This study investigated the prevalence of use of substances of abuse in healthy young adults in relation to navigational strategies measured with the 4/8VM task. We found that response learners, compared with spatial learners, reported significantly more use of substances such as tobacco and cannabis and had double the lifetime consumption of alcohol. Therefore, as hypothesized, the prevalence of use of substances of abuse was high in response learners. A longitudinal study will be needed to establish the causal relationship between response strategies and drug use. In other words, the use of response strategies early in life could predispose an individual to drug use, and conversely, drug use could increase the probability of using of response strategies. It is most likely a combination of both and we provide evidence for the two mechanisms below. Importantly, this is the first study to demonstrate an association between use of drugs of abuse and the use of response strategies in a dual solution task.

In support of the theory that strategy may influence use of drugs of abuse, previous studies showed that response navigational strategies emerge as early as age 7 years old (Bohbot et al., 2012; Lin et al., 2012), well before the onset of using abused substances. In other words, cue sensitive response learners (measured with our virtual navigation task, the 4/8VM) may also be more responsive to reward cues, making them more susceptible to trying and using drugs.

Substances of abuse may also promote the use of caudate nucleus-based response learning through their stimulation of the striatum (White, 1996). In turn, people who regularly engage in striatal dependent reward seeking behavior may be more likely use response learning strategies when navigating. Specifically, dopamine release has been measured in the caudate nucleus of participants not only exposed to amphetamines (Boileau et al., 2007), cocaine (Cox et al., 2009), and alcohol (Barrett et al., 2008), but also to other types of rewards, which are more common such as chocolate (Small et al., 2001) and video games (Koepp et al., 1998; Erickson et al., 2010). In fact, video game users, engaging in only 9 h of video games per week or more, were shown to have a significantly larger striatum (including the nucleus accumbens and caudate nucleus) (Kuhn et al., 2011). In another study gray matter in the striatum at baseline predicted the level of video game skill acquired by the research participants (Erickson et al., 2010). In this study, gray matter in the hippocampus had no impact on participant's ability to acquire skills with the video game. Furthermore, studies that specifically investigated superior visuospatial performance in action video game experts demonstrated that this skill was not correlated with gray matter in the hippocampus, but rather with gray matter in the right posterior parietal cortex (Tanaka et al., 2013). In another study, the volume of the entorhinal cortex, which sends afferent projections to the hippocampus, negatively correlated with playing action video games (Kuhn and Gallinat, 2013) suggesting that the entorhinal cortex shrinks with time playing action video games. Interestingly, the same region of the brain positively correlated with time playing logic and puzzle games. These results are consistent with the hypotheses derived from a study by Foerde and Shohamy (2011) showing that delaying feedback timing will shift from learning based on the striatum to hippocampus. Therefore, in the case of video games, the immediate rewards present in action video games would stimulate the striatum to grow and the entorhinal cortex to shrink, whereas the delayed rewards present in puzzles or logic games would stimulate the entorhinal cortex to grow (Foerde and Shohamy, 2011; Smith-Dijak et al., 2013; Shohamy and Adcock, 2010). While a region of interest analysis shows a correlation between a composite measure of time playing video games and grey matter in the hippocampus, Kuhn and Gallinat (2013) did not report whether the hippocampus also correlated negatively to action video games, as did the entorhinal cortex. Interestingly, consistent with the findings of the current paper, the authors did report a significant correlation between time playing video games and both internet addiction and alcohol consumption. Therefore, reward seeking behavior may engage the striatum which in turn would promote response navigational strategies. Since reward seeking behavior can be expressed at a very young age in childhood (for example in the form of a child seeking food rewards like chocolate, or material rewards such as toys, games, and playing video games), reward seeking behavior in childhood may also stimulate the striatum and precede the onset of response navigational strategies which were measured as early as 7 years of age in ∼5% of the children tested by Lin et al. (2012). In summary, reward seeking behavior at a very young age could engage the striatum and response learning, and predispose to drug seeking behavior.

