The effects of acute administration on hippocampus-dependent learning and memory

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 2001). Cocaine addiction affects roughly 2 million people in the USA, with 1.5 million of them identified as “cocaine users,” and every day there are 1700 new users (U.S. Department of Health and Human Services 2011). In addition to cocaine's negative health consequences including cardiovascular, pulmonary, and psychiatric complications (Brody et al. 1990; Haim et al. 1995; Lange and Hillis 2001), cocaine has been reported to be the most commonly used illicit drug among patients seeking emergency care (40.3%; SAMHSA 2011). 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. 1999). In addition to the pleasurable effects, acute cocaine has also been shown to improve cognition in humans (Garavan et al. 2008) and enhance learning and memory in laboratory rodents (Wood et al. 2007). However, these procognitive effects during initial cocaine exposure may be responsible for the formation of maladaptive drug-context/-cue associations that may facilitate the development of compulsive drug-seeking behavior. In support of this hypothesis, studies have shown that laboratory rodents learn to self-administer cocaine (e.g., Richardson and Roberts 1996; España et al. 2010) and associate a specific context with cocaine reward (e.g., Spyraki et al. 1982; Vidal-Infer et al. 2012) remarkably quickly. 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. 1969; Lenoir et al. 2007; Kerstetter et al. 2012; Perry et al. 2013). 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 1998; Thomas et al. 2008). Among these regions, the hippocampus may be a critical site for both the rewarding effects of acute cocaine (Kuhar et al. 1991; Koob et al. 1994; Everitt et al. 1999; Dackis and O'Brien 2001; Anderson and Pierce 2005) as well as formation and maintenance of cocaine-context associations (Grant et al. 1996; Childress et al. 1999; Kilts et al. 2001; Wexler et al. 2001) due to its involvement in both reward and learning and memory (Aggleton et al. 1986; Burgess et al. 2002; Daumas et al. 2005; for review, see Tulving and Markowitsch 1997). 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. 2003, 2006). Similarly, studies suggest that the dorsal hippocampus controls context-induced reinstatement (Fuchs et al. 2005, 2007; Xie et al. 2010; Wells et al. 2011). 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 2007; Ramirez et al. 2009). Moreover, Vorel et al. (2001) showed that theta burst stimulation in the ventral hippocampus resulted in relapse of extinguished cocaine self-administration. 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 2007, 2009; Segal et al. 2010). 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 1993). However, the effects of cocaine on LTP are mixed (see Table 1 for a summary of results). For example, Smith et al. (1993) found that acute cocaine (30–60 µM) blocked induction of LTP in the CA1 region of the hippocampus without affecting NMDA receptors or already established LTP. In contrast, Stramiello and Wagner (2010) found that enhanced dopaminergic signaling associated with acute cocaine application (6 µM) increased hippocampal LTP in the CA1 subregion. Nevertheless, these contradicting results may be explained by the fact that different drug concentrations were used by these studies: 30–60 µM by Smith et al. (1993) and 6 µM by Stramiello and Wagner (2010). In support of the differential effects of low and high doses of cocaine on LTP, Thompson et al. (2005) showed that while lower cocaine concentrations (5–10 µM) enhanced hippocampal LTP, inhibition of LTP was observed with a higher concentration of cocaine (30 µM). Also in line with these results, Wood et al. (2007) found that an acute moderate dose of cocaine disrupted contextual and cued fear conditioning, whereas a low dose of acute cocaine enhanced both types of learning. 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.

Table 1.

Effects of cocaine on hippocampal LTP

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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. For example, phosphorylation of extracellular signal-regulated kinases -1 and -2 (ERK1/2), a protein required for both hippocampus-dependent learning and hippocampal LTP (Gooney et al. 2002), was elevated in the dorsal hippocampus following cocaine CPP (Tropea et al. 2008). 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 2001; Trifilieff et al. 2006), was increased following cocaine CPP (Tropea et al. 2008). In addition to ERK1/2 and CREB, cAMP-dependent protein kinase (PKA) seems to be required for the formation and maintenance of cocaine-context memories. For example, Cervo et al. (1997) showed that post-training intracerebroventricular injections of a PKA inhibitor disrupted the consolidation of cocaine CPP. 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.

