is observed.

In this type of experiment, animals are repetitively treated with a particular drug for a period of time and then challenged with a different drug after a defined drug-free period. Although the animal has experienced a different drug, locomotor sensitivity to the challenge drug is observed, indicating a common molecular substrate.

For example, caffeine, cocaine, and amphetamine have all been shown to produce cross-sensitization to nicotine-induced hyperlocomotion Collins and Izenwasser, ; Celik et al.

Others studies have demonstrated cocaine and ethanol exhibit cross-sensitization of locomotor effects Itzhak and Martin, The findings for nicotine and ethanol are mixed, with some studies reporting no cross-sensitization Watson and Little, ; Darbra et al.

There are, however, other behavioral measures that clearly illustrate a common molecular interaction between these two substances. In this respect, rats with prior exposure to nicotine show increased ethanol consumption Blomqvist et al. In addition, drugs acting through nAChRs, including a partial agonist varenicline and non-selective antagonist MEC , reduce ethanol consumption in both rodents and humans Le et al.

This review has summarized multiple different mechanisms that underlie persistent, long-lasting changes in synaptic efficacy following administration of addictive drugs. It is becoming more and more evident that nicotinic receptors significantly facilitate the induction and maintenance of plasticity—including LTP, LTD, and structural changes—in the hippocampus, amygdala, and mesolimbic dopaminergic system, thus contributing to the molecular underpinnings of nicotine and alcohol addiction.

Nicotine exerts its powerful effects by a dynamic, parallel activation, and desensitization of nAChRs. Up-regulation of nAChRs following nicotine treatment reflects a compensatory response to excessive receptor stimulation, and there is compelling experimental evidence to suggest this plays a major part in nicotine dependence.

Although few studies have addressed ethanol-induced synaptic plasticity via interactions with nicotinic receptors, ethanol undoubtedly potentiates nAChR currents and drugs targeting nAChRs can attenuate voluntary alcohol consumption in both rodents and humans. Importantly, there is a need to understand the molecular and cellular ramifications of co-administration of nicotine and ethanol due to the high comorbidity of these substances in human addicts.

Future studies should aim to unravel the common neural mechanisms shared by these two drugs. This review has touched upon the behavioral outcomes of repeated administration of drugs of abuse, thus suggesting that long-lasting changes in synaptic strength and modification of neurotransmitter release contribute to locomotor sensitization.

Both nicotine and ethanol alone clearly induce behavioral sensitization, and cross-sensitization may or may not occur between these two substances. At this time, a large body of literature exists regarding the mechanism of action of nicotine but there is still much to be elucidated pertaining to ethanol's actions at nAChRs for synaptic plasticity and behavioral sensitization.

Clearly, nicotine can enhance cognitive function and propagate LTP and thereby these processes are likely, at least in part, what underlie the highly addictive nature of this compound. Reports from human users of cognitive deficits and strong cue-induced cravings during nicotine withdrawal undoubtedly contribute to the high incidence of relapse. Medications that target neural substrates directly involved in both learning and addiction may offer a novel pharmacotherapeutic approach for nicotine dependence as well as other drugs of abuse.

More intriguing yet is the possibility that novel therapeutic avenues may be directed to diminish drug-associated memories or facilitate the formation of new memories with less maladaptive behavioral consequences.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Key Function of Nicotinic Receptors. Physiology of nicotinic receptors The nicotinic receptors are cylindrically-shaped proteins imbedded in synaptic walls that act as chemically-controlled sodium channels also called ligand-gated sodium channels that penetrate through the cell walls of post-synaptic nerves and myocytes at the skeletal neuromuscular junctions.

Guyton and Hall The channel opening in the nicotinic receptor normally lasts less than a millisecond because the enzyme, cholinesterase, rapidly breaks down acetylcholine. Guyton and Hall Toxic levels of cholinesterase inhibitors prevent the breakdown of acetylcholine. Taylor Clinical Picture Due to Nicotinic Effects of Cholinesterase Inhibitors These events help to explain why the initial phase of toxicity is manifested by over-stimulation characterized by myoclonic jerks, fasciculations and muscle spasms followed by weakness progressing to paralysis.

Locations of Nicotinic Receptors. Nicotinic receptors are located in the See also Figure 6 Skeletal neuromuscular junctions. Sympathetic and parasympathetic nervous system. Autonomic ganglia.

Central nervous system. Clinical findings are related to effects on the: Neuromuscular junctions of skeletal muscles. Fasciculations and myotonic jerks, followed by weakness and paralysis. Sympathetic nervous system due to ganglionic stimulation of the adrenal gland. See Figure 5 Hyperglycemia, glycosuria, ketosis. Schenker, Louie et al. Erdman Leukocytosis with a left shift. Tachycardia, tachydysrhythmias. Erdman Urinary retention.

Clark Nicotinic Mnemonic. The table below shows a mnemonic for remembering the nicotinic signs of cholinesterase inhibitor toxicity M onday. M ydriasis pupillary dilation. T uesday. W ednesday.