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Official websites use. Share sensitive information only on official, secure websites. It has long been hypothesized that conditioning mechanisms play major roles in addiction. Specifically, the associations between rewarding properties of drugs of abuse and the drug context can contribute to future use and facilitate the transition from initial drug use into drug dependency. On the other hand, the self-medication hypothesis of drug abuse suggests that negative consequences of drug withdrawal result in relapse to drug use as an attempt to alleviate the negative symptoms. In this review, we explored these hypotheses and the involvement of the hippocampus in the development and maintenance of addiction to widely abused drugs such as cocaine, amphetamine, nicotine, alcohol, opiates, and cannabis. Studies suggest that initial exposure to stimulants i. In line with the self-medication hypothesis, withdrawal from stimulants, ethanol, and cannabis results in hippocampus-dependent learning and memory deficits, which suggest that an attempt to alleviate these deficits may contribute to relapse to drug use and maintenance of addiction. Interestingly, opiate withdrawal leads to enhancement of hippocampus-dependent learning and memory. Given that a conditioned aversion to drug context develops during opiate withdrawal, the cognitive enhancement in this case may result in the formation of an augmented association between withdrawal-induced aversion and withdrawal context. Therefore, individuals with opiate addiction may return to opiate use to avoid aversive symptoms triggered by the withdrawal context. Overall, the systematic examination of the role of the hippocampus in drug addiction may help to formulate a better understanding of addiction and underlying neural substrates. Addiction is a major worldwide health problem that results in maladaptive behavioral changes, some that can last a lifetime. This behavioral plasticity, often times maladaptive, must be associated changes in neural plasticity. In fact, it has been noted multiple times that there is a high degree of overlap between the neurobiology of learning and memory and the neurobiology of addiction e. Drugs of abuse are often linked to disrupted learning, but the relationship between drugs of abuse and learning is more complex as drug use and abuse is also associated with the development of strong but maladaptive memories that contribute to drug-seeking behavior and addiction. It is the overarching premise of this review that initial or acute use of drugs can facilitate the development of maladaptive memories between drug effects and environmental stimuli and that these associated memories can exert strong behavioral control and facilitate drug-seeking behavior and relapse. With continued use of drugs, learning deficits emerge along with cognitive inflexibility. While there are multiple types of learning, this review will focus on hippocampus-mediated learning. The hippocampus is perhaps the iconic brain region associated with learning and memory. For instance, the work of Scoville and Milner with patient H. The patient H. This is particularly problematic because declarative memories contribute to self-definition as they encompass memories of events and autobiographical memories. As part of an essential role in declarative memory formation, the hippocampus is especially good at binding information together to form complex representations Sutherland and Rudy ; for review, see Yonelinas that are necessary for spatial and contextual memory formation O'Keefe and Dostrovsky ; Kim and Fanselow ; Kim and Lee ; Loureiro et al. In addition to involvement in long-term declarative memory formation, the hippocampus is also well known as one of the brain regions that demonstrate a high-level synaptic plasticity, often assessed by changes in long-term potentiation LTP ; Teyler and DiScenna ; Lynch et al. The high degree of plasticity in the hippocampus and the ability of this region to support contextual and declarative memories may facilitate drug-induced changes in hippocampal function that have a profound effect on behavior. It is clear that the physiological effects of drugs of abuse can become associated with contextual information, contributing to future drug-seeking behavior Bardo et al. Because of the critical role of the hippocampus in learning contextual information Smith and Mizumori , drug-associated changes in hippocampal function may contribute to the development of maladaptive drug-context associations. With continued drug use, adaptations including tolerance occur and these changes could disrupt hippocampal function. Chronic drug use is often associated with cognitive deficits Ornstein et al. Furthermore, withdrawal symptoms for multiple drugs of abuse include cognitive deficits Solowij ; Jacobsen et al. It is beyond the scope of this review to discuss all drugs of abuse; therefore, we will focus on cocaine, amphetamine, nicotine, ethanol, opiates, and cannabis, examining for each drug the effects of acute administration, chronic administration, and withdrawal on hippocampus learning and hippocampal synaptic plasticity. In addition, because there is substantial evidence showing that self-administration and yoked-administration of drugs result in the same effects on hippocampal plasticity Thomas and Everitt ; Thomas et al. Evidence from human subject studies along with laboratory animal studies will be reviewed. Cocaine, a highly addictive psychostimulant derived from the leaf of Erythroxylon coca , is often characterized by compulsive use and obsessive drug seeking Dackis and O'Brien Cocaine addiction affects roughly 2 million people in the USA, with 1. Department of Health and Human Services In addition to cocaine's negative health consequences including cardiovascular, pulmonary, and psychiatric complications Brody et