The effects of acute amphetamine on hippocampus-dependent learning and memory

Racemic α-methylphenethylamine (amphetamine, also known as speed) was first discovered by Barger and Dale in 1910 and later synthesized and marketed under the brand name Benzedrine to treat a variety of conditions such as narcolepsy, depression, Parkinson's disease, and pulmonary dysfunction (Heal et al. 2013). 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 2007). Owing to these effects, millions of Benzedrine tablets, under the name of “Energy tablets,” were given to the members of the American and British military (Bett 1946) as well as Japanese soldiers during World War II, and the release of the amphetamine stockpiles after the war resulted in an amphetamine-dependency epidemic in Japan (Masaki 1956). 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 1937; Tidy 1938; Bett 1946), which resulted in a widespread prescription of amphetamine-based medications and eventually amphetamine addiction peaked in mid-2000s (CDC 2007). Today amphetamine dependence is a widespread problem (CDC 2007). According to Substance Abuse and Mental Health Services Administration (SAMHSA 2005), 1.4 million Americans had used methamphetamine, an N-methylated derivative of amphetamine, in the last year. Moreover, the rate of amphetamine or methamphetamine abuse-related hospitalization more than tripled between the years 1993 and 2003 (SAMHSA 2006a). 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 2007).

Shortly after its initial release as a prescription drug in 1935, procognitive effects of amphetamine (e.g., improved intelligence, concentration, and intellectual performance) were reported in humans (Guttmann and Sargant 1937; Tidy 1938). These initial studies were later confirmed by studies showing enhanced memory consolidation (Soetens et al. 1993), memory recall (Zeeuws and Soetens 2007), attention and psychomotor performance (Johnson et al. 2000; Silber et al. 2006), information processing (Halliday et al. 1994), logical reasoning (Johnson et al. 2000), and working memory (Mattay et al. 2000) by amphetamine and its derivatives such as dextroamphetamine in humans. 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. 2008). 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 2010), Morris water maze (Packard and McGaugh 1994; Brown et al. 2000; Cao et al. 2013), radial arm-maze (Strupp et al. 1991), and avoidance conditioning (Doty and Doty 1966). 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. 1998). Studies also showed that amphetamine and methamphetamine produced significant CPP (Carr et al. 1988; Bardo et al. 1999; Parker et al. 2004; Thorn et al. 2012, Han et al. 2014) and self-administration (Lyness et al. 1979; Piazza et al. 1989, 1990, 1991; Krasnova et al. 2010; McClung et al. 2010), which suggests that the rewarding effects of amphetamine and methamphetamine facilitated the formation of drug-context associations. 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. 1983; Gold et al. 1984; Morimoto et al. 1987) and methamphetamine administration (Heysieattalab et al. 2016). Moreover, evidence suggests that acute methamphetamine-induced enhancement of hippocampus-dependent learning as well as amphetamine CPP are dependent on the upregulation of ERK1/-2 and CREB in the hippocampus (Gerdjikov et al. 2004; Cao et al. 2013). Therefore, it is possible that enhanced hippocampus-dependent learning and memory by acute amphetamine administration may drive the formation of drug/reward-context associations by enhancing hippocampal plasticity. This hypothesis is supported by the results showing that acute injections of amphetamine enhanced morphine CPP (Blaiss and Janak 2006) and conditioned approach to sucrose (Blaiss and Janak 2007). 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.

Effects of acute, chronic, and withdrawal from chronic nicotine on hippocampus-dependent learning and memory

Prolonged exposure to tobacco products, particularly cigarette smoking, continues to be the leading cause of preventable premature death claiming more than 400,000 people's lives in the USA each year (20% of all deaths; Benowitz 2010; U.S. Department of Health and Human Services 2014). Accordingly, active and passive tobacco use has been causally linked to deaths from cancer, cardiovascular disease, and pulmonary disease (Sandler et al. 1985; Carbone 1992; McBride 1992; Sherman 1992). 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 2010).

