Is it true that smoking changes your brain somehow, making it harder to stop smoking? If so, how does that happen? Is there anything that can be done to change it back? Yes, that's true. When you smoke, your brain changes in response to the very high levels of nicotine delivered by cigarettes.
Those brain changes cause you to become addicted to nicotine, and that addiction can make stopping smoking very difficult. Nicotine is the chemical in tobacco that keeps you smoking. Nicotine that gets into your body through cigarettes activates structures normally present in your brain called receptors. When these receptors are activated, they release a brain chemical called dopamine, which makes you feel good. This pleasure response to dopamine is a big part of the nicotine addiction process.
Over time, as you continue to smoke, the number of nicotine receptors in your brain increases. Addicted smokers have billions more of these receptors than nonsmokers do. The pharmacological properties of the nAChRs to agonists such as ACh, nicotine or ethanol is highly dependent on its subunit composition and location of the receptor Yu et al.
Moreover upon exposure to nicotine and ethanol, nicotinic receptors can undergo changes in expression stoichiometries or receptor number and function which may underlie aspects of physical dependence and withdrawal symptoms Nashmi et al.
Since the majority of alcoholics are also smokers, determining the coincident molecular underpinnings in the development of their dependence may be useful in treating these addictions. This review will attempt to consolidate the available information regarding nicotinic receptor-mediated synaptic plasticity and integrate these enduring neural adaptations with current models of addictive disorders. We will look at a myriad of addictive processes, the underlying neural circuits and how these pathways converge for addictive behaviors to emerge.
The complexity of addictive disorders suggests there are a considerable number of possible targets for intervention that could potentially reverse drug-induced neural adaptations. We will aim to focus this paper towards nicotinic receptor-mediated neuroplasticity, with an emphasis on nicotine and ethanol. In addition to alterations in glutamatergic signaling, there is ample evidence showing other neurotransmitter systems, such as the cholinergic and dopaminergic, play a vital role in modulating the induction, duration, and magnitude of synaptic plasticity Otani, ; Drever et al.
ACh acts on a variety of different pre- and post-synaptic receptors throughout the brain resulting in profoundly different outcomes depending on receptor location and subunit composition Alkondon and Albuquerque, Thus far, most studies have implicated the involvement of G-protein coupled muscarinic receptors in mediating these synaptic changes; however, more recently nAChRs have come under investigation to understand their part in these processes. In this section, the role of nAChRs in the modulation of neurotransmission and drug-induced plasticity will be discussed for the brain loci that have been implicated to be important for the development of nicotine and ethanol addiction.
The mesolimbic dopaminergic system, encompassing DA neurons originating from the ventral tegmental area VTA that project to the nucleus accumbens NAc and PFC, has long been recognized as an important pathway mediating behavioral responses to natural rewards as well as drugs of abuse. Essentially, all drugs of abuse enhance extracellular DA in the NAc Di Chiara and Imperato, and blocking dopaminergic transmission will attenuate the reinforcing properties of the drug Corrigall et al.
Furthermore, this DA signal provides convergent information to the system regarding reward expectation and environmental cues related to drug intake Di Chiara, ; Berke and Hyman, It is not surprising, therefore that drug-induced neural adaptations have been discovered in this circuit and presumably contribute to addiction.
The VTA is modulated by excitatory glutamatergic inputs arising from the PFC, bed nucleus of the stria terminalis, amygdala, pontomesencephalic tegmental nuclei Mao and McGehee, , and by a large population of inhibitory GABAergic interneurons Johnson and North, ; Theile et al. Figure 2. Schematic representation of nAChR subtypes and circuit function in the mesolimbic dopaminergic system.
Both ethanol and nicotine stimulate dopamine release in the accumbens by modulating the activity of VTA neurons via nAChRs Champtiaux et al. In the presence of physiologically relevant doses of nicotine — nM Nguyen et al.
Therefore, nicotine's mechanism of action and downstream consequences are attributed to both receptor activation and desensitization Mansvelder et al. The propensity of these receptors to desensitize depends largely on the subunit composition of the nAChR assembly. These nicotinic receptors will also subsequently desensitize in the presence of nicotine with a net result being a reduction in the inhibitory control of GABA on dopaminergic transmission Mansvelder and McGehee, Hence, the cumulative result of nicotine acting on nAChRs in the VTA is enhanced excitatory input onto DA neurons which triggers reward-related high frequency burst firing resulting in increased accumbal DA outflow Corrigall et al.
Several labs have investigated the specific subunit compositions of the nAChRs that may be critical in the development of nicotine dependence using cell-based heterologous expression systems, transgenic mouse lines, and pharmacological manipulations using nAChR ligands in animal behavior models Tapper et al.
The effects of ethanol in the VTA are more complex than the effects of nicotine. Ethanol, unlike nicotine, is not a direct agonist at nAChRs Cardoso et al. While local perfusion of ethanol into the VTA does not increase DA release in the accumbens, infusion of ethanol into the accumbens does elevate extracellular DA to a similar degree as systemic administration Ericson et al.
However, ethanol infused into both regions simultaneously resulted in higher DA levels than when injected into the NAc alone Lof et al. It should be mentioned here that in addition to nAChRs, ethanol is known to modulate DA neurotransmission through actions at other molecular targets [for review Vengeliene et al. For example, ethanol 10—80 mM acting on pre-synaptic D 1 receptors can increase excitatory glutamate transmission in the VTA and enhance DA release Xiao et al. Several subunit-specific antagonists have been administered to mice both systemically and by direct infusion into the brain.
