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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Mol Neurobiol. Author manuscript; available in PMC May 18, 2009.
Published in final edited form as:
PMCID: PMC2683366
NIHMSID: NIHMS110746

Modulation of Hippocampus-Dependent Learning and Synaptic Plasticity by Nicotine

Abstract

A long-standing relationship between nicotinic acetylcholine receptors (nAChRs) and cognition exists. Drugs that act at nAChRs can have cognitive-enhancing effects and diseases that disrupt cognition such as Alzheimer’s disease and schizophrenia are associated with altered nAChR function. Specifically, hippocampus-dependent learning is particularly sensitive to the effects of nicotine. However, the effects of nicotine on hippocampus-dependent learning vary not only with the doses of nicotine used and whether nicotine is administered acutely, chronically, or withdrawn after chronic nicotine treatment but also vary across different hippocampus-dependent tasks such as the Morris water maze, the radial arm maze, and contextual fear conditioning. In addition, nicotine has variable effects across different types of hippocampal long-term potentiation (LTP). Because different types of hippocampus-dependent learning and LTP involve different neural and molecular substrates, comparing the effects of nicotine across these paradigms can yield insights into the mechanisms that may underlie the effects of nicotine on learning and memory and aid in understanding the variable effects of nicotine on cognitive processes. This review compares and contrasts the effects of nicotine on hippocampus-dependent learning and LTP and briefly discusses how the effects of nicotine on learning could contribute to nicotine addiction.

Keywords: Nicotine, Hippocampus, Learning, LTP, Addiction, Contextual learning, Fear conditioning, Nicotinic receptors, Acetylcholine

Introduction

Understanding the function of the hippocampus was revolutionized with the work of Penfield and Milner [1]. In the 1950s, an individual, now familiar to most psychologists and neuroscientists as patient HM, underwent a radical procedure to treat his epilepsy; bilateral medial temporal lobe tissue, including the hippocampus, was removed. Postoperatively, HM displayed anterograde amnesia and temporally graded retrograde amnesia [1]. Numerous studies of patient HM and others with similar neuronal damage revealed that the hippocampus plays a critical role in the transfer of short-term memories to long-term memories. Since these initial studies, research involving neuropsychological patients and animal models has further elucidated hippocampal function. It is clear that, in addition to playing a critical role in the formation of long-term memories, the hippocampus is critically involved in integrating and processing spatial and contextual information. Theories of hippocampal function have proposed that the hippocampus is involved in forming configural associations between stimuli such as those involved in learning a context or to navigate in space [2, 3]. The ability of the hippocampus to aid in the formation of long-term memories and to process configural information may be one reason that the hippocampus is believed to be important for declarative memory function. Declarative learning and memory processes are involved in defining who we are and anchor us to past events, places, and experiences [4]. Thus, the hippocampus is not only critically involved in learning but also plays an important role in defining the self. Diseases and drugs that disrupt these processes have a grave impact on daily function and could have long-lasting effects on an individual’s behavior.

Disorders such as schizophrenia, Alzheimer’s disease, and nicotine addiction are associated with alterations in cholinergic function in the hippocampus and in cognition. Schizophrenia is associated with hippocampal dysfunction [5] and changes in hippocampus-dependent cognitive processes such as contextual information processing [6]. Given that there is a particularly high incidence of smoking amongst patients with schizophrenia [7], a finding thought to be indicative of self-medication [8], understanding the effects of nicotine on contextual information processing may yield insights into this debilitating disorder. Alzheimer’s disease has long been associated with loss of cholinergic function in the hippocampus [9, 10] and is associated with severe deficits in declarative memory. Furthermore, cholinergic drugs have been found to have beneficial effects for those with the disorder [11, 12] suggesting the importance of understanding how nicotine alters cholinergic processes. Finally, addiction in general has been linked to changes in hippocampal function [13-15], and nicotine addiction is no exception [16]. Given that changes in cholinergic processes and hippocampal function are associated with multiple diseases, understanding the effects of cholinergic drugs such as nicotine on hippocampus-dependent learning and synaptic plasticity will facilitate the development of treatments for such diseases.

An overarching goal of this review is to examine the similarities and differences in the behavioral and neural effects of nicotine on hippocampus-dependent learning and plasticity. To accomplish this goal, we will briefly review the structural and functional characteristics of nicotinic acetylcholinergic receptors (nAChRs), the hippocampus, the effects of acute, chronic, and withdrawal from chronic nicotine on synaptic plasticity as measured with long-term potentiation (LTP), and the effects of nicotine on hippocampus-dependent learning with particular emphasis on contextual learning1. Finally, as an example of how the effects of nicotine on hippocampus-dependent learning could contribute to a disease, we will examine the interaction between nicotine, learning, and addiction.

nAChRs

Nicotinic acetylcholinergic receptors are a class of ligandgated ion channels that are assembled from five subunits out of at least 17 identified subunits and are differentially expressed in both the central and peripheral nervous systems [18-21]. Neuronal nAChRs have a pentameric structure and are comprised of either α (α7-α10) subunits or a combination of α (α2-α6) and β (β2-β4) subunits [22-25]. In the central nervous system, the α4β2* (which includes subclasses differentiated by the inclusion of α3, α5, or α6 subtypes [26, 27]) and α7 nAChRs are the two predominant nAChR subtypes [28, 29], but they have diverse functional properties [30-32]. α4β2* nAChR subtypes show high affinity for nicotine, desensitize slowly, and show long-lasting inhibition by mecamylamine (a broad-spectrum nAChR antagonist) [21, 33, 34]. Conversely, α7 nAChR subtypes show lower affinity for nicotine but high affinity for α-bungarotoxin, desensitize rapidly, and show short-lasting inhibition by mecamylamine [21, 34-38].

Both the α7 and α4β2* nAChR subtypes have properties that could contribute to the cognitive-enhancing effects of nicotine. For example, both nAChR subtypes are located in the hippocampus, both are expressed presynaptically and postsynaptically which suggests they could modulate both presynaptic and postsynaptic processes involved in synaptic plasticity and both gate calcium, which could enhance memory through activation of second messengers involved in synaptic plasticity or by facilitating neurotransmitter release [30-32, 35, 39-47]. Whereas both α7 and α4β2* nAChRs have properties that could contribute to the effects of nicotine on learning and memory, differences in their functional properties suggest that these receptors may have divergent influences on these cognitive properties. This possibility will be explored as we review the effects of nicotine on hippocampal LTP, spatial learning, spatial working memory, and contextual learning.