al. These figures highlight cocaine addiction as a disease with devastating consequences; thus, understanding the processes underlying the development and maintenance of cocaine addiction is vital. Despite its negative health consequences, when acutely administered cocaine activates the brain's reward circuitry, producing a euphoric state that serves as a reinforcer for future cocaine use Volkow et al. In addition to the pleasurable effects, acute cocaine has also been shown to improve cognition in humans Garavan et al. In support of this hypothesis, studies have shown that laboratory rodents learn to self-administer cocaine e. The rewarding effects of cocaine are so powerful that a number of studies have shown that an especially addiction-prone subset of laboratory animals trained to self-administer cocaine prefer cocaine over feeding and mating and compulsively self-administer cocaine at fatal rates Deneau et al. This suggests that the coupling of cocaine's procognitive effects with overstimulation of the reward system may result in dysregulated behavioral outcomes rather than enhancement of behavioral control. There are several brain regions within the mesolimbic circuit that are directly affected by cocaine, including reward-related regions such as the nucleus accumbens and ventral tegmental area as well as regions that control cognition such as the prefrontal cortex and hippocampus Bardo ; Thomas et al. Among these regions, the hippocampus may be a critical site for both the rewarding effects of acute cocaine Kuhar et al. For example, permanent lesions of the dorsal, but not ventral hippocampus, as well as temporary inactivation of the dorsal hippocampus by local muscimol infusions impaired cocaine conditioned place preference CPP; Meyers et al. Similarly, studies suggest that the dorsal hippocampus controls context-induced reinstatement Fuchs et al. In contrast to the dorsal hippocampus, the ventral hippocampus has been shown to mediate cue-induced and cocaine-primed reinstatement of cocaine self-administration Rogers and See ; Ramirez et al. Moreover, Vorel et al. It is also possible that dorsal and ventral hippocampus may differentially contribute to the stress-induced relapse to cocaine seeking as studies have shown that stress affects synaptic plasticity in these regions in opposite ways. That is, while stress diminished synaptic plasticity in the dorsal hippocampus, ventral hippocampal synaptic plasticity was enhanced by stress Maggio and Segal , ; Segal et al. Therefore, ventral hippocampus may assume a greater role in reinstatement of cocaine-seeking behavior during a period of high stress such as cocaine withdrawal. But this hypothesis has not been directly examined. These studies establish the hippocampus as the focal region for the formation and maintenance of long-term memories that support cocaine-context and cocaine-cue associations. In support of the hippocampus as the primary target of cocaine in modulating drug-related memories, acute cocaine has also been shown to alter hippocampal LTP, a form of synaptic plasticity that may underlie learning and memory Bliss and Collingridge However, the effects of cocaine on LTP are mixed see Table 1 for a summary of results. For example, Smith et al. In support of the differential effects of low and high doses of cocaine on LTP, Thompson et al. Also in line with these results, Wood et al. Given that, in the absence of tolerance to cocaine, it is likely that most first-time cocaine users initially administer lower doses of cocaine, and therefore, they are subject to both rewarding and procognitive effects, which may underlie enhanced hippocampal plasticity that leads to maladaptive drug-associated memories. In addition to acute cocaine-induced enhancement of hippocampal LTP, there is also evidence showing that acute cocaine positively modulates the activation of the proteins within the cell signaling cascades that support long-term memory formation. Similarly, phosphorylation of hippocampal cAMP-response element binding protein CREB , a transcription factor that plays a major role in synaptic plasticity and long-term memory formation Abel and Lattal ; Trifilieff et al. For example, Cervo et al. These results suggest that within a limited dose range, acute cocaine augments hippocampal plasticity and activity of cell signaling cascades that support hippocampal LTP, which may enhance the formation of the maladaptive drug-context memories. It is possible that augmented hippocampal function may result in drug-context-triggered cravings and drug seeking as initial cocaine use turns into cocaine addiction with chronic cocaine abuse. In contrast to acute cocaine's procognitive effects, chronic cocaine users have been repeatedly shown to exhibit a variety of neuropsychological deficits ranging from disrupted executive function, visuoperception, and psychomotor function Bolla et al. These deficits were positively correlated with the severity of cocaine addiction Ardila et al. Accordingly, chronic cocaine administration also leads to impaired spatial learning in rodents that were exposed to cocaine during adulthood Mendez et al. Chronic cocaine-induced learning deficits also seem to be long-lasting as studies suggest that the impairing effects of chronic cocaine exposure persist during cocaine withdrawal Kelley et al. These studies suggest that chronic cocaine exposure may result in a diminished ability to learn new associations. This effect of chronic cocaine use may be particularly problematic because inability to change established drug-context associations or to learn new associations that may counteract the maladaptive ones may facilitate the maintenance of cocaine addiction. For example, exposure therapy for addiction focuses on reversing learned drug-context and drug-cue associations to reduce context or cue-triggered craving, drug seeking, and drug relapse Rosenthal