Drug addiction has been considered to be a chronic brain disease, defined by a motivational brain circuit whose function can increase individual’s susceptibility to drug abuse. Addiction in general has been linked to a reward system that involves various brain regions including; motor areas involved in habit formation (eg. Ventral tegmental area (VTA) and more specifically the nucleus accumbens (NAc)), as well as the hippocampus involved in habit maintenance through neuroplasticity. The hippocampus has an interesting feature that differentiates it from other regions involved in the pleasure circuit; it has the ability to create new neurons and alter synaptic strength based on learning experiences (neuroplasticity). This is an interesting function of the brain, because it allows for adult hippocampal neurogenesis (AHN); a process involved in the strengthening and optimizing neuronal connections (Castilla-Ortegaa, et al., 2016). Drug addiction in general have shown to increase signs of reward-seeking behaviour, that can often lead to a lack of control and high risk of relapse. In particular, cocaine is a highly addictive and popular drug with numerous side effects such as; paranoia, strokes and even death (Drug Use and Abuse in Canada, n.d.). In the United States alone, around 35.5 million Americans have admitted to using cocaine at least once in they’re life, and 1.5 Europeans have admitted to using at least once a month (The Truth About Cocaine, n.d.). Cocaine was first used in the South Americas by the aboriginals, as means of getting an energetic buzz (Cocaine, 2018).  Due to the popularity and risk of addiction characterized by chronic cocaine use, attempting to distinguish the underlying mechanisms that predict risk of relapse may help diminish susceptibility to drug addiction before it occurs, helping to create preventative-type treatments. In this review, the effects of chronic cocaine on AHN will be studied, and in turn the affects of AHN on predicting risk of cocaine relapse.

Cocaine is mainly associated with the excitation of the brain’s neural circuitry, by inhibiting dopamine reuptake and increasing dopamine resting in synaptic cleft. This increase in synaptic dopamine density allows for post-synaptic activation (Understanding Drug Abuse and Addiction: What Science Says, 2016) (Castilla-Ortegaa, et al., 2016). This has been related to the feeling of euphoria experienced by individuals who use the drug. Glucose is the main energy source of the brain, so that the brain increases use of glucose during neuronal activation (Understanding Drug Abuse and Addiction: What Science Says, 2016). Cocaine has been shown to have long lasting affects on the brain, with Positron Emission Tomography (PET) scans showing less glucose activation produced by individuals with cocaine addictions, than those without (Understanding Drug Abuse and Addiction: What Science Says, 2016). These results suggest that cocaine may be correlated to the brain’s neuronal activation, so that reduction in brain activity leads to long-term changes worth assessing. The neurobiological mechanisms underlying drug addiction, are best understood in association to the motivational brain circuit, in which the hippocampus seems to lend its involvement.  Since the hippocampus has been closely linked to learning and memory through the consolidation of synaptic connection, drug addiction must be affected by neuroplasticity in a way that involves learning and memory (Keralapurath, Briggs, & Wagner, 2015) (Castilla-Ortegaa, et al., 2016). In other words, since neuronal activation has been associated to chronic cocaine abuse, it is safe to assume that learning and memory will affect the mechanisms that make cocaine addictive and even risk relapse.