An estimated 15%–19% of the U.S. population has been reported to use nicotine products habitually (CDC 2012). Nicotine's rewarding effects seem to play a major role in the development of nicotine dependence (Watkins et al. 2000). In humans, nicotine results in euphoria, increased energy and arousal, and suppressed anxiety (Pomerleau and Pomerleau 1985, 1992; Stolerman and Jarvis 1995; Benowitz 1996). Accordingly, in animals, acute injections of nicotine leads to CPP (Fudala et al. 1985; Risinger and Oakes 1995; Vastola et al. 2002; Grabus et al. 2006; Brielmaier et al. 2008; Kutlu et al. 2015a). Similarly, there is also evidence showing that smokers learn to associate nicotine's effects with specific contexts and cues (Dols et al. 2000, 2002; Thewissen et al. 2005), suggesting humans and animals learn to associate nicotine's rewarding effects with specific contextual cues. In addition to its rewarding effects, acute nicotine has cognitive enhancing properties in humans. Specifically, acute nicotine administration enhances attention (Parrott and Craig 1992; Bates et al. 1995; Hahn et al. 2007; Hong et al. 2011), learning and memory (Mangan and Golding 1983; Peeke and Peeke 1984; Warburton et al. 1986; Colrain et al. 1992), and information processing (Wesnes and Warburton 1983; Provost and Woodward 1991; for review, see Sherwood 1993). 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.g., cued learning) in rodents. 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 1999; Gould and Higgins 2003; Gould 2003a; Gould and Lommock 2003; Gould et al. 2004; Wehner et al. 2004; Davis et al. 2006, 2007; Davis and Gould 2006, 2007; Raybuck and Gould 2007; Gulick and Gould 2008; Kenney and Gould 2008; Tian et al. 2011; Portugal et al. 2012a, b), as well as spatial object recognition (Kenney et al. 2011), spatial learning and memory in Morris water maze (Abdulla et al. 1996; Sharifzadeh et al. 2005), and spatial working memory in radial arm maze tasks (Levin and Torry 1996; Levin et al. 1997, 1998). 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. 2008; Wing and Shoaib 2008). 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. There is evidence showing that even though 80% of smokers express willingness to quit (CDC 2002) and 40% of them attempt to quit (CDC 2005), only 3% of them successfully quit (Hughes et al. 2004). 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 2008). In addition to these general symptoms, cognitive deficits such as difficulty concentrating (Pomerleau et al. 2000), disrupted working memory (Jacobsen et al. 2005; Mendrek et al. 2006), verbal memory problems (Jacobsen et al. 2005), increased response time (Snyder et al. 1989; Bell et al. 1999), and problems in paired-associate learning (Kleinman et al. 1973) were observed during nicotine withdrawal. 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. 2005; Davis and Gould 2009; Raybuck and Gould 2009; Gould et al. 2012, 2014a; Portugal et al. 2012a, b; Wilkinson and Gould 2013). 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. 2013; Gould et al. 2014a). 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 1985). In support, nicotine has been shown to alleviate cognitive deficits in various mental disorders such as schizophrenia (Adler et al. 1993; for review, see Parikh et al. 2016) and attention deficit/hyperactivity disorder (ADHD, Potter and Newhouse 2008; Evans and Drobes 2009; for review, see Kutlu et al. 2015b), two populations that show higher rates of smoking (38%–42% of ADHD population, Pomerleau et al. 1995; 80%–90% in schizophrenia, George and Krystal 2000; de Leon and Diaz 2005). 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. 2005; Patterson et al. 2010). 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.