and Kutlu Reduced ability to make new associations during chronic cocaine use or cocaine withdrawal may disrupt cognitive flexibility and increase the likelihood of relapse. Importantly, reduced hippocampal function during chronic cocaine use and cocaine withdrawal may be responsible for the decreased ability to form adaptive associations to counteract context-drug memories as studies found that hippocampal function was altered with chronic administration of cocaine London et al. For example, cocaine administration produced increased BOLD signal in the hippocampus of cocaine-dependent human subjects compared with saline administration Breiter et al. Also, chronic cocaine self-administration resulted in reduced glucose metabolism in the hippocampus in humans and nonhuman primates London et al. These results suggest a central role for changes in the hippocampus in cocaine-induced cognitive deficits. However, in contrast to reduced hippocampus-dependent learning during chronic cocaine and withdrawal, there is also evidence showing that chronic in vivo cocaine administration resulted in enhanced LTP Thompson et al. Thompson et al. In line with these results, other studies found enhanced LTP 3 d after chronic cocaine administration Guan et al. Interestingly, Thompson et al. In line with the results of Thompson et al. Therefore, there is a potential discrepancy between behavioral studies showing disrupted hippocampal learning and memory Melnick et al. These contradicting results might have risen because of the fact that behavioral studies cited in this review tested their subjects in long-term withdrawal between 5 wk and 4 mo. Importantly, Thompson et al. In support of this hypothesis, Del Olmo et al. Thus, the dose of cocaine and the length of time from the last drug administration seem to be major determinants of cocaine's effects on hippocampal learning and memory and may explain some of the cognitive deficits exhibited by cocaine users. It is also important to note that increased LTP does not necessarily mean increased learning Saucier and Cain Overall, the studies cited clearly show that initially cocaine enhances hippocampus-dependent learning and memory resulting in strong cocaine-context associations, which may lead to drug-seeking behavior and chronic cocaine abuse. In turn, chronic cocaine exposure alters hippocampus function and results in hippocampal cognitive deficits during withdrawal, which may contribute to impaired cognitive flexibility and inability to reverse cocaine-context associations, contributing to relapse. However, the euphoric effects of amphetamine were quickly discovered and subsequently amphetamine has been abused for its rewarding properties such as sensations of pleasure, self-confidence, energy, and alertness CDC In the USA, early studies that provided a platform for the prescription of amphetamine to reverse combat fatigue largely ignored its addictive properties Guttmann and Sargant ; Tidy ; Bett , which resulted in a widespread prescription of amphetamine-based medications and eventually amphetamine addiction peaked in mids CDC Today amphetamine dependence is a widespread problem CDC Moreover, the rate of amphetamine or methamphetamine abuse-related hospitalization more than tripled between the years and SAMHSA a. Importantly, despite its initial pleasurable effects, amphetamine has serious negative health consequences with prolonged abuse. These effects include physical symptoms such as decayed teeth, weight loss, skin lesions, stroke, and heart attack as well as mental symptoms such as paranoia, hallucinations, anxiety, irritability, social isolation, aggressiveness, and violence CDC Shortly after its initial release as a prescription drug in , procognitive effects of amphetamine e. These initial studies were later confirmed by studies showing enhanced memory consolidation Soetens et al. Because of its attention-improving properties amphetamine was used to treat ADHD but then this treatment was replaced by drugs with fewer psychoactive side effects Wilens et al. Animal studies also showed that, similar to other stimulants, acute amphetamine and methamphetamine enhanced hippocampus-dependent learning and memory in the T-maze Ito and Canseliet , Morris water maze Packard and McGaugh ; Brown et al. However, these procognitive effects were dose-dependent as higher doses of acute amphetamine resulted in deficits in hippocampus-dependent learning and memory Blokland et al. Studies also showed that amphetamine and methamphetamine produced significant CPP Carr et al. In line with acute amphetamine's enhancing effects on hippocampus-dependent learning and memory, hippocampal LTP was also increased by acute amphetamine Delanoy et al. This hypothesis is supported by the results showing that acute injections of amphetamine enhanced morphine CPP Blaiss and Janak and conditioned approach to sucrose Blaiss and Janak Together with studies showing that acute amphetamine produced procognitive effects as well as enhanced hippocampal plasticity, these results show that development of amphetamine-dependence may be influenced by augmentation of drug-context associations. In spite of its acute procognitive effects, chronic use of amphetamine and methamphetamine has devastating effects on cognition, including impaired memory, attention, cognitive flexibility, cognitive inhibition, and decision making Ornstein et al. These cognitive deficits persist during amphetamine and methamphetamine withdrawal Kalechstein et al. Similar to results from human studies, animal studies also indicate cognitive deficits in hippocampus-dependent spatial learning tasks such as the spatial object recognition, T-maze and Morris water maze during amphetamine Mandillo et al. In addition, there is evidence showing that deficits in the hippocampus-dependent learning and memory paralleled reductions in hippocampal LTP induced by methamphetamine