In addition to augmenting transmitter release, drugs of abuse can induce long-lasting plasticity within midbrain DA centers following both acute and chronic drug administration Gao et al. In the VTA, drug-evoked NMDA-mediated plasticity may occur in a similar fashion to that seen in the hippocampus and requires activation of pre-synaptic voltage-gated ion channels.
Activation of nAChRs by nicotine likely influence the persistent potentiation of these excitatory synapses Jin et al. The striatum is a heterogeneous structure, with distinct anatomical and functional subterritories that can be broadly classified into the dorsal and ventral striatum. The dopaminergic neurons arising from the VTA project to the ventral striatum NAc and part of the olfactory tubercle , while the dorsal striatum caudate-putamen receives dopaminergic inputs primarily from the substantia niagra pars compacta.
The ventral striatum is highly involved in the reinforcing effects of drugs of abuse and receives extensive excitatory afferents from the PFC, amygdala and hippocampus Carelli, ; Volkow et al. On the other hand, efferent projections from the motor cortex to the dorsal striatum allows this subregion to gate sensorimotor function and have been implicated in the advanced stages of habitual drug seeking Fasano and Brambilla, ; Gerdeman et al.
In the proposed model, ACh released from tonically active striatal cholinergic interneurons normally acts on these receptors to gate the probability of DA release and enhance the contrast between tonic and phasic firing patterns. Initial nicotine administration causes a reduction of dopamine release from tonically active neurons; however, a reward-related burst of action potentials will result in even greater transmitter release due to loss of the normal modulatory control of endogenous Ach Zhou et al.
Besides anatomical and connectivity differences, there are clear distinctions in DA signaling between the ventral and dorsal striatum which govern their specific brain functions and behavioral output. For example, initial drug use will favor DA release in the NAc shell rather than the dorsolateral striatum Pontieri et al.
Furthermore, these two regions respond differently to stimulus trains that mimic action potentials, with tonic and phasic firing eliciting greater DA release from the dorsolateral striatum and NAc shell, respectively Zhang et al. In summary, DA release in the striatum is modulated by different nAChRs on pre-synaptic DAergic terminals in a frequency-dependent and region-specific manner. Neuronal morphological changes, including increases in spine density or dendritic length, have been reported following environmental enrichment or drug administration Johansson and Belichenko, ; Leggio et al.
In the NAc, long-lasting structural plasticity has been demonstrated in MSN following nicotine administration; however, these changes may be dependent on treatment schedule and cohort age.
One study found an increase in dendritic length and spine density in the NAc and PFC of adult rats after intermittent subcutaneous injections of nicotine Brown and Kolb, while another reported significant increases in dendritic length and branch number in the NAc shell of adolescent but not adult rats after continuous nicotine administration Table 1 McDonald et al.
The PFC is a key brain region regulating executive cognitive function, attention, and working memory. Dysregulation of normal signaling in the PFC, paralleled by deficits in cognitive performance, have been observed in disorders such as Alzheimer's disease, schizophrenia, ADHD, and Parkinson's disease Picciotto and Zoli, Interestingly, nicotine has been shown to enhance cognition and attention in people suffering from these disorders Rezvani and Levin, It is now well established that drugs of abuse may take over the normal operations of this system, driving impulsivity and compulsive behaviors characteristic of addiction Lasseter et al.
Recent neuroimaging studies of PFC activity in drug-addicted subjects point to global dysfunction in this region that is associated with a greater incidence of relapse and heavier drug use Goldstein and Volkow, In the PFC, the relative timing of action potentials in pre- and post-synaptic neurons is critically important for determining the direction of synaptic plasticity, either LTP or LTD, and is referred to as spike-timing-dependent plasticity STDP Markram et al.
When the pre-synaptic spike occurs before the post-synaptic spike in a time-sensitive manner, robust LTP is induced; in contrast, reversing the order of stimulation will result in LTD. Nicotine will increase the threshold for induction of STDP under the same stimulus conditions by reducing dendritic calcium signals that normally occur with action potential propagation.
Application of a GABA A receptor antagonist or increasing dendritic calcium signals with burst-like, post-synaptic stimulation blocked nicotine's effects and produced STDP similar to that of control conditions. The authors speculate that one way nicotine may improve cognition is by increasing the signal-to-noise ratio during PFC neural processing Couey et al. Nicotinic receptors have long been known to play a significant role in cognition and disruption of normal nAChR function has been demonstrated in diseases such as Alzheimer's and schizophrenia Paterson and Nordberg, An important aspect of addiction is the development of context-drug associations and the formation of memories that link drug-predictive cues to the reinforcing properties of the substance.
Studies in both animals and humans have highlighted the importance of associated learning of drug intake with both environmental and internal cues in mediating future drug-seeking and relapse Fuchs et al. The hippocampus and amygdala have been implicated in mediating some of the cognitive-enhancing effects of nicotine, supported by findings that show microinfusion of nAChR agonists can enhance memory-related functions, while antagonists impair them Ohno et al.
For example, direct infusion of nicotine into basolateral nucleus of the amygdala enhanced working memory and facilitated the acquisition and consolidation of short- and long-term memories; on the other hand, infusion of MLA had opposite effects on memory performance Barros et al. In addition, nicotine dose-dependently stimulates the release of norepinephrine in the amygdala and hippocampus by activating nAChRs localized on norepinephrinergic neurons in the brainstem Fu et al.
Norepinephrine contributes to memory function and the stress response Liang et al. 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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