The Hippocampus

When compared to other areas of the brain, the hippocampus is structurally and functionally unique. In fact, the anatomical layout of the hippocampus may endow the structure with functional capacities necessary for certain forms of learning and memory. Unlike cortical areas that contain a large number of reciprocal connections, the hippocampus is primarily a unidirectional circuit (Fig. 1a). The structure and connectivity of the hippocampus is no doubt critical to the special information-processing capabilities that have been attributed to it. Information from a variety of unimodal and polymodal cortical areas projects to the entorhinal cortex, an area that provides input to the hippocampus. The primary output of the entorhinal cortex is to the dentate gyrus (DG) via the perforant pathway (PP) with secondary outputs projecting to the CA3 and CA1 regions. The granule cells of the DG give rise to the mossy fiber pathway that projects to the CA3 region. The outputs of the pyramidal cells of the CA3 region then form the Schafer collaterals (SC) that project to the CA1 region and the commissural fibers that connect to the contralateral hippocampus. CA1 pyramidal cells project back to the entorhinal cortex as well as to the subiculum, which then projects to the entorhinal cortex. Afferents from the entorhinal cortex form back projections that innervate the same cortical areas that initiated hippocampal activation via the entorhinal cortex. The connections described above comprise the major pathways of the hippocampus [for a detailed review, see 48].

Fig. 1
The role different hippocampal subregions play in various aspects of learning and memory and the effects of nicotine on synaptic plasticity in these regions as measured by LTP (see text for details). a Inputs and outputs of three hippocampal subregions ...

Different regions of the hippocampus are thought to contribute, to varying extents, to diverse functions such as episodic memory, spatial learning, contextual learning, and working memory (Fig. 1a). Based on computational modeling, the DG is thought to be involved in forming orthogonal representations of input from the entorhinal cortex [49]. A prime example of this is the formation of specific nonoverlapping place cells in the DG from grid cells of the entorhinal cortex [50]. As would be expected, DG lesions lead to deficits in the encoding of spatial memory [51] and in differentiating spatial locations in rodents [52]. Recent functional magnetic resonance imaging work in humans also suggests a role for the DG, in conjunction with the CA3 region, in forming distinct representations of subtly different stimuli [53].

The pyramidal cells of the CA3 region are unique in that a large portion of their input comes from recurrent collaterals forming an extensive autoassociative network. Such connections allow neurons of the CA3 region that are activated separately to become rapidly associated with one another. Thus, the CA3 region is thought to be important for making rapid multimodal associations between diverse stimuli, the hallmark of episodic memory, as well as holding spatial information in working memory [49]. In addition, the CA3 region has been found to be important for making associations between objects or odors and a context [54] and in associating a context with a shock [55]. A related function of the CA3 is its critical contribution to pattern completion, in which a fully detailed memory is recalled based on only a few inputs. A number of studies have demonstrated an integral role for the CA3 region in spatial pattern completion [56, 57]. Finally, inputs from the mossy fiber and perforant pathways into the CA3 region, respectively, are thought to be differentially involved in the acquisition and retrieval of a memory [51].

The CA1 region has been implicated in a number of functions including forming temporal associations, memory consolidation, and memory retrieval. Disruption of CA1 function alters the ability of animals to learn temporal patterns [58, 59] and retrieve spatial memories [60]. Given the large number of back projections from the CA1 region to cortical regions that have afferent connections with the hippocampus and that a number of theories of hippocampal functioning postulate that memory is consolidated to cortical regions over time ([61] but see [62]), it is not surprising that the CA1 has also been found to be important for the long-term consolidation of memory [63].

Nicotinic acetylcholine receptors are widely distributed throughout the hippocampus. α7 nAChRs are present in all hippocampal subregions, with the highest concentration in the DG [64]. α4 and β2 subunits are also located throughout the hippocampus, with the highest density in the DG and CA1 regions [65]. Nicotinic receptors are located on both glutamatergic pyramidal cells and GABAergic interneurons. On pyramidal neurons, α7 nAChRs are densely localized both presynaptically and postsynaptically with sparse somatic localization [64, 66] whereas β2-containing nAChRs are more densely localized postsynaptically and at the soma with less-dense presynaptic localization [66, 67]. In interneurons, α7 nAChRs are localized presynaptically [68] and both α7 and α4β2* nAChRs are localized to somatodendritic compartments [69-71]. The relative contribution of α7 and α4β2* nAChRs to interneuron activation depends on the interneuron subtype and layer within the hippocampus [69-71]. For example, in the CA1 region, most interneurons in the stratum pyramidale display little activation by nAChRs whereas interneurons in stratum oriens are modulated by both α7 and α4β2* nAChRs [69-71]. Thus, the net effect of nicotine on neural activity in the hippocampus is complex (see [70] for a more detailed discussion) as nicotine can modulate the transmission of information by altering both interneuron and pyramidal cell activation.

In summary, the regions of the hippocampal formation act in concert to quickly and efficiently process and encode episodic, spatial, contextual, and temporal memories. Understanding how the different hippocampal subregions contribute to memory formation can yield specific clues as to where nicotine may act in the hippocampus to alter learning and memory.

LTP

Long-term potentiation is a widely accepted model of synaptic plasticity that is thought to underlie learning and memory processes [72, 73]. LTP is manifested as increased synaptic efficiency lasting over an hour that is induced by brief high-frequency stimulation of presynaptic neurons [74]. Inducing LTP in vitro has proven to be a fruitful model in which the cellular and molecular mechanisms that support learning and memory can be easily investigated. Many of the molecules and mechanisms that have been found to be important for different aspects of LTP have subsequently been found to be important in spatial learning [75] and fear conditioning [76]. For instance, simple passive avoidance learning was found to induce LTP [77] and the same mechanism that maintains long-lasting LTP also maintains spatial memory [78]. Given this background, exploring the effects of nicotine on LTP may assist in our understanding of the cellular and molecular mechanisms that form the basis for the effects of nicotine on learning and memory.

In the hippocampus, acetylcholine is thought to modulate learning and memory by altering the oscillatory rhythms that result from the interaction of the various hippocampal subregions [79]. Altering such rhythms may result in an increase in the recruitment of various cell-signaling molecules known to be involved in synaptic plasticity as measured by LTP. To explore how nAChRs may alter such processes, studies have examined the effects of nicotine on LTP using high-frequency stimulation (HFS) of presynaptic neurons for induction (Fig. 1b). Many of the mechanisms that have been found to underlie HFS-induced LTP have been found to be important in learning and memory tasks [75, 76]. Other studies have explored the effects of nicotine on short-term potentiation (STP), in which short bursts of HFS lead to a form of potentiation that degrades to baseline within minutes (also known as subthreshold stimulation), to determine if nicotine can change STP to LTP. A handful of studies have also looked at nicotine-induced LTP in vivo and in vitro in which the drug is applied or administered in the absence of tetanic stimulation yet results in LTP induction. Finally, the effect of chronic nicotine treatment and withdrawal prior to in vitro LTP induction has also been explored.