withdrawal Swant et al. These results indicate that amphetamine withdrawal disrupts cognition, including hippocampus-dependent learning and memory and associated hippocampal plasticity. These cognitive problems may underlie relapse to amphetamine use as amphetamine administration may be seen as a way to self-medicate these deficits. Overall, similar to other stimulants, when administered acutely amphetamine has procognitive effects including enhanced hippocampus-dependent learning and memory. Acute amphetamine's procognitive properties may result in augmentation of drug-context associations and contribute to the development of amphetamine addiction. In contrast, withdrawal of amphetamine following chronic use results in deficits in hippocampus-dependent learning and memory. In addition to the failure to reverse already established drug-context associations, relapse to amphetamine use may be motivated by attempts to self-medicated for withdrawal-induced cognitive deficits. Accordingly, active and passive tobacco use has been causally linked to deaths from cancer, cardiovascular disease, and pulmonary disease Sandler et al. Although nicotine, the main psychoactive component in tobacco, may play less of a role in the development of these conditions compared with other toxins in the tobacco extract, it is the main component leading to addiction. Therefore, by causing repeated use and prolonged exposure to toxins, nicotine should be considered as the indirect cause of the smoking-related diseases and deaths Benowitz Nicotine's rewarding effects seem to play a major role in the development of nicotine dependence Watkins et al. In humans, nicotine results in euphoria, increased energy and arousal, and suppressed anxiety Pomerleau and Pomerleau , ; Stolerman and Jarvis ; Benowitz Accordingly, in animals, acute injections of nicotine leads to CPP Fudala et al. Similarly, there is also evidence showing that smokers learn to associate nicotine's effects with specific contexts and cues Dols et al. In addition to its rewarding effects, acute nicotine has cognitive enhancing properties in humans. Specifically, acute nicotine administration enhances attention Parrott and Craig ; Bates et al. In agreement with human studies, there is a great body of evidence suggesting that acute nicotine augments hippocampus-dependent contextual and spatial learning and memory while not affecting hippocampus-independent subtypes of learning e. For example, numerous studies from both our group and other laboratories showed that acute nicotine enhanced hippocampus-dependent contextual and trace fear conditioning, but not cued fear conditioning Gould and Wehner ; Gould and Higgins ; Gould a ; Gould and Lommock ; Gould et al. It is possible that the formation of nicotine-context associations may benefit from these procognitive effects of acute nicotine. That is, through promoting hippocampal plasticity, acute nicotine may enhance formation of drug-context associations and promote future nicotine use evoked by contextual and environmental cues. In support of this hypothesis, there is evidence showing that contextual cues associated with nicotine reward reinstate extinguished nicotine self-administration in rats Diergaarde et al. Therefore, these studies support the possibility that acute nicotine-induced enhancement of hippocampus-dependent learning and memory may contribute to development of nicotine-dependence. Once nicotine dependence is established, it is especially difficult to reverse habitual use of nicotine. One of the main contributors to this low rate of successful quitting is the negative symptoms experienced during nicotine withdrawal. Negative symptoms include irritability and restlessness, anxiety, social problems, increased food consumption, constipation, and craving for nicotine Benowitz In addition to these general symptoms, cognitive deficits such as difficulty concentrating Pomerleau et al. In line with these reports, animal studies also showed that while chronic nicotine did not have any effect on hippocampus-dependent contextual and trace fear conditioning, nicotine withdrawal impaired hippocampal learning and memory Davis et al. Overall, human and animal studies demonstrate hippocampus-dependent learning and memory enhancement during initial nicotine exposure and cognitive deficits during nicotine withdrawal. These results may suggest that initial nicotine exposure results in strong nicotine-context associations that support drug-seeking behavior, which may facilitate the transition into chronic nicotine use. Chronic use leads to neuronal adaptations that produce tolerance to the enhancing effects of nicotine and withdrawal deficits in hippocampus learning Wilkinson et al. Importantly, the nicotine withdrawal deficits in learning may increase the chance of relapse to avoid these negative symptoms. In line with this interpretation is the self-medication hypothesis of addiction, which states that one of the major contributors to addiction is the drive to reduce the negative symptoms that arise during drug withdrawal Khantzian In support, nicotine has been shown to alleviate cognitive deficits in various mental disorders such as schizophrenia Adler et al. Also in support of the self-medication hypothesis, there is evidence showing that cognitive deficits during nicotine withdrawal predict future relapse to nicotine use Rukstalis et al. Thus, increased relapse to nicotine use during withdrawal may be a mechanism to self-medicate for withdrawal-induced cognitive deficits akin to what occurs with the cognitive impairments seen in mental disorders. As the previous section explained, while acute nicotine enhances hippocampus-dependent learning and memory, these processes are disrupted during nicotine withdrawal. Evidence from electrophysiology studies support these conclusions and suggest that altered hippocampal plasticity by acute nicotine