There is a transition from voluntary use to involuntary compulsive use of substances of abuse (Schwabe et al., 2011). Voluntary use is dependent on the prefrontal cortex and dorsomedial striatum and involves goal-directed behaviors. This behavior is driven by the hedonic effects of the drugs and/or rewards. In contrast, involuntary use depends on the dorsolateral striatum and involves habitual action that are independent of the expected outcome (Everitt et al., 2001; Everitt and Robbins, 2005). Dopamine is involved in the development of habitual actions, and as mentioned earlier, is increased in the striatum after drug use. Habitual response to drugs of abuse have especially been shown to develop remarkably fast (Dickinson et al., 2002; Miles et al., 2003). As such, drug use can lead to a fast transition from goal-directed behavior to habitual action and drug addiction.

Since response learners show less activity and gray matter in the hippocampus than spatial learners (Iaria et al., 2003; Bohbot et al., 2007), the current results may also reflect an impact of drug use on hippocampal based spatial strategies. Interestingly, acute nicotine has been shown to positively affect certain cognitive domains (Swan and Lessov-Schlaggar, 2007). In addition, several rodent studies have shown that differential doses of nicotine facilitates spatial memory (Socci et al., 1995; Abdulla et al., 1996; Bernal et al., 1999), while others have shown that chronic nicotine exposure negatively affects spatial memory and hippocampal morphology (Scerri et al., 2006). Therefore, nicotine may have positive effects on spatial memory with acute administration, but detrimental effects under chronic administration. In our study, participants were neither given nor deprived of tobacco. Therefore, the potential effects of tobacco on navigational strategies result from chronic consumption and do not result from acute effects of tobacco on non-smokers, or withdrawal effects in smokers. Consistent with previous studies, chronic tobacco consumption was detrimental to spatial memory strategies in the current study.

Abrous et al. (2002) taught rats to self-administer nicotine at similar levels to those of a heavy smoker. They found that nicotine had several deleterious effects on the dentate gyrus of the hippocampus: decreased neurogenesis, decreased expression of a cell adhesion protein associated with cell migration, and increased cell death. Their results provide a physiological explanation for deficits in hippocampal based tasks seen in rodents. For example, Scerri et al. (2006) found that rats given high doses of nicotine had impairments learning a spatial task such as the Morris Water Maze. The same group reported less neurogenesis in the dentate gyrus of rats given high doses of nicotine compared with rats given low doses of nicotine and nicotine naive rats. In human smokers, chronic nicotine exposure is associated with a lower concentration of an axonal cell marker in the hippocampus when compared with non-smokers (Gallinat et al., 2007). Although nicotine is a main constituent of tobacco smoke, humans inhale countless numbers of other toxic substances while smoking. These substances could also affect the integrity of the hippocampus. Indeed, rats exposed to chronic cigarette smoke have neuropathological alterations in the hippocampus (Ho et al., 2012). Therefore, through affecting the morphology of the hippocampus, smoking could decrease the likelihood of using spatial learning strategies.

In addition, we found a correlation between tobacco and cannabis use and so it follows that response learners, who consumed a significant amount of cigarettes in their lifetimes, were more likely to smoke cannabis than spatial learners. However, aside from cigarette smoking, smoking cannabis may also affect the use of spatial strategies due to its impact on the hippocampus and spatial memory. This impact is noted in rodent as well as human literature. Rubino et al. (2009) found that adolescent rats pretreated with tetrahydrocannabinol (THC), the active substance contained in cannabis, show impaired spatial memory in adulthood, measured by a radial maze task. The same group also found morphological changes in the dentate gyrus of THC pretreated rats. Further, heavy cannabis use negatively correlated with gray matter in human hippocampus (Yucel et al., 2008) while moderate cannabis use was associated with reduced performance on a logical memory task, that is generally considered to be a measure of episodic memory (Indlekofer et al., 2009). Cannabis use has also been associated with decreased activity in the hippocampus during an associative memory task (Jager et al., 2007). In summary, cannabis use was shown to be detrimental to the hippocampus.

A recent study supports the hypothesis that substances of abuse have a negative impact on hippocampus-dependent spatial learning and promotes caudate-nucleus dependent response learning. Researchers looked at the impact of reward processing on spatial and response learning in mice: drug (morphine)-rewarded mice performed significantly better than control mice on a cue discrimination task that involved stimulus-response learning. In contrast, drug-rewarded mice were significantly impaired in a spatial task compared with control mice (Baudonnat et al., 2011). The group also saw an altered expression pattern of phosphorylated CREB, a transcription factor associated with learning, in drug reinforced mice: CREB was expressed in the striatum of mice irrespective of the task (cue or spatial). Control mice showed CREB expression in the striatum or hippocampus depending on whether they leaned the cue task or spatial task, respectively. Therefore, drug reinforcement negatively affected hippocampal learning in favor of response learning (Gabriele et al., 2009). These results combined with the toxic effects of drugs on hippocampal integrity may have adverse long term effects on cognition.