The effects of acute ethanol on hippocampus-dependent learning and memory

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. 1998). Indeed, severe health problems have been associated with alcohol overconsumption, including medical conditions ranging from cardiovascular and psychiatric diseases to certain cancers (e.g., mouth, liver, and esophageal cancers), and liver cirrhosis (Rehm et al. 2003). In its 2014 “Global status report on alcohol and health” the World Health Organization (WHO) stated that alcohol abuse is linked to more than 200 health problems and responsible for ~3.3 million deaths world-wide every year (5.9% of all deaths), which establishes alcohol as one of the most harmful drugs of abuse to human health.

In addition to the overall health problems caused by alcohol abuse, alcoholism is also known to cause cognitive impairments (Ryan and Butters 1983; see Stavro et al. 2013 for a meta-analysis) with over 50% of alcoholics reporting memory and cognition problems (Vetreno et al. 2011). 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. 1998; Shimizu et al. 1998; Matthews et al. 2002; Berry and Matthews 2004), the radial arm maze (Matthews et al. 1995, 1999; Vandergriff et al. 1995; White et al. 1997, 1998), the sandbox maze (Rajendran and Spear 2004), and contextual fear conditioning (see Table 2 for the summary of acute ethanol's effects on hippocampus-dependent learning and memory) (Melia et al. 1996; Gould 2003b; Gould and Lommock 2003; Wehner et al. 2004; Gulick and Gould 2007, 2008).

Table 2.

Effects of acute alcohol on hippocampus-dependent and hippocampus-independent learning

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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. 1999; O'Keefe et al. 2014), which suggests that lower doses of ethanol may have some beneficial effects on human health. 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. 1985), successful ethanol self-administration (Sinden and Le Magnen 1982) and ethanol CPP (Bienkowski et al. 1996; Cunningham and Henderson 2000). In fact, higher doses resulted in decreased ethanol self-administration and conditioned place aversion (CPA; Cunningham and Henderson 2000). Furthermore, Sinden and Le Magnen (1982) 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 (2007) 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. That is, Gulick and Gould's (2007) results suggest that lower doses of ethanol may enhance the formation of ethanol-context/cue associations initially, which may facilitate future ethanol intake. 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.

The effects of acute and chronic opiate exposure on hippocampus-dependent learning and memory

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.S. population is ~8% (SAMHSA 2006b), opiate prescription use in chronic pain patients can be as high as 90% (Chabal et al. 1997; Manchikanti et al. 2004) and up to 16% of these patients have been documented to abuse prescribed opiates (Manchikanti et al. 2006). 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. 1985). However, as Koob et al. (1989) hypothesized, opiates’ positive effects are counterbalanced by severe negative consequences of opiate withdrawal such as aches and pain, agitation, anxiety, muscle cramps, nausea, and sleep disturbances (Alexander and Hadaway 1982; Jaffe 1990; West and Gossop 1994). Accordingly, while laboratory rodents learn CPP for morphine (Bardo et al. 1984, 1995; Tzschentke and Schmidt 1995; Milekic et al. 2006), heroin (Bozarth 1987; Bardo et al. 1995), methadone (Steinpreis et al. 1996), and oxycodone (Niikura et al. 2013), they also show CPA to the contexts associated with spontaneous withdrawal (Myers and Carlezon 2010) and precipitated withdrawal induced by opiate receptor antagonists such as naloxone (Jin et al. 2005; Stinus et al. 2005; Li et al. 2007; Manwell et al. 2009). 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.g., amphetamine and cocaine). 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. 1999; Darke et al. 2000; Ornstein et al. 2000; Curran et al. 2001; Davis et al. 2002). Abusers of morphine, heroin, and methadone show impairments in episodic memory (Curran et al. 2001), visual memory, verbal memory, information processing, problem solving (Darke et al. 2000), word fluency and attention (Davis et al. 2002), and spatial tactile and verbal memory (Hill and Mikhael 1979; Ornstein et al. 2000). In addition to the effects of chronic abuse of opiates, Curran et al. (2001) showed that a single dose of methadone resulted in impaired episodic memory in a population tolerant to opiates. Although several studies have suggested that opiate abuse-related cognitive decline may be linked to compromised frontal lobe function (Robinson and Kolb 1999; Ornstein et al. 2000), studies examining the effects of opiate exposure on hippocampus morphology and hippocampus-dependent learning and memory suggested that some of the cognitive deficits observed in opiate abusers may be related to altered hippocampal function. For example, opiates have been shown to inhibit adult neurogenesis in the hippocampus (Eisch et al. 2000) and alter proteins associated with hippocampal synaptic density such as clathrin (Morón et al. 2007). Moreover, acute morphine has also been shown to disrupt spatial memory retention in Morris water maze (Farahmandfar et al. 2010) and Y-maze (Ma et al. 2007), another hippocampus-dependent task (Retailleau et al. 2013). There is also evidence showing that chronic heroin and morphine impair hippocampus-dependent spatial learning in Morris water maze (Means et al. 1996; Tramullas et al. 2008), radial arm maze and Y-maze (Spain and Newsom 1991). 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. 2008), which suggests that chronic opiates may interfere with hippocampus-dependent learning through increased hippocampal neurotoxicity and cell-death. Finally, in addition to their effects on hippocampus-dependent learning and hippocampal function, both acute (Ito et al. 2001) and chronic opiate exposure (Ito et al. 2001; Salmanzadeh et al. 2003) have been shown to disrupt hippocampal plasticity in the form of decreased hippocampal LTP. 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.