and withdrawal from chronic nicotine is largely responsible for these effects. For example, Alkondon et al. In addition to the effects of acute administration of nicotine and other direct nAChR agonists, hippocampal plasticity has been shown to be altered during nicotine withdrawal. For example, Yamazaki et al. Therefore, the alterations of hippocampal LTP are in parallel with behavioral effects of acute nicotine and nicotine withdrawal on hippocampus-dependent learning. Thus, altered LTP may underlie the development of nicotine addiction through formation of drug-context associations during early use and the development of cognitive deficits during chronic use and withdrawal. For example, Gould et al. Similarly, the same study also showed a temporal shift in learning-related dorsal hippocampal PKA peak activation as a result of systemic acute nicotine administration. Finally, nicotine also modulates the activation of the transcription factor CREB in the hippocampus. Overall, the above-mentioned studies provide strong evidence indicating that nicotine's control over hippocampal cell signaling cascades and consequently hippocampal plasticity may be an underlying factor for enhancement of drug-context memories by acute nicotine and cognitive deficits observed during nicotine withdrawal. In summary, the results of the cited studies suggest that initially nicotine enhances drug-context associations, which leads to the development of sustained nicotine use and consequently nicotine dependence. While chronic nicotine does not seem to alter hippocampus-dependent learning and memory, these processes are impaired during nicotine withdrawal. This effect also seems to contribute to maintenance of nicotine dependence as smokers may self-medicate for withdrawal-induced cognitive deficits by returning to nicotine use. Alcoholism is a complex behavioral and physiological phenomenon in which the abuser progressively loses control over alcohol consumption despite its negative health consequences Koob et al. Indeed, severe health problems have been associated with alcohol overconsumption, including medical conditions ranging from cardiovascular and psychiatric diseases to certain cancers e. In addition to the overall health problems caused by alcohol abuse, alcoholism is also known to cause cognitive impairments Ryan and Butters ; see Stavro et al. The results from laboratory animal studies also demonstrate alcohol's impairing effects on cognition. Specifically, acute ethanol administration impaired hippocampus-dependent learning and memory in the Morris Water Maze Markwiese et al. In contrast, there is evidence showing that light to moderate alcohol intake 1—2 drinks per day may decrease the risk of cardiovascular mortality, coronary heart disease, and stroke in humans Fagrell et al. In addition, there is evidence showing that unlike higher doses of ethanol, lower doses are required for ethanol-induced dopaminergic reward signaling Gessa et al. In fact, higher doses resulted in decreased ethanol self-administration and conditioned place aversion CPA; Cunningham and Henderson Furthermore, Sinden and Le Magnen showed that low-dose ethanol self-administration linearly increased during 5 d of training whereas self-administration of a high-dose ethanol decreased significantly below saline levels. In line with these observations, Gulick and Gould found that while higher doses of acute ethanol resulted in deficits in both hippocampus-dependent contextual and hippocampus-independent cued fear conditioning, lower doses of ethanol enhanced both types of learning. This report is critical in terms of understanding how alcohol-context and alcohol-cue associations are formed following initial alcohol consumption. The data showing sustained self-administration and CPP with lower doses and decreased self-administration and CPA with higher doses of ethanol are also in support of this hypothesis. Therefore, these results suggest that a lower dose of ethanol facilitates maladaptive ethanol-context associations by enhancing reward processes and contextual and cued learning necessary for these maladaptive associations to occur. As described earlier, both rewarding and procognitive effects of initial alcohol exposure may predict increased rates of subsequent alcohol intake through enhanced drug-context learning. In addition to possible enhancement of hippocampus-dependent learning and memory with low doses of ethanol, studies also showed that prolonged ethanol consumption uniformly resulted in hippocampus-dependent spatial learning deficits Bond and Di Giusto ; Beatty et al. Binge ethanol exposure also results in necrotic cell death and neurodegeneration in the hippocampus Obernier et al. Moreover, evidence from studies examining the effects of ethanol on hippocampal plasticity suggests that chronic ethanol inhibits hippocampal LTP Durand and Carlen ; Tremwel and Hunter ; Roberto et al. Roberto et al. The ethanol-induced changes in MAPK-CREB pathway are crucial to understanding the molecular mechanisms underlying the hippocampal deficits during chronic ethanol exposure because numerous studies have shown that activation of this cell signaling pathway is necessary for long-term memory formation e. Overall, these studies show that chronic ethanol can inhibit cell signaling cascades involved in learning through activation of GABAergic receptors and blockage of NMDA receptors in the hippocampus. Evidence from human studies seems to be in agreement with animal studies showing chronic ethanol-induced cognitive impairments and disrupted hippocampal function. For example, impairments in learning and memory Ryan and Butters ; Vetreno et al. These cognitive deficits also persisted during abstinence Fein et al. These learning and memory problems may contribute to relapse to alcohol use and maintenance of alcohol addiction as individuals with withdrawal-induced cognitive