The various LTP induction protocols have been used to investigate the effects of nicotine on plasticity in different pathways of the hippocampus (Fig. 1b). The effect of nicotine on STP has been studied in the SC-CA1 pathway in which the afferents arise from the CA3 region and in the adjacent temporoammonic (TA)-CA1 pathway in which the afferents arise from the entorhinal cortex. In addition, the ability of nicotine to enhance HFS-induced LTP has been explored in the PP-DG pathway, which constitutes the main input from the entorhinal cortex to the hippocampus proper. Finally, nicotine-induced LTP has been explored in the SC-CA1 pathway in vitro and in the PP-DG pathway in vivo. These various hippocampal subregions and pathways are thought to contribute to the different aspects of learning and memory that the hippocampus supports [49]. Thus, understanding how nicotine affects LTP and STP and induces LTP in the different subregions may yield clues as to how nicotine alters different learning and memory processes.

LTP in the SC-CA1 Pathway

In the SC-CA1 pathway, nicotine has been found to induce LTP in the absence of tetanic stimulation, as well as facilitate LTP induction by subthreshold stimulation (i.e., turn STP into LTP). Nicotine-induced (1-10 μM; the concentration of nicotine in smokers reaches about 0.5 μM [80]) LTP was blocked by kappa-bungarotoxin, an α3- and β2-containing nAChR antagonist, suggesting an integral role for α3β2-containing nAChRs [81]. Furthermore, nicotine-induced LTP required calcium influx via L-type calcium channels [82] as well as the activation of mitogen-activated protein kinases [83]. However, unlike many types of tetanic-induced LTP, nicotine-induced LTP in the SC-CA1 pathway did not require N-methyl-d-aspartate (NMDA) receptor activation or retrograde signaling via nitrous oxide [84]. Thus, nicotine may facilitate calcium signaling such that NMDA-mediated calcium signaling is not necessary. In addition, nicotine may induce LTP by modulating the release of other neurotransmitters that may then increase synaptic efficiency, a contention that is supported by the fact that nicotine-induced LTP in the SC-CA1 pathway has been found to be dependent upon noradrenergic signaling [81].

Nicotine has also been found to decrease the threshold for LTP induction in the SC-CA1 pathway. Administration of 1-10 μM nicotine to hippocampal slices subjected to subthreshold stimulation resulted in LTP induction even though the stimulation only induced STP in control slices [85]. Subthreshold facilitation of LTP also occurred in the presence of non-α7 nAChR agonists (epibatidine and A85380) and an α7 nAChR antagonist (methyllycaconitine; MLA) [86, 87]. These findings suggest that the facilitation of synaptic plasticity by nicotine required both the activation of non-α7 nAChRs and the inactivation of α7 nAChRs. Recent work suggests that α2-containing nAChRs may also be important for this effect, as nicotine applied to hippocampal slices obtained from α2 nAChR knockout (KO) mice did not change STP into LTP [88].

There are at least three mechanisms by which nicotine may act to turn STP into LTP. The first mechanism is via disinhibition of pyramidal cells through alterations in the signaling of GABAergic interneurons. Activation of nAChRs localized to GABAergic interneurons has been found to increase activity in CA1 pyramidal cells, presumably via inhibiting other inhibitory interneurons that synapse directly onto pyramidal cells [69, 89]. Alternatively, a second manner by which nicotine might facilitate LTP induction is via a decrease in inhibitory interneuron activity that may occur following desensitization of nAChRs located on the interneurons [87, 88, 90]. Finally, a third possibility is that nicotine may act postsynaptically at CA1 pyramidal cells to reduce the threshold for LTP induction in the SC-CA1 pathway [91] by increasing calcium signaling or neuronal excitability.

Nicotine is not only capable of enhancing plasticity in the CA1 region but is also capable of decreasing synaptic efficiency. For example, in the SC-CA1 pathway, nicotine was found to enhance long-term depression [92] and decrease the likelihood of LTP induction [91, 93]. Whether nAChR activation resulted in potentiation or degradation of synaptic efficiency in the SC-CA1 pathway depended upon the timing of postsynaptic nAChR activation relative to SC stimulation [91, 93] and the type and location of nAChRs involved [69]. In addition, in the adjacent TA-CA1 pathway, nicotine suppressed the induction of LTP, an effect that appears to depend on the presence of α2 nAChRs [88]. Enhanced LTD could contribute to the enhancement of learning and memory by decreasing the contribution of neurons not involved in the encoding of the memory and thus increasing the signal-to-noise ratio of those neurons involved. Alternatively, if LTD decreases the efficiency of inhibitory processes, this could lead to disinhibition of other cells resulting in increased learning-related activity. Thus, the effects of nicotine on synaptic plasticity in the CA1 region are multifaceted, with the overall effect of nicotine dependent upon a host of interactions between incoming stimulation via the temporoammonic pathway and SCs as well as the nAChR subtypes involved.

LTP in the PP-DG Pathway

In the PP-DG pathway, nicotine-induced LTP in vivo as well as enhanced HFS-induced LTP in vitro. Nicotine (1.1 mg/kg) induced LTP in vivo in anesthetized mice [94, 95]. In vivo LTP was partially induced by the administration of choline (an α7 nAChR agonist) or epibatidine and fully induced following the administration of both agonists. However, the dose of nicotine used to induce LTP is much higher than those required for the enhancement of learning and memory and approaches doses of nicotine that induce seizures in mice [96, 97]. Furthermore, the animals were anesthetized during LTP induction using urethane, an anesthetic that has been found to potentiate the function of α4β2 nAChRs [98]. Thus, the relationship between in vivo drug-induced LTP in the PP-DG pathway and the effects of nicotine on learning and memory are not altogether clear.

Nicotine (5 μM) has also been found to enhance HFS-induced LTP in the PP-DG pathway in vitro. This enhancement is dependent upon the action of nicotine at α7 nAChRs, as MLA but not DHβE (a high-affinity nAChR antagonist, e.g., α4β2 nAChRs) blocks the effect, and it is absent in α7 nAChR KO mice [99, 100]. The enhancement of LTP by nicotine also appears to depend on glutamatergic and calcium-mediated processes. Blocking either NMDA receptors or L-type calcium channels prevents the enhancement as does blocking ryanodine receptors but not IP3 receptors, both of which are involved in gating calcium release from intracellular stores [99]. Welsby et al. [99] suggest that stimulation of α7 nAChRs by nicotine prior to LTP induction fills ryanodine-receptorsensitive stores with calcium, and following HFS there is a larger amount of calcium-induced calcium release from these stores leading to greater LTP. However, this may not be the only cellular process underlying the effect, as mGluRs as well as PKA activation have also been found to be important for the enhancement of LTP in the PP-DG pathway by nicotine [99, 100]. A comparison of these findings to those exploring the effects of nicotine on transforming STP into LTP in the SC-CA1 pathway suggests that the effects of nicotine in these two pathways involve different nAChR subtypes and rely upon different cellular processes.