The effects of cannabis on hippocampus-dependent learning and memory

Cannabis is a flowering plant that has long been used for the production of hemp-based goods (e.g., hemp oil and hemp fiber) and medicinal purposes (Hillig 2005). Some subspecies of cannabis that are selectively bred for a high yield of Δ9-tetrahydrocannabinol (THC), the main psychoactive constituent in the cannabis, are used in recreational drugs such as hashish and marijuana. 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. In addition to the discussions on legalization of cannabis products, with 40% of the population having used marijuana at least once in their lifetime and ~23% current users, the prevalence of marijuana use is well-above cocaine, heroin, methamphetamine, inhalant abuse; matching cigarette smoking and alcohol use (SAMHSA 2014). 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 2009; Volkow et al. 2014). However, marijuana users also self-report positive effects of cannabis, including relaxation, analgesia, happiness, creativity, social benefits, and improved sleep (Goode 1970; Berke and Hernton 1974; Green et al. 2003). In line with the positive emotional effects of cannabis, THC-induced CPP (Valjent and Maldonado 2000; Braida et al. 2004; Ji et al. 2006; Le Foll et al. 2006) and THC self-administration (Takahashi and Singer 1979; Justinova et al. 2003; Braida et al. 2004) have been shown in laboratory animals. 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. 1995; Lichtman and Martin 1996; Da Silva and Takahashi 2002; Cha et al. 2007; Niyuhire et al. 2007) as well as contextual fear conditioning (Lemos et al. 2010; Stern et al. 2012). In line with the animal studies, human studies also suggest that acute cannabinoids result in impaired memory (Tinklenberg et al. 1970; Ferraro 1980; for review, see Ranganathan and D'Souza 2006). 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 2000; Budney et al. 2003; for review, see Budney and Hughes 2006). These symptoms have been shown to be reversed by reexposure to THC (Budney et al. 2007). Comparative studies found that nicotine and cannabis withdrawal syndromes share similar negative symptoms (Vandrey et al. 2005, 2008; Budney et al. 2008). 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. 1998, 1999; Crowley et al. 1998; Copeland et al. 2001; Coffey et al. 2002; Stephens et al. 2002; Vandrey et al. 2005; Copersino et al. 2006). 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 1993; Solowij 1995; Pope and Yurgelun-Todd 1996). There is evidence showing that rats undergoing THC withdrawal show deficits in hippocampus-dependent spatial learning (Wise et al. 2011). 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.