deficits attempt to self-medicate. In line with chronic ethanol's impairing effects on cognition is a condition known as Wernicke—Korsakoff syndrome WKS , which results from a prolonged alcohol exposure-induced thiamine deficiency. WKS is characterized by gradual impairments in memory function that spread into other cognitive domains as chronic alcohol use is maintained Ryan et al. Thus, WKS is associated with myriad of cognitive deficits such as impairment in verbal processing Cermak et al. WKS patients exhibited extensive damage to the hippocampus that was linked to the memory deficits Sullivan and Marsh ; Caulo et al. Specifically, hippocampal volume in WKS patients was greatly reduced to a level comparable to patients with Alzheimer's disease Sullivan and Marsh Moreover, an fMRI study showed that the hippocampal activity detected in controls during memory encoding and recognition was absent in the patients with WKS Caulo et al. Results from WKS patients clearly indicate that prolonged alcohol exposure has deleterious effects on hippocampus function and morphology, which may be the source of hippocampus-dependent learning and memory deficits. Therefore, ethanol-induced neural damage and hippocampus-dependent learning deficits may contribute to the negative symptoms of alcoholism. In conclusion, lower doses of acute ethanol enhance both hippocampus-dependent contextual and hippocampus-independent cued learning while higher doses of ethanol disrupt both types of learning. Nevertheless, hippocampus-dependent learning may be especially sensitive to the effects of acute ethanol because numerous studies suggest that acute ethanol alters hippocampal function. In contrast, chronic ethanol's detrimental effects on hippocampus-dependent learning and hippocampal function are relatively ubiquitous and one-sided. That is, chronic ethanol exposure alters hippocampal anatomy, disrupts hippocampal plasticity, and changes hippocampal cell signaling leading to impairments in hippocampus-dependent learning. These effects may contribute to the cognitive deficits that characterize ethanol-related syndromes such as WKS. Overall, given that acute ethanol enhances and chronic ethanol disrupts hippocampus-dependent learning, it is possible that initially learned drug-context memories are enhanced by acute ethanol and remain relatively unaltered during chronic ethanol use due to an inability to reverse established ethanol-context memories. This hindered ability to update drug-context association with new information may contribute to the persistence of and relapse to ethanol addiction. Opiates are a class of psychoactive compounds naturally derived from the opium poppy or synthetically produced that include morphine, diacetylmorphine diamorphine or heroin , codeine, oxycodone, and methadone. Opiates such as oxycodone are legally prescribed to patients for pain management. Importantly, legally prescribed opiates lose their analgesic effects as tolerance develops, which, in some cases, results in drug dependence as patients try to achieve analgesic potency or avoid withdrawal symptoms. Consequently, although the prevalence of opiate addiction in the U. This suggests that opiate addiction is a potential risk to widespread segments of the population. In addition to its analgesic effects, opiate-induced euphoria is the leading cause for opiate-seeking in nontherapeutic addicts but not in therapeutic addicts who abuse opiates for its analgesic potency McAuliffe et al. However, as Koob et al. Accordingly, while laboratory rodents learn CPP for morphine Bardo et al. It is important to note that development of CPA to withdrawal symptoms is in line with the fact that opiate withdrawal symptoms are usually considered more severe than symptoms associated with stimulant withdrawal e. Thus, it is possible that avoidance of withdrawal plays an especially important role in opiate dependence. Similar to cocaine and ethanol, opiate abuse also correlates with long-lasting cognitive deficits in humans Rogers et al. Abusers of morphine, heroin, and methadone show impairments in episodic memory Curran et al. In addition to the effects of chronic abuse of opiates, Curran et al. Although several studies have suggested that opiate abuse-related cognitive decline may be linked to compromised frontal lobe function Robinson and Kolb ; Ornstein et al. For example, opiates have been shown to inhibit adult neurogenesis in the hippocampus Eisch et al. Moreover, acute morphine has also been shown to disrupt spatial memory retention in Morris water maze Farahmandfar et al. There is also evidence showing that chronic heroin and morphine impair hippocampus-dependent spatial learning in Morris water maze Means et al. Moreover, the impairing effects of chronic administration of opiates on spatial memory have been linked to an increase in proteins associated with apoptosis such as Fas, FasL, and Bad in the cortex and hippocampus Tramullas et al. Finally, in addition to their effects on hippocampus-dependent learning and hippocampal function, both acute Ito et al. These results show that both acute and chronic opiate administration result in deficits in hippocampus-dependent learning and memory and, therefore, it is difficult to explain sustained opiate use by enhanced drug-context memories in this case as there is no evidence suggesting that acute administration of opiates may enhance hippocampus-dependent learning and memory. Nevertheless, studies showing that laboratory rodents successfully learn CPP to opiates suggest that normal drug-context learning occurs through the reinforcing effects of the opiates. Opiates may be different from the other drugs of abuse reviewed here as low doses of opiates do not enhance memory; instead, opiate withdrawal may alter hippocampal function contributing to formation of memories linking the aversive effects of withdrawal and withdrawal context. As