LTP in Chronic Nicotine-Treated Animals

In addition to the effects of acute nicotine on LTP, chronic nicotine treatment and withdrawal following chronic nicotine could result in altered hippocampal function leading to changes in synaptic plasticity. Chronic nicotine administration in these experiments consisted of twice daily injections of 1 mg/kg of nicotine for 10-17 days. The last injection of nicotine occurred well before the brain was dissected such that no nicotine was present in the brain slice at the time of recording unless added. Thus, it is an open question as to whether these studies examined the effects of chronic nicotine administration or withdrawal from chronic nicotine. Nonetheless, in the SC-CA1 pathway of hippocampal slices obtained from rats treated with chronic nicotine, LTP could be induced with normally subthreshold stimulation protocols (i.e., such stimulation usually results in STP). This effect was blocked by the application of mecamylamine or DHβE [85, 86]. If acute nicotine (1 μM) was applied to slices taken from chronic nicotine-treated animals, the amount of stimulation needed to induce LTP was lower than that required in acute nicotine-treated slices obtained from chronic nicotine-naïve animals. However, unlike in naïve animals, MLA did not further facilitate subthreshold LTP in chronic nicotine-treated animals, suggesting that the α7 nAChRs may be thoroughly desensitized and therefore may no longer contribute to the facilitation of LTP following chronic treatment [86]. In contrast, non-α7 nAChRs may not be desensitized to the same extent as α7 nAChRs and therefore may contribute to LTP facilitation in slices obtained from chronic nicotinetreated animals. The effect of chronic nicotine treatment on the facilitation of subthreshold LTP in the SC-CA1 pathway may also be due to the upregulation of high-affinity nAChRs following chronic nicotine treatment [101-103]. An increase in high-affinity receptors may lead to a reduced threshold for LTP induction in the SC-CA1 pathway in chronic nicotine-treated animals by enhancing the effect of cholinergic signaling during subthreshold stimulation.

In rats withdrawn from chronic nicotine administration for 2 days, the ability for subthreshold stimulation to result in LTP in the SC-CA1 pathway was attenuated and after 23 days of withdrawal completely diminished [104]. Following 4 days of withdrawal, nicotine applied directly to slices no longer facilitated subthreshold stimulation, an effect that appears to be due in part to alterations in glutamate receptor function [104]. Furthermore, following withdrawal from chronic nicotine, α7 nAChRs on GABAergic interneurons are functionally upregulated, possibly leading to a decrease in overall activity that may contribute to the attenuated enhancement that occurs during withdrawal [104].

In the PP-DG pathway, enhanced LTP following HFS was found in slices obtained from chronic nicotine-treated animals. Unlike in slices obtained from naïve animals, the effect in chronic nicotine-treated animals does not appear to depend upon nAChR activation at the time of induction as the application of either MLA or mecamylamine prior to the tetanus did not block the enhancement [99, 100]. However, the enhancement of LTP in the PP-DG pathway of chronic nicotine-treated animals still required the activation of mGluRs and ryanodine receptors. This suggests that the enhancement of PP-DG LTP by chronic nicotine is due to alterations in processes downstream from nAChRs, such as calcium-mediated cell signaling [99]. Similar to the mechanism suggested for the effects of acute nicotine on LTP in this pathway, Welsby and colleagues [99] suggest that the enhanced LTP in the PP-DG pathway in the chronic nicotine-treated animals is a result of an increase in the amount of calcium in ryanodine-sensitive intracellular stores due to persistent nAChR activation before slices are prepared. The increased stores of calcium may then lead to greater calcium-induced calcium release following HFS and thus enhanced LTP. Overall, despite the paucity of studies exploring the effects of chronic nicotine on LTP induction in the various hippocampal subregions, it appears that acute and chronic nicotine act via overlapping yet subtly different mechanisms.

In summary, the various effects of nicotine on different LTP stimulation protocols in different areas of the hippocampus suggest a number of possible mechanisms by which nicotine may act to enhance learning and memory processes. Enhancement of HFS LTP in the PP-DG pathway by nicotine suggests that connections normally formed during learning may be stronger when formed in the presence of nicotine. Alternatively, the ability of nicotine to transform STP into LTP in the SC-CA1 pathway suggests that nicotine may either strengthen cell processes normally involved in learning or recruit additional processes. Such changes may lead to enhanced learning and plasticity via altered patterns of memory encoding, although it should be noted that the doses of nicotine used in the in vitro studies (1 μM in the SC-CA1 and 5 μM in the PP-DG pathway) are potentially higher than those concentrations of nicotine found in smokers of around 0.5 μM [80]; however, equating the nicotine concentration infused into a slice to those found in the plasma of smokers is contentious, and understanding how in vivo concentrations translate to in vitro preparations is an important issue. Finally, the relevance of nicotine-induced LTP to understanding the effects of nicotine on learning and memory are not altogether clear due to the indiscriminate nature of the LTP induction. Such effects may be important for other effects of nicotine, such as sensitization of reward pathways [105-107], alterations in psychiatric patients that use nicotine [8, 108], or protection against the effects of neurodegenerative diseases [109, 110].

The studies reviewed in the prior paragraphs also suggest that different nAChR subtypes modulate different types of LTP in the various subregions of the hippocampus. For example, the enhancement by nicotine of HFS LTP in the PP-DG pathway depends primarily upon the activation of α7 nAChRs, whereas the change from STP to LTP in the SC-CA1 pathway by nicotine involves both the desensitization of α7 nAChRs and the activation of non-α7 nAChRs. Thus, if activation of non-α7 (e.g., α4β2* nAChRs) receptors are found to be involved in the enhancement of a learning task, we can hypothesize based on the current evidence that the mechanism underlying this enhancement may be nicotine acting to turn STP into LTP in the SC-CA1 pathway as opposed to enhancing LTP in the PP-DG pathway. In this manner, LTP studies can suggest potential mechanisms involved in the effects of nicotine on learning.

Even with the studies reviewed here, considerable work remains to be done on understanding the effects of nicotine on LTP and how this relates to the effects of nicotine on learning and memory. For example, would nicotine facilitate subthreshold stimulation in the PP-DG pathway? Would nicotine enhance HFS-induced LTP in the SC-CA1 pathway? Can nicotine induce LTP in vivo at doses similar to those used to enhance learning and memory in conscious animals? Could nicotine enhance LTP or facilitate subthreshold stimulation in vitro at concentrations that more closely approximate those seen in smokers? Compared to HFS, would nicotine have similar effects using an LTP induction paradigm that approximates the firing patterns of neurons during learning [111], such as theta stimulation? Identifying how nicotine alters these various forms of LTP induction and identifying the receptor subtypes and signaling molecules involved will significantly further our understanding of how nicotine alters learning and memory processes.

Spatial Learning

A prediction that results from studies examining the effects of nicotine on LTP is that acute nicotine should enhance hippocampus-dependent learning. Indeed, nicotine enhances many types of hippocampus-dependent learning but the story is complex as effects vary across learning tasks. The Morris water maze is a hippocampus-dependent spatial learning task that requires animals to use extra maze cues to learn the location of a hidden platform in a pool of water [112]. Training generally takes several days and learning of the task is measured as a decreased latency to discover the hidden platform across sessions or as time spent in the vicinity of the platform during a test session in which the platform has been removed. Both acute and chronic nicotine alter performance of this task, but results are not consistent across studies (Table 1). Acquisition of the Morris water maze takes multiple sessions. Thus, studies examining the effects of nicotine on acquisition of this task require nicotine administration over multiple days. This raises the question as to whether such studies are examining the effects of acute or chronic nicotine on acquisition of the task, which is a particularly important question because nicotine desensitizes nAChRs, although to different degrees depending on nAChR subunit composition and treatment duration [113].