In the brain the VTA and hippocampus create a communication loop, spanning to the Nucleus accumbens and other regions involved in perception of reward (JE & AA., 2005). This system has been linked to reward-seeking behaviour as well as the formation of long–term memory through the interaction of dopaminergic pathways. The release of dopamine into the hippocampus by the VTA, produces an increase in long-term potentiation (LTP) (JE & AA., 2005) that has been associated with increase of AHN (Castilla-Ortegaa, et al., 2016) and learning. Drugs such as cocaine, are known to interact with this hippocampus-VTA loop, causing persistent modifications of neural plasticity associated with addictive behaviours (Liu, Pu, & Poo, 2005). Studies have shown that after cocaine administration, dopamine increases susceptibility to LTP through the VTA projections to the hippocampus, by decreasing GABA (inhibitory neurotransmitter) efficiency (Liu, Pu, & Poo, 2005). The increase in LTP receptivity with dopamine and the depression of inhibitory response, may explain the underlying mechanisms behind associative learning of drug-seeking behaviours through the mechanisms of learning and memory. In other words, cocaine’s addictive properties, may be partly due to the strengthening of synaptic connection, in association to the increase of dopamine during drug use. Moreover, studies have shown that the presentation of drug-related cues can reinstate drug-seeking behaviour (Otis, et al., 2018), further proving the importance of memory formation in drug addiction and risk of relapse. Administering memory antagonists to mice reduced they’re sensitivity to drug addiction associated with decreasing ability to retrieve memories, consistent with the idea that addiction requires an increase in neural plasticity associated to cocaine-related memories. For example, the result in conditioned place preference (CPP) exhibited by rats with cocaine addictions, also helps illustrate the importance of memory retrieval for the development of drug addiction (Castilla-Ortegaa, et al., 2016) (Otis, et al., 2018). The learning of these associations are often called cocaine-stimulus associations (CSA), which are the product of learning cues associated to the availability of a drug, that are then linked to the euphoric feeling produced by it (Castilla-Ortegaa, et al., 2016). Thus those with higher susceptibility to drug addiction for example, will have an increase response to CSA’s, potentially affecting the hippocampal-VTA loop. By seeking and taking the drugs, the individual’s goal-directed behaviour is modulated by synaptic connections associated to the reward of the drugs and the learning of the triggers (Castilla-Ortegaa, et al., 2016). By increasing synaptic association between the drug and the memory, habits are formed, making the individual more susceptible to relapse in the future.  

When acutely administered, Cocaine activates the neural circuitry (Munir, Gould’, & J., 2019) (as previously explained). The pleasurable affects occurring during acute cocaine use may be responsible for the consolidation of memory in the hippocampus that leads to increased risk of relapse. Although during this acute phase, cocaine can seem to increase neural plasticity, studies have shown that over time cocaine can cause inability to control drug-seeking behaviour; a result characterized by negative affects of AHN and neural activity. For example, following a stressful event such as withdrawal, an acute user may experience an increase in drug-seeking behaviour that also increase LTP in association to negative feelings. These feelings proceeding stressful events can lead to relapse (Munir, Gould’, & J., 2019), which again can strengthen the association between reward and drug use, making addiction difficult to recover from due to  neuroplasticity.  Studies have shown a difference between acute and chronic cocaine users, that may allow for the underpinning of neoplastic mechanisms involved in drug addiction and risk of relapse. Studies have shown that rats who underwent long-term cocaine administration experienced more neuronal change after withdrawal (Keralapurath, Briggs, & Wagner, 2015), than those who underwent short-term cocaine administration. Consistent with these findings are the results that mice exposed to small doses of cocaine demonstrated enhanced learning, while large doses of cocaine demonstrated impaired learning (Munir, Gould’, & J., 2019). These findings suggest that learning and memory associated to drug addiction occur during the acute phase of addiction, aiding the development of maladaptive drug-associated memories. During chronic cocaine abuse, studies show that withdrawal only increases individual drug-seeking behaviour due to stress-related response to the lack of drugs. In other words, since the individual’s dopaminergic pathways become dependent on the stimulation of cocaine for they’re activation, the absence creates a downregulation of dopaminergic activation, increasing GABA activity (Keralapurath, Briggs, & Wagner, 2015), causing the individual a greater discomfort than individuals who administer cocaine acutely. In cases of chronic use cocaine increases LTP and AHN, allowing the individual to feel euphoric and encode the memory by enhancing hippocampal-VTA connections. But, in chronic cases, the individual is overcome by habituation where overtime AHN (Castilla-Ortegaa, et al., 2016) is lost unless continuously strengthened by cocaine (Castilla-Ortegaa, et al., 2016) (Keralapurath, Briggs, & Wagner, 2015). This continuous feedback requiring overstimulation that leads to a dependency, is the route of addiction.

In conclusion, cocaine created an excitatory response in the brain involving the dopaminergic pathways in both the brain regions involved with reward and with learning. This suggests that drug addiction is linked to the affects memory has on learning reward in association to the pleasurable affects of drug taking. In more detail, cocaine increases dopamine while decreasing GABA inhibitory responses. The influx in excitation causes a euphoric feeling in the individual that may be associated with CSA’s that allow for stronger retrieval during instances of stress such as drug withdrawal. In instances of chronic drug use, withdrawal creates a response that decreases ACH due to lack of excitatory neurotransmitters (previously provided by the administration of cocaine), creating a stronger drug-seeking behavioural response, and in turn increasing risk of relapse. Further research into the way of increasing ACH during periods of withdrawal could help establish prevention-based treatment against substance addiction as a disorder.

References

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