mentioned, opiate withdrawal is often more severe than stimulant withdrawal Alexander and Hadaway ; Jaffe ; West and Gossop Earlier models of opiate addiction, such as Wikler's , proposed that avoidance of withdrawal symptoms is a major motivator for continued drug use. Also, latter models followed Wikler's hypothesis by describing opiate addiction as a balance between positive reward and negative withdrawal reinforcers Koob et al. In line with these models, rodents learn to avoid contexts paired with spontaneous Myers and Carlezon or opioid antagonist precipitated opiate withdrawal Jin et al. Human studies also report conditioned withdrawal symptoms to specific contexts O'Brien et al. For example, O'Brien et al. These withdrawal symptoms occurred in a sound-attenuated room in the presence of a specific background music and odor. Conditioned withdrawal symptoms were tested following saline injections. The results of this study showed that participants exhibited strong conditioned withdrawal symptoms to the withdrawal context in the absence of naloxone. Moreover, there is qualitative evidence suggesting that contexts associated with withdrawal increased drug craving in opiate addicts Wikler These results suggest that human opiate addicts also learn conditioned place aversion to the withdrawal context, which may contribute to future use of opiates in attempts to self-medicate to reduce negative symptoms associated with a withdrawal context. Interestingly, opiate withdrawal is linked to normalization and enhancement of hippocampus-dependent learning and memory. For example, studies showed that while short-term withdrawal disrupted performance in the Y-maze Ma et al. Furthermore, there are data showing that spontaneous withdrawal from chronic morphine enhanced the acquisition of cocaine-self administration He and Grasing , suggesting that drug-context learning may be enhanced during opiate withdrawal. More direct evidence for enhancement of future drug seeking as a result of associations between withdrawal symptoms and withdrawal context came from Kenny et al. These studies indicate that hippocampus-dependent drug withdrawal-context associations may reinforce future drug use to avoid negative withdrawal symptoms. Studies examining hippocampal plasticity are in agreement with the view of enhanced opiate withdrawal-related memories. For example, Mansouri et al. Similarly, Ito et al. This effect was reversed when the slices were treated with morphine, suggesting reexposure to morphine following withdrawal reversed the withdrawal-induced enhancement of hippocampal plasticity. Similarly, Salmanzadeh et al. There was also another study showing that morphine withdrawal following repeated injections of morphine reduced hippocampal LTP Pu et al. However, discrepancies between chronic morphine administration regimens continuous vs. Still, it is possible that continuous administration of opiates via osmotic mini-pumps or drinking water may mimic prolonged opiate abuse better than short-term intermittent injections. In summary, in contrast to acute and chronic opiate administration, converging evidence from multiple studies suggests that hippocampal plasticity may be enhanced during opiate withdrawal. Overall, the studies reviewed here suggest a potential contributing factor for sustained opiate abuse. That is, strong memories are formed about the rewarding effects of opiates, as reflected by strong CPP, whereas the association between aversive withdrawal symptoms and the context is augmented by enhanced hippocampus-dependent learning and plasticity during withdrawal from chronic opiate administration. Thus, the withdrawal-associated context may produce a strong drive for self-medication in an attempt to ameliorate severe context-evoked withdrawal symptoms, which could result in relapse to opiate use and continued addiction. This effect may be dependent on the enhancement of hippocampal LTP and phosphorylation of cell signaling kinases critical for hippocampal plasticity such as MAPKs. Cannabis is a flowering plant that has long been used for the production of hemp-based goods e. Cannabis use currently receives increasing amount of attention in the USA as both medicinal and recreational marijuana are legalized or decriminalized in more than 20 states. Although usually perceived as a milder form of drug, like other drugs of abuse, short-term and long-term marijuana use has been linked to adverse health effects such as anxiety, psychosis, pulmonary problems as well as cognitive problems with prolonged use Hall and Degenhardt ; Volkow et al. However, marijuana users also self-report positive effects of cannabis, including relaxation, analgesia, happiness, creativity, social benefits, and improved sleep Goode ; Berke and Hernton ; Green et al. In these regards, cannabis exhibits similar properties with other drugs of abuse, namely rewarding effects with initial use. However, like opiates and unlike ethanol, cocaine, amphetamine, and nicotine, acute administration of THC and cannabidiol have been shown to disrupt hippocampus-dependent spatial learning in the Morris water maze and radial arm maze Lichtman et al. In line with the animal studies, human studies also suggest that acute cannabinoids result in impaired memory Tinklenberg et al. Therefore, in the case of cannabis, drug-context associations are formed in spite of hippocampal learning difficulties associated with cannabis use. Cannabis dependence also results in a withdrawal syndrome during abstinence, which is characterized by heightened anxiety, irritability, negative mood, restlessness, shakiness, sleeping difficulty, stomach pain, strange dreams, sweating, and weight loss Kouri and Pope ; Budney et al. These symptoms have been shown to be reversed by reexposure to THC Budney et al. Comparative studies found that nicotine and cannabis withdrawal syndromes share similar negative symptoms