Table 1
The effects of nicotine on the water maze

In a study that administered 0.07 mg/kg nicotine once daily to young and aged rats starting 3 days prior to training and continuing throughout training, nicotine improved acquisition in the aged but not the young rats [114]. It should be noted that the young rats required 7 days of training (four sessions per day) whereas the aged rats required 14 days of training. Nicotine did improve recall or retention in the young but not the aged rats. However, in another study, young and aged rats administered 0.2 mg/kg nicotine before all Morris water maze sessions (two trials per day for 3 days) both showed no effect of nicotine [115].

The dose of nicotine and the treatment duration may determine whether nicotine enhances or disrupts spatial learning. In mice, administration of 0.7 mg/kg nicotine 4 days before training disrupted learning but administration of 0.35 or 0.7 mg/kg nicotine starting 5 days before training and continuing for the 4 days of training improved learning [116]. It is possible that the deficits seen in the group that received nicotine prior to but not during training could reflect some type of withdrawal effect; however, results from another study suggest that this may not be the case. Rats treated with 0.7 mg/kg nicotine twice daily either for 1 day at 10 days before training or for 10 days with the last treatment 24 h before training both showed enhanced acquisition of the Morris water maze [117]. Clearly, methodological differences, such as differences in strains, doses, and drug treatments, are important variables in the effects of nicotine on spatial learning but procedural differences across studies complicate direct comparisons.

Multiple studies suggest that the hippocampus may be the site of action for the effects of nicotine on spatial learning as measured with the Morris water maze. Rats trained in the Morris water maze (3 days, two trials per day) that received direct infusion of nicotine (1 μg) into the dorsal hippocampus immediately after the last trial showed enhanced recall [118]. In addition, α7 nAChRs in the hippocampus may be involved in acquisition of the Morris water maze. Mice that received bilateral hippocampal delivery of the rat α7 nAChR gene had a greater rate of acquisition than control mice but showed a similar level of learning [119]. Finally, the disruptive effects of nicotine on the Morris water maze may also be related to changes in hippocampal function; a 4-mg/kg per day treatment for 10 days disrupted acquisition of the Morris water maze and also decreased neurogenesis in the hippocampus [120]. Nicotine self-administration has also been shown to decrease neurogenesis and markers of synaptic plasticity in the hippocampus [121]. Together, these studies suggest that the hippocampus may be a critical site of action for the effects of nicotine on spatial learning. In addition, α7 nAChRs may modulate acquisition of spatial learning but it remains to be determined which nAChRs are involved in the effects of nicotine on Morris water maze learning.

Spatial Working Memory

Just as nicotine alters spatial learning, nicotine has also been shown to alter spatial working memory. The radial arm maze is a hippocampus-dependent task used to measure spatial working memory, in which subjects must remember the locations of baited versus unbaited arms [122]. A radial arm maze typically has eight or 16 arms, all or some of which are baited with food and placed in a room with a number of extra maze cues. Animals are placed in the center of the maze and allowed to explore the arms to obtain the food rewards. Entries to already-visited arms are scored as working memory errors and entries into arms not previously baited with food are scored as reference memory errors. Findings concerning the effect of acute nicotine on radial arm maze performance have been complex (Table 2). While a number of studies found that acute nicotine administration (0.07 or 0.14 mg/kg) improved performance in the radial arm maze in rats [123-125], others found either an effect in aged but not young rats [126] or variable effects across experiments [127, 128]. Furthermore, some studies found a lack of an effect at the same doses of nicotine as used in prior studies [129, 130] and one experiment found a trend towards a deficit [131].

Table 2
The effects of nicotine on the radial arm maze

In contrast to the variable effects with acute nicotine, chronic nicotine has been shown to improve radial arm maze performance. Studies have shown that multiple doses of chronic nicotine (3.4 mg/day (given via a Silastic pellet) or 5 and 12 mg/kg per day for 3 or 4 weeks) improve performance in the radial arm maze [126, 132-135]; however, two studies found no effect of treatment with 5 mg/kg per day for 4 weeks [136, 137]. It appears that the effects of chronic nicotine on this task remain after treatment stops as cessation of chronic nicotine treatment did not disrupt working memory but instead rats continued to outperform controls [132, 138].

Both α7 nAChRs and α4β2* nAChRs and the ventral hippocampus appear to be involved in spatial working memory and in the effects of nicotine on radial arm maze performance. Lesions of the ventral hippocampus blocked the effects of chronic nicotine on performance in the radial arm maze [134] and chronic nicotine reversed deficits induced by septohippocampal lesions [135]. Acute infusion of MLA or DHβE into the ventral hippocampus disrupted spatial working memory in the radial arm maze [139]. Furthermore, chronic infusion of DHβE into the ventral hippocampus also disrupted performance in the radial arm maze and nicotine ameliorated this deficit [131].

It is interesting that withdrawal from chronic nicotine does not disrupt performance in the radial arm maze [132, 138] in light of reports in humans that nicotine withdrawal disrupts working memory [140-142]. Most likely, different tasks are differentially affected by nicotine withdrawal due to the involvement of diverse neural areas and substrates in the various tasks. For example, the effects of nicotine on radial arm maze performance are mediated by the ventral hippocampus and chronic nicotine has been shown to increase nAChR number in the dorsal but not ventral hippocampus [117]. Thus, it is possible that the lack of withdrawal-associated disruption of radial arm maze performance could be related to a lack of change in ventral hippocampal nAChR number during chronic nicotine treatment. If this were the case and changes in nAChR number and/or function underlie withdrawal symptoms, then cognitive tasks that engage the dorsal hippocampus may be susceptible to the effects of withdrawal from chronic nicotine treatment.

The molecular mechanisms that may underlie the effect of nicotine on working memory have not yet been explored. Working memory generally relies upon fast neural transmission as information is kept online to assist in decision making [143]. Thus, neurotransmitter systems involved in such transmission, such as glutamate, acetylcholine, and GABA may underlie working memory by causing transitory changes in cell signaling similar to those involved in short-term memory. Given the interaction between nAChRs and glutamate (see “Contextual Learning” section), this would be a useful starting point for delineating the mechanisms by which nicotine alters spatial working memory. The mechanisms that underlie the effects of nicotine on working memory may contrast those that underlie the consolidation of long-term memories. Long-term memory is dependent upon gene transcription and protein synthesis [144, 145], processes that nicotine is capable of modifying [146, 147]. Therefore, nicotine likely alters working memory and long-term memory via distinct mechanisms. The mechanisms by which nicotine alters long-term memory has been explored using contextual learning as a model.