Data showing a concurrent impairment of spatial memory and promotion of response learning in drug-taking mice (Baudonnat et al., 2011) are consistent with the observation of an inverse relationship between gray matter in the caudate nucleus of the striatum and hippocampus, in both humans (Bohbot et al., 2007) and rodents (Lerch et al., 2011). In the human study, participants' MRIs were regressed against a measure of spatial strategies with voxel based morphometry (Fig. 5). Results showed a positive correlation between spatial memory and gray matter in the hippocampus and a negative correlation with the caudate nucleus of the striatum. Importantly, gray matter in the hippocampus and caudate nucleus were negatively correlated such that an increase in gray matter in one area was associated with a decreased gray matter in the other (Bohbot et al., 2007). In rodents, a prospective training study showed that mice trained on a spatial memory version of the Morris water task had a significant increase in gray matter in the hippocampus, in contrast to the mice trained on the stimulus-response version of the task, whereby they learned to swim to a visibly identified platform (Lerch et al., 2011). Importantly, after only five training days, significant morphological changes occurred, providing evidence for the fact that experience has a significant impact on gray matter. As in the human MRI study, gray matter in the hippocampus and striatum of trained mice were negatively correlated (Fig. 5). These data suggest that using the caudate nucleus-dependent response strategy comes at a cost for the hippocampus-dependent spatial strategy. As argued earlier, reward seeking behaviors may be present at a very young age in childhood, thereby promoting the caudate nucleus at a cost for the hippocampus very early on in life. In fact, response strategy users exhibit a decrease in hippocampus to striatal volume from age 8 to 18 while spatial strategy users exhibit an increase in hippocampus to striatal volume from childhood to adolescence (Lin et al., 2012). Consequently, the inverse relationship between the caudate nucleus of the striatum and the hippocampus was found in rodents and in humans, in terms of gray matter (Fig. 5) and function (Packard and McGaugh, 1996; Iaria et al., 2003), suggesting that reward seeking behavior, possibly in childhood, can promote the striatum at the expense of the hippocampus.

It is well established that substances of abuse have a negative impact on hippocampal integrity and function; however, the reverse relationship may also be true: an impaired hippocampus could also increase vulnerability to substance use and addiction. In a rodent study, suppression of adult hippocampal neurogenesis increased vulnerability to addiction and increased resistance to extinction in rats trained to self-administer cocaine (Noonan et al., 2010). Stress is a factor known to suppress hippocampal neurogenesis (Tanapat et al., 2001). Rodents experiencing great amounts of stress by being exposed to a predator's smell, in this case a fox, were shown to have significantly reduced neurogenesis in the hippocampus. Therefore, early stress may have an impact on the hippocampus, which in turn will increase vulnerability to substance abuse. Mothers of response strategy users reported having experienced significantly more stressful events during pregnancy compared with mothers of spatial strategy users (Schwabe et al., 2012). In fact, even genetic differences have been shown to be associated with the use of response strategies (Bueller et al., 2006; Banner et al., 2011). In summary, an impaired hippocampus will increase vulnerability to substance abuse. Engagement in substance abuse early in life, or later in life, will further increase stimulation of the striatum at the expense of the hippocampus.

Conversely, a number of studies have looked at the protective effect of exercise on rodent models of drug addiction (McMillan et al., 1995; Cosgrove et al., 2002; Smith et al., 2008; Smith and Pitts, 2011) because voluntary wheel running (considered exercise) is associated with increased neurogenesis in the dentate gyrus of the hippocampus (van Praag, 2008). For example, Smith and Pitts (2011) showed that voluntary wheel running before drug self-administration reduced acquisition and levels of active drug seeking behaviors when compared with the behavior of rodents who were not allowed to exercise. Similar to rodents, exercise increases the size of the hippocampus in humans (Erickson et al., 2011), and exercise attenuates cigarette cravings and withdrawal symptoms in humans (Taylor et al., 2007). Since spatial learning strategies are associated with increased activity and gray matter in the hippocampus (Iaria et al., 2003; Bohbot et al., 2007), spatial learners could be less likely to exhibit reward seeking behaviors in a similar fashion to exercise. In fact, spatial learning stimulates growth in the hippocampus, beyond the effects of exercise (Lerch et al., 2011).