Vandrey et al. Moreover, as shown by self-report studies, the majority of cannabis users indicated that negative withdrawal symptoms were the major reason for their inability to quit and they attempted to self-medicate these symptoms, which usually resulted in relapse to cannabis use Budney et al. Also similar to nicotine withdrawal, marijuana users show cognitive deficits during abstinence from cannabis such as impaired mathematical skills, disrupted verbal expression, altered encoding and retrieval of verbal memories, attentional problems, and executive function deficits Block and Ghoneim ; Solowij ; Pope and Yurgelun-Todd There is evidence showing that rats undergoing THC withdrawal show deficits in hippocampus-dependent spatial learning Wise et al. Overall, these studies suggest that both acute administration and abstinence from cannabis result in difficulties in cognition. Therefore, in line with self-medication hypothesis, it is possible that while hippocampus-dependent memory enhancement seen with nicotine is not apparent for cannabis, relapse to cannabis use due to withdrawal-induced cognitive and emotional deficits is a possible contributing factor for the maintenance of cannabis addiction. Disruption of hippocampus-dependent learning as a result of acute cannabis use may result from deficits in hippocampal plasticity. For example, acute THC reduced the amplitude of both spontaneous and conditioned stimulus evoked potentials in the hippocampus Campbell et al. Moreover, THC eliminated the firing of the neurons in the CA1 subregion of the hippocampus induced by delayed match-to-sample task performance Heyser et al. Furthermore, like THC, acute cannabinoid receptor agonists e. For example, Puighermanal et al. Moreover, enhanced hippocampal plasticity has been documented in mice lacking CB1 receptors Bohme et al. In line with a modulatory role of CB1 receptors in hippocampal plasticity, CB1 activation has been shown to inhibit glutamatergic synapses in the hippocampus Takahashi and Castillo , indicating a negative regulation of NMDAR-dependent long-term memory formation by CB1 receptors. Although a majority of studies examining the effects of acute cannabinoids on hippocampal plasticity reported impaired hippocampal LTP, there is also evidence for disruption of LTP during withdrawal following chronic THC administration Hoffman et al. Specifically, Hoffman et al. Similarly, Fan et al. However, human chronic marijuana smokers have been shown to exhibit downregulated CB1 receptors in a variety of brain regions including the hippocampus Hirvonen et al. This result seems to be conflicting with studies showing improved hippocampal plasticity with deletion or inhibition of CB1 receptors. The downregulation does not speak to the functional state of the receptors and thus, it is possible that these receptors may be more responsive to endocannabinoids, which may result in increased efficiency of the endocannabinoid system compared with systems where CB1 receptors are inhibited or completely absent. Thus, these studies suggest that both acute and withdrawal from chronic THC disrupted hippocampal LTP and these effects were associated with CB1 receptor activation. Given the apparent parallels between impairments in hippocampus-dependent learning and memory and disrupted hippocampal LTP, it is likely that disrupted hippocampal plasticity may underlie the hippocampus-dependent learning and memory deficits observed following acute cannabinoid agonism and withdrawal from chronic cannabinoid administration. Overall, the studies cited here clearly show that both acute administration of THC and THC withdrawal lead to cognitive deficits and these effects are mediated by CB1 receptor-mediated disruption of hippocampal plasticity. Given that removal of cognitive deficits exhibited by chronic marijuana smokers is one of the major motivators for relapse to smoke marijuana Budney et al. In summary, the studies reviewed here provide evidence for the involvement of hippocampus-dependent learning and memory as well as hippocampal plasticity in development and maintenance of addiction. Specifically, acute administration of stimulants such as cocaine, nicotine, and amphetamine, as well as alcohol enhances hippocampus-dependent learning and memory. It is possible that this augments drug-context associations and contributes to future drug use. On the other hand, opiates and cannabis seem to disrupt hippocampus-dependent learning and memory following acute administration. Nevertheless, both opiates and cannabis produce strong CPP, suggesting that successful drug-context associations are formed regardless. In addition to the enhancement of drug-context associations during acute administration of these drugs, all drugs of abuse reviewed here except opiates produce strong deficits in hippocampus-dependent learning and memory and attenuated hippocampal plasticity during withdrawal, which may motivate attempts to self-medicate resulting in relapse and maintenance of drug use. In the case of opiates, unlike other drugs of abuse, withdrawal leads to enhanced hippocampus-dependent learning and memory, which may facilitate the development of context-evoked withdrawal symptoms that could facilitate relapse. Overall, human and laboratory animal studies suggest a significant role of drug-induced alterations of hippocampus-dependent learning and memory in development and maintenance of drug addiction. As a library, NLM provides access to scientific literature. Learn Mem. Find articles by Munir Gunes Kutlu. Find articles by Thomas J Gould. Received Mar 15; Accepted Jul Open in a new tab. Effects of acute alcohol on hippocampus-dependent and hippocampus-independent learning. Similar articles. Add to Collections. Create a new collection. Add to an existing collection. Choose a collection Unable to load your collection due to an error Please try again. Add Cancel.