Contextual Learning

Both spatial learning and contextual learning involve the hippocampus [2, 3] but, until recently, few studies have examined the effects of nicotinic acetylcholinergic influences on contextual learning [148-153]. As contextual learning and spatial learning involve different brain regions [154, 155], different neurotransmitter receptor subtypes [156-158], different cellular substrates [159-162], and different genes [163], nicotine may alter one form of hippocampus-dependent learning through different cellular and molecular mechanisms than those involved in another form of hippocampus-dependent learning. Thus, the pattern of effects of nicotine, whether it be acute, chronic, or withdrawal from chronic nicotine treatment, in spatial learning may not be the same as in contextual learning.

Fear conditioning has proven to be a powerful tool for examining the effects of nicotine on contextual learning. In fear conditioning, animals are trained to form an association between conditioned stimuli (CS) and a foot shock unconditioned stimulus (US). Conditioned stimuli can be a discrete stimulus such as a tone or a complex, configural stimulus such as a context. One session of two training trials produces robust learning of two different associations, the auditory CS-shock association (i.e., cued conditioning) and the training context-shock association (i.e., contextual conditioning). Commonly, 24 h after conditioning, the strength of the contextual association is tested by returning the conditioned animal to the training chamber and scoring freezing, a behavioral measure of fear. Later, the strength of the cued association is tested by placing the animal in an altered context chamber that has features that are distinct from the training chamber. In the altered context chamber, generalized freezing is first measured. If animals have formed a specific contextual association with the training context, levels of freezing to the altered context should be low. After assessing altered context freezing, the auditory CS is sounded and the strength of the auditory CS-shock association is measured.

This paradigm allows the investigator to measure two associations in the same subject; specifically a context-US association and a discrete cue-US association. Importantly, these two associations involve different neural substrates. Learning to associate the context with the US is hippocampus and amygdala dependent ([164, 165] reviewed in [166]); the dorsal hippocampus appears to be particularly important for forming contextual associations [167-169]. On the other hand, learning to associate the auditory CS with the foot shock US involves many of the same brain regions as contextual fear conditioning but not the hippocampus [164]. Thus, fear conditioning allows for the assessment of both hippocampus-dependent and hippocampus-independent learning in the same animal after a single training session. This not only allows experimenters to compare the effects of drugs on two different types of learning and potentially identify neural substrates involved in the effects of the drugs but also provides built-in controls that facilitate understanding of the drug effects. For example, if a drug alters both contextual and cued fear conditioning, this suggests that the drug is acting on processes common to both types of learning (e.g., common learning and neural processes, anxiety, shock sensitivity, attention, or locomotor activity). However, if a drug only alters contextual conditioning, this suggests that the drug is acting on processes specific to the context-US association.

Just as the neural substrates of fear conditioning are well defined, the underlying molecular substrates have also been identified [170]. NMDA receptors are critically involved in fear conditioning [171-173]. Activation of NMDA receptors can lead to activation of multiple cell signaling molecules involved in learning that include cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), calmodulin kinase II, and extracellular-regulated kinase (ERK) [174-176]. Furthermore, both PKA and ERK can activate cAMP response element binding protein (CREB), a gene transcription factor involved in fear conditioning [177, 178]. The same molecular targets underlying fear conditioning have also been shown to be involved in LTP [76], and many of these substrates have been shown to be altered by nicotine [44, 47, 179]. Thus, the next step in identifying the cellular substrates of the effects of nicotine on contextual learning is to identify if nicotine administration during conditioning alters these substrates and in which brain region nicotine is acting to alter these processes.

Numerous studies have shown that nicotine given prior to training and testing enhances contextual fear conditioning but not cued fear conditioning in mice (Table 3) [148-151, 180-183], an effect that lasts at least 1 week [150]. These effects are dose dependent as a 0.09-mg/kg dose of nicotine that produces plasma nicotine levels in mice similar to those in smokers (of about 0.1 μM [184]) enhances learning [149, 150, 180, 181, 183, 184] but higher doses of nicotine disrupt contextual fear learning [148, 185]. The specificity of the effects of nicotine on contextual but not cued fear conditioning suggests that nicotine is not altering common processes that would affect both contextual and cued fear conditioning such as anxiety, locomotor activity, or attention. Furthermore, these behavioral results suggest that nicotine is either acting in the hippocampus or areas efferent or afferent of the hippocampus to enhance contextual conditioning. In support of direct effects in the hippocampus, infusion of nicotine (0.35 μg) into the hippocampus enhanced contextual fear conditioning but had no effect on cued fear conditioning [186]. Furthermore, infusions above the hippocampus into cortex or below the hippocampus into thalamus, two areas that also have a high density of nAChRs [32, 65], were without effect on fear conditioning. These results strongly suggest that nicotine works in the hippocampus to enhance contextual fear conditioning and provides a target neural area to examine for nicotine-induced changes in cellular, molecular, and genetic processes during learning.

Table 3
The effects of nicotine on contextual fear conditioning

Once a neural area involved in the behavioral effects of nicotine on contextual fear conditioning is identified, the chain of underlying neurobiological events from the level of receptor activation to changes in protein activation and gene expression in that area can be studied. Nicotine is most likely altering contextual fear conditioning through actions at nAChRs. Whereas there are multiple nAChRs, the α7 and α4β2* nAChRs are the two predominant nAChRs in the central nervous system and both are highly expressed in the hippocampus [65, 187]. The broad-spectrum nAChR antagonist mecamylamine blocks the enhancement of contextual fear conditioning by nicotine [148]. While this suggests that nicotine is enhancing contextual fear conditioning through receptor-mediated processes, it also provides a hint as to what nAChR subtypes may be involved. Mecamylamine has higher affinity for α4β2* nAChRs than α7 nAChRs [34, 188]. This leads to a prediction that altering α4β2* nAChR function will alter the enhancement of contextual fear conditioning by acute nicotine. This has been tested both genetically and pharmacologically. The α4β2 nAChR antagonist DHβE blocked the enhancement of contextual fear conditioning by nicotine but the α7 nAChR antagonist MLA did not [180, 186]. In addition, no enhancement of contextual fear conditioning by nicotine was seen in β2 KO mice but enhancement was seen in α7 KO mice [189, 190]. Neither genetic disruption of nAChRs nor nAChR antagonists disrupted fear conditioning in young mice ([148, 152, 153, 180, 186, 189] but see [190]) suggesting that, unlike in the radial arm maze, nAChRs modulate contextual fear conditioning but activation of nAChRs is not necessary for fear conditioning to occur.