To date, there are few longitudinal studies in humans that associate brain areas with vulnerability to addiction. Cheetham et al. (2012) reported that adolescents who started using cannabis had smaller orbitofrontal cortex (OFC) volumes prior to initiation of drug use than their non-drug using peers. The OFC is associated with impaired decision making in drug addiction (London et al., 2000) while an intact OFC plays an important role in spatial learning: an intact OFC is essential for acquisition and consolidation of spatial memory in rats (Vafaei and Rashidy-Pour, 2004) and it is involved in the retrieval of route related contextual information in humans (Brown et al., 2010). Consistent with these findings, repeated high-frequency transcranial magnetic stimulation (rTMS) of another region of the frontal cortex, the dorsolateral prefrontal cortex (DLPFC), reduced cigarette consumption (Amiaz et al., 2009; Feil and Zangen, 2010). Furthermore, spatial strategies assessed with the 4/8VM have been associated with increased gray matter in the OFC (Dahmani and Bohbot, 2013). Therefore, the OFC is involved with both reward based decision making and spatial navigation. Thus, decreased function of the OFC may not only impact an individual's propensity to seek rewards but may also decrease their likelihood of using a spatial navigation strategy.

It would also be of interest in future studies to examine navigational strategies in addicts and use this information to guide intervention strategies. For example, response strategy patients may be more responsive to extinction training, while spatial strategy patients may be more responsive to cognitively guided therapies.

In summary, we found that a greater proportion of response learners smoked cannabis and smoked a greater number of cigarettes in their lifetime than spatial learners. Response learners also had double the lifetime consumption of alcohol relative to spatial learners. Further, we found a positive correlation between smoking cigarettes and smoking cannabis. Cue-driven individuals may be more likely to use response navigational strategies and try and use drugs later in life.

Data in the literature also show that chocolate and video games stimulate dopamine release in the striatum. Video games are associated with a larger striatum, action video games are negatively correlated with grey matter in the entorhinal cortex and skills gained with video game playing are not associated with the hippocampus, but are associated with a larger striatum at baseline. Even the visuospatial superiority noted in action video game experts was not associated with gray matter in the hippocampus. Therefore, the vulnerability to substance abuse reported in this paper may be preceded by reward seeking behaviors in childhood such that individuals who seek rewards (foods such as chocolate, toys, games, video games etc.), also seek novelty and display response navigational strategies at the expense of hippocampus-based spatial memory strategies.

Additional research is required to elucidate the causal link between drug use and the use of response strategies. Numerous questions also remain concerning anatomical correlates between drug use and the use of response strategies. Although it is unclear as to whether the same regions of the striatum are involved in response learning and addiction, studies have shown an inverse relationship between the function and gray matter of the hippocampus and caudate nucleus of the striatum. Therefore regular reward stimulation may come at a cost and compromise the hippocampus. In turn, reduced gray matter in the hippocampus has been associated with an increased risk for numerous neurological and psychiatric disorders such as Schizophrenia (Pantelis et al., 2003), post-traumatic stress disorder (Gilbertson et al., 2002), depression (Amico et al., 2011) and Alzheimer's disease (Apostolova et al., 2006; Swan and Lessov-Schlaggar, 2007). Therefore, substance abuse may be preceded by reward seeking behaviors in childhood such that individuals who seek rewards, novelty, and display response navigational strategies at the expense spatial memory strategies during navigation, also have increased risks of neurological and psychiatric disorders associated with reduced gray matter in the hippocampus. Such individuals would benefit from a physical exercise program or stimulation of the frontal cortex, which have been shown to reduce drug seeking behavior. In addition, a cognitive training program designed to increase the use of hippocampal-based spatial strategies may benefit these individuals in combination with cognitive behavioural therapies aimed at reducing reward-seeking behaviors.