To further examine the involvement of both the hippocampus and α4β2* nAChRs in the enhancement of contextual fear conditioning, mice received direct infusion of DHβE into the hippocampus paired with systemic nicotine treatment. Systemic nicotine enhanced contextual fear conditioning in vehicle-infused mice, as would be expected based on prior results [148, 151, 181], but nicotine did not enhance contextual fear conditioning in mice that received hippocampal infusions of DHβE [186]. These results further support the argument that the hippocampus is critically involved in the effects of nicotine on contextual fear conditioning and that hippocampal α4β2* nAChRs mediate these effects. In addition, these results, in conjunction with the finding that nicotine infused into the hippocampus is sufficient to enhance contextual fear conditioning [186], demonstrate that nicotine is acting in the hippocampus and not in another structure in parallel to enhance contextual fear conditioning. If nicotine were acting in parallel in multiple areas to enhance contextual fear conditioning, inhibition of nAChRs in the hippocampus should not block the enhancement because nAChRs in areas working in parallel could still contribute to the enhancement of learning.

The cellular mechanism(s) through which nicotine enhances contextual learning are not yet clear. Nicotine both activates and desensitizes nAChRs [23, 25]. Thus, acute systemic nicotine may enhance contextual fear conditioning via activation, desensitization, or activation and subsequent desensitization of α4β2* nAChRs. However, if desensitization of α4β2* nAChRs is critical for the effect of acute systemic nicotine on contextual fear conditioning, then functional inactivation of these receptors should also enhance contextual fear conditioning. However, no deficits in fear conditioning were seen in β2 KO mice, mice treated with mecamylamine or DHβE [148, 152, 153, 180, 186, 189]. Thus, α4β2 nAChR activation or activation followed by desensitization must be the mechanism through which acute nicotine enhances contextual fear conditioning.

As stated, α4β2* nAChRs are not critically involved in contextual fear conditioning but instead modulate the learning. This suggests that, during contextual fear conditioning, nicotine may alter cell signaling pathways that underlie the learning. The glutamate system is critically involved in fear conditioning; inhibition of NMDA receptors disrupts fear conditioning [171-173]. If NMDA-receptor-mediated activation of PKA, ERK, and CREB underlie contextual fear conditioning, then modulation of these cell-signaling molecules by nicotine could enhance contextual conditioning. Multiple studies suggest that nAChRs and glutamate receptors may interact to support learning. nAChRs could contribute to the cellular depolarization necessary for NMDA receptor activation. Allen and colleagues [191] demonstrated that basal forebrain neurons, which provide the primary cholinergic innervation of the hippocampus, corelease acetylcholine and glutamate. It is possible that corelease of acetylcholine and glutamate could lead to nAChR facilitation of NMDA receptor activation. In support, numerous studies have shown that nAChRs mediate excitatory currents in hippocampal neurons [192-194]. In fact, Ji et al. [91] demonstrated that currents mediated by postsynaptic hippocampal pyramidal cell nAChRs could contribute to the depolarization necessary to remove the magnesium block of NMDA receptors.

Experimental data support the contention that the nAChR-mediated and glutamate-receptor-mediated processes interact during contextual fear conditioning. Whereas administration of the AMPA receptor antagonist NBQX alone [195] or mecamylamine alone [148] did not alter fear conditioning, coadministration of NBQX and mecamylamine disrupted contextual fear conditioning [196]. This supports the hypothesis proposed by Ji et al. [91] that nAChRs in the hippocampus, similar to AMPA receptors, could contribute to the depolarization necessary to remove the magnesium block of NMDA receptors. In addition to interacting with AMPA receptors, nAChRs could also interact with NMDA receptors during contextual fear conditioning. In support, mice treated with a dose of the NMDA receptor antagonist MK801 that was subthreshold for altering fear conditioning showed disrupted contextual fear conditioning when also treated with mecamylamine [196]. Thus, mecamylamine, while having no effect on fear conditioning alone, shifts the dose response curve for MK801 disruption of fear conditioning to the left. This suggests that, during fear conditioning, nAChR and NMDA receptors may be mediating similar processes. Both nAChRs and NMDA receptors gate calcium and therefore both receptors could contribute to the activation of calcium-mediated cell signaling [31, 197]. Thus, during contextual fear conditioning, nAChRs and glutamate receptors may interact and support similar processes involved in the synaptic plasticity necessary for contextual fear conditioning. Nicotine may enhance contextual fear conditioning by increasing the contribution of nAChRs to those processes.

As stated earlier, both NMDA-receptor-mediated and nAChR-mediated processes can activate ERK and ERK is critically involved in contextual fear conditioning [47, 179, 198]. Hence, nicotine could enhance contextual fear conditioning by increasing signaling through the ERK pathway. In support, a dose of the ERK inhibitor SL327 that was subthreshold for disrupting contextual fear conditioning blocked the enhancement of contextual fear conditioning by nicotine [199]. Whereas further work is needed to fully elucidate the complete mechanisms involved in the enhancement of contextual fear conditioning by acute nicotine, to date, we know that nicotine acts in the hippocampus at α4β2* nAChRs to enhance contextual fear conditioning and that interactions between nAChRs and glutamate receptors may lead to enhanced activation of ERK and increased contextual fear conditioning.

In addition to acute nicotine interacting with learning processes to alter plasticity, chronic nicotine treatment may directly cause changes to the brain that result in altered learning. No enhancement of contextual learning was seen in mice treated chronically for 14 days with a dose of nicotine (6.3 mg/kg per day) that produced the same plasma nicotine level as the acute dose of nicotine (0.09 mg/kg) that enhanced learning and yielded plasma nicotine levels well within the range seen in smokers [184]. A similar noneffect of chronic nicotine on contextual fear conditioning was obtained in rats treated with 0.21 mg/kg per day via daily subcutaneous injections [185]. These results suggest that chronic nicotine treatment alters neural function and results in tolerance for the effects of nicotine on contextual fear conditioning.

If chronic nicotine alters hippocampal processes involved in contextual fear conditioning, then administration of a nAChR antagonist to mice treated chronically with nicotine may disrupt contextual fear conditioning. Furthermore, withdrawal of nicotine treatment could also disrupt contextual fear conditioning. Both scenarios have been demonstrated to be true. Whereas administration of DHβE to control mice before conditioning has no effect [180], administration of DHβE to mice treated chronically with nicotine disrupted contextual fear conditioning [200]. This suggests that chronic nicotine treatment alters neural function underlying contextual fear conditioning by modifying either nAChRs and/or processes mediated by nAChRs. Withdrawal studies also provide support for the contention that chronic nicotine treatment results in neural changes that alter contextual fear conditioning. Numerous studies have demonstrated that 24 h after withdrawal from 12 days of chronic nicotine treatment contextual but not cued fear conditioning was disrupted [183, 184, 200-203]. These findings suggest that withdrawal alters processes specific to contextual fear conditioning and not processes that could affect both cued and contextual fear conditioning. Thus, acute nicotine enhances contextual fear conditioning but chronic nicotine treatment produces neural adaptations that results in tolerance and withdrawal deficits in contextual conditioning when treatment terminates. Interestingly, contextual but not cued conditioning in rats is enhanced 2 weeks following termination of 14 days of twice daily injections using a ramping procedure from 0.5 to 1.1 mg/kg [204]. This suggests that withdrawal effects may not only dissipate but may rebound resulting in effects opposite of those that occur immediately following withdrawal. Further work needs to be done to identify when changes occur during withdrawal and how long they last.

It is currently unknown if the same processes that are involved in the enhancement of contextual fear conditioning by nicotine are altered by chronic nicotine treatment. It has been demonstrated, however, that the same nAChR subtypes involved in the effects of acute nicotine on contextual fear conditioning are involved in the nicotine withdrawal deficits in contextual fear conditioning. Mice lacking the β2 nAChR subunit did not show nicotine withdrawal disruption of contextual fear conditioning but wild-type littermates did and DHβE precipitated withdrawal [200]. In contrast, α7 nAChR KO mice displayed nicotine-withdrawal-induced disruption of contextual fear conditioning. These results suggest that both the acute effects of nicotine and changes in neural function that occur during chronic nicotine treatment are mediated by α4β2* nAChRs. This is only the first step in exploring if the acute and chronic effects of nicotine on contextual fear conditioning involve the same substrates.

Nicotine, Contextual Learning, and Addiction

While the hippocampus is associated with learning and declarative processes, an increasing amount of work suggests that the hippocampus is also a substrate of addiction. Numerous studies have shown that the hippocampus is involved in developing context-drug associations. For instance, the dorsal hippocampus is involved in contextual reinstatement of cocaine-seeking behavior and the ventral hippocampus is involved in cued reinstatement of cocaine-seeking behavior [13]. In addition, inhibition of protein synthesis in the hippocampus disrupts morphine-conditioned place preference [205]. This result suggests that changes in gene expression in the hippocampus could contribute to addictive behaviors; this has been supported by multiple studies. Exposure to ethanol-associated contextual stimuli reinstated drug-seeking behavior and increased hippocampal c-fos expression in rats previously trained to self-administer ethanol [206]. Similarly, training in conditioned place preference for amphetamine increased c-fos expression in the hippocampus of rats [207]. Furthermore, extended training in a morphine-conditioned place preference paradigm altered gene expression in the hippocampus of rats [208]. Changes in gene expression are not limited to laboratory animals. An examination of gene expression in postmortem hippocampi from cocaine abusers found significant dysregulation of genes related to synaptic plasticity and neuronal structure [14], suggesting that drug abuse changes the function and structure of the hippocampus. These changes may underlie formation of maladaptive drug-cue associations. In support, smoking-related cues evoked changes in hippocampal activity in smokers but not nonsmokers [209-211]. Thus, drug-induced changes in hippocampal function could facilitate the formation of maladaptive drug-cue and drug-context associations that could facilitate cravings and continued use. Continued use could lead to further functional and structural changes in the hippocampus and other brain regions that could contribute to withdrawal symptoms as well as impaired decision making associated with addiction.

The hippocampus is one part of an interconnected network of neural structures involved in both learning and addiction. Thus, changes to the hippocampus may alter more than just hippocampal function. The hippocampus has efferent connections with many brain regions involved in addiction such as the amygdala, prefrontal cortex, and the ventral striatum [15, 212]. Because one function of the hippocampus is facilitating long-term memory storage in other areas, alterations in hippocampal function could also alter function in other areas involved in drug abuse and addiction. The hippocampus receives dopaminergic input from midbrain dopamine cells and in turn projects to the prefrontal cortex and ventral striatum, areas involved in behaviors such as impulse control, decision making, and reward evaluation [15]. Increased dopaminergic input to the hippocampus due to drug intake and subsequent output to areas important for behaviors related to addiction could result in the formation of strong maladaptive contextual associations. In support, it has been proposed that the hippocampus may provide information about novelty that stimulates dopamine release from the ventral tegmental area [213]. Thus, the effects of drugs of abuse, such as nicotine, on hippocampal function not only could contribute to addiction through facilitating the development of maladaptive associations that maintain drug-seeking behavior but may also facilitate the development of long-lasting changes in other structures involved in addiction.

The studies reviewed demonstrate how nicotine can alter synaptic plasticity and learning and also suggest how the effects of nicotine on learning could contribute to nicotine addiction. For example, acute nicotine enhances contextual conditioning via high-affinity nAChRs in the hippocampus, most likely α4β2* nAChRs [186]. This ability of nicotine to enhance cognitive processes may reinforce repeated use while facilitating the development of drug-context associations that can trigger cravings. This possibility is supported by studies showing that animals will develop a learned preference for a context associated with nicotine [214-216]. Repeated nicotine use may transition into chronic use, which could alter neuronal function resulting in tolerance and cognitive deficits when nicotine is withdrawn. Data from studies in mice have shown that tolerance for the effects of nicotine on contextual conditioning develops with chronic administration and deficits occur when treatment ceases [184]. In addition, numerous studies of smokers have demonstrated that nicotine withdrawal disrupts cognitive function [141, 142, 217, 218]. These deficits, along with cued and context-evoked cravings, could lead to relapse. Not surprisingly, changes in cognition during abstinence are predictive of relapse [219]. Thus, examining how nicotine alters different types of learning will further our understanding of the neural substrates of learning and aid in understanding how nicotine-associated changes in behavior can lead to addiction.

Summary

In comparing the effects of nicotine on LTP, spatial learning, spatial working memory, and contextual learning, it is clear that the effects of nicotine vary across tasks. Studies in LTP demonstrate that nicotine has differential effects on synaptic plasticity depending upon the hippocampal regions examined and the different nAChR subtypes involved. This may explain the range of effects of nicotine on different hippocampus-dependent tasks. For instance, whereas the dorsal hippocampus and α4β2* nAChRs are involved in the enhancement of contextual fear conditioning by nicotine [186], the ventral hippocampus and both α7 and α4β2* nAChRs [136, 137, 220] appear to be involved with the effects of nicotine on spatial working memory. Thus, results from one type of hippocampus-dependent learning do not necessarily extend to other types of hippocampus-dependent learning. This should not be surprising because different types of hippocampus-dependent learning involve different neural and cellular substrates [154-161, 163, 221].

Overall, the findings discussed in this review provide insight into the molecular, cellular, and behavioral mechanisms by which nicotine alters declarative memory processes via changes in hippocampal function. These findings have implications for understanding schizophrenia, Alzheimer’s disease, and, in particular, nicotine addiction. Such work lays the foundation for the development of new treatments for those afflicted with these potentially lifechanging disorders.

Acknowledgements

We thank Karen Coletti for assistance with the figure and acknowledge excellent suggestions from anonymous reviewers. Cited work from the authors’ laboratory was funded in part by the National Institute on Drug Abuse (NIDA) grant DA017949 (TJG) and the National Institute on Alcohol Abuse and Alcoholism grant AA015515 (TJG). JWK was supported by NIDA training grant DA07237.

Footnotes

1Studies that use nicotine tartrate salt vary in whether they report doses based on salt weight or nicotine base weight. When studies reported doses as salt weight, we converted them to free base. If a study did not specify, we used the dose they reported. For a detailed discussion of this, see [17].

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