**2. The mesolimbic system: a locus for drug and non-drug-related rewards**

### **2.1 Experiencing rewards and learning to predict them**

The mesolimbic system has been a traditional focus of drug addiction research, since it is a key substrate for reward and motivated behavior. The mesolimbic system comprises the accumbens (also called "ventral striatum") and the midbrain ventral tegmental area (VTA) as its main brain nodes and dopamine (often considered as the molecule of "pleasure and happiness" [24]) as its major neurotransmitter [25, 26]. The dopaminergic projection neurons in the VTA release dopamine to the accumbens—either at its core or shell subdivisions—as well as to memory-related limbic brain regions such as the prefrontal cortex, the hippocampus, and the amygdala (**Figure 1B**) [25, 27]. Conversely, these brain regions regulate VTA activity. Specifically, GABAergic inhibitory pathways from the accumbens may either stimulate [28] or exert inhibitory feedback control [29] over dopamine release by targeting either the dopaminergic VTA projection neurons or the inhibitory VTA interneurons [30, 31]. For their part, the glutamatergic limbic regions are all reciprocally interconnected, and they also project to the accumbens and to the VTA either directly or by indirect polysynaptic pathways, to stimulate dopamine release [27, 28, 32, 33] (**Figure 1B**). This illustrates that reward and memory systems in the brain are closely interrelated, which makes sense considering that learning is often driven by rewards, punishments, and their anticipation (**Figure 1B**) [34].

The dopaminergic mesolimbic system is involved in experiencing pleasure, and it is directly activated by primary rewards such as palatable food or sexual behavior [24], novel stimuli [35], or pleasant music [36]. By engaging its reciprocal connections to the limbic regions, the accumbens is important for determining the motivational valence of stimuli and for assessing learning incentives. In other words, the accumbens discriminates appetitive from aversive stimuli and decides in which degree they are "liked" or "wanted" [24, 37]. In agreement to this, preclinical research reveals a role of the accumbens in many forms of learning such as in spatial navigation [38], novel object and place recognition [39], fear conditioning [40], or instrumental behavior [41] (see "preclinical models of learning" in **Box 1**), and dopamine in the mesolimbic system promotes an activated state of alertness, arousal, or "seeking" that would facilitate exploration and reward gathering [42]. Moreover, the accumbens has an important role in anticipating the occurrence of rewards by learning which stimuli predicts them (i.e., acquiring conditioned reward-stimuli associations; **Table 1**) [43]. By association with a rewarding stimulus, a neutral stimulus becomes a conditioned reward and gains incentive motivational salience, being able to activate the mesolimbic reward system by itself [34].

When in the presence of dependence-inducing drugs, the dopaminergic mesolimbic system is highly activated, engaging different neurobiological mechanisms depending on the substance (e.g., inhibition of dopamine reuptake cocaine and methamphetamine [44, 45], stimulation of dopaminergic VTA neurons alcohol, methamphetamine, nicotine, cannabinoids [46–49], inhibition

**Anhedonia:** A reduced ability to feel pleasure or joy; a loss of interest for activities or stimuli that were previously engaging for the individual and elicited positive emotions. It is often a symptom of low mood (depression-like behavior). Persons with SUDs may suffer anhedonia or "loss of reward" for experiences that are not related to drugs.

**Appetitive, aversive:** Qualities of stimuli: rewarding (appetitive) or disliking (aversive).

**Craving:** An intense, uncontrollable, and anxious desire to use the drug. It is usually elicited by drugassociated stimuli and it may lead to relapse in drug use.

**Declarative memory:** This memory overlaps with the most common concept of "memory" as it refers to the ability to learn (and also recall, forget, etc.) facts, concepts, or words, life events, and spatial or contextual stimuli (e.g., when America was discovered, what you had for dinner yesterday, where the car was stationed, etc.).

**Dorsal striatum:** A motor control brain center that works in consonance with cortical brain regions (cortico-striatal circuit) to select and initiate appropriate goal-directed responses. The dorsal striatum also transforms the goal-directed actions that are repeatedly rewarded into automatic habits.

**Drug sensitization (vs drug tolerance):** Exacerbation of the rewarding or psychomotor effects of the drug, as a result of the neuroadaptations induced by repeated drug exposure. There is also evidence of the opposite effect, drug tolerance, meaning that the drug progressively blunts its actions.

**Drug-associated stimuli:** Those stimuli (objects, places, people, feelings, etc.) that, by associative learning processes, have been "linked" to the effects of the drug or to drug availability. The presence of these stimuli is a main cause of relapse, as they trigger both craving feelings and uncontrollable drugseeking and drug-taking habits.

**Escalation (in drug intake):** The phenomenon by which the person progressively increases drug use, leading to excessive drug intake. It is also evidenced in the preclinical drug self-administration model, where the animal progressively self-administers more quantities of the drug as the task progresses.

**Executive functions:** A set of high-level cognitive skills that is important for "ruling" behavior. They involve decision-making, planning, reasoning, attentional control, cognitive flexibility, inhibition of undesired behaviors, etc.

**Goal-directed behavior:** Response directed to obtain a reward. It is planned, conscious, and often useful.

**Habits:** "Automatic" and involuntary responses that require minimal cognitive resources to be executed. They are generated after a goal-directed response has been repeated and rewarded numerous times. While habits are adaptive for everyday functioning, a main problem in drug addiction is that behaviors associated to drugs (drug-seeking, drug-taking, etc.) also become uncontrollable habits, contributing to relapse in drug use.

**Incentive (motivational) salience:** Refers to the intensity of attention, attraction, or desire ("wanting") that is elicited by a stimulus. It is usually related to its rewarding value. Drugs and drug-related stimuli gain incentive motivational salience in addiction.

**Limbic regions:** Brain regions mainly involved in the regulation of cognition and emotion. This review considers the prefrontal cortex, the hippocampus, and the amygdala as main brain limbic areas. They are impaired by addictive drugs.

**Long-term potentiation (LTP), long-term depression (LTD):** A form of neuroplasticity that changes the strength of a synapse, for example, as a result of learning processes or after exposure to a drug of abuse. In the LTP, the postsynaptic neuron increases its response (e.g., more neurotransmitter is released, or more neurotransmitter receptors are generated), while in the LTD the postsynaptic response is debilitated.

**Mesolimbic system:** Brain system mainly comprised by the VTA and the accumbens. It is important for experiencing, predicting, and assessing rewards and thus for motivated (i.e., goal-directed) behavior. It is also involved in the motor-activating effects of drugs.

**Neuron:** The main nerve cell in the brain that processes and transmits information through the synapsis. The main parts of a neuron are depicted in **Figure 2**. **Projection neurons** possess long axons that allow communication between distant brain regions, while **interneurons** have shorter axons, limited to a single brain area.

**Neuroplasticity:** Neuroplasticity or neuroadaptation refers to changes in the anatomical structure (dendrites, axon, nuclei, etc.) and function (synaptic strength, neurotransmitter release, etc.) of neurons, in response to environmental or internal stimuli. Another form of neuroplasticity is the generation of new neurons in the adult brain (adult hippocampal neurogenesis). Brain neuroplasticity is modulated by drugs of abuse, yielding an aberrant pattern of brain functioning that contributes to generate and maintain addiction.

**Neurotoxicity:** The effect of a hazardous substance that may involve an irreversible loss of the neuron's anatomy and function and even its death. Addictive drugs such as alcohol, methamphetamine, or heroin have demonstrated neurotoxicity.

**Neurotransmitters:** Chemical messengers synthetized by the neurons that transmit information between them, acting on specific receptors in the synapse. **Glutamate** is the main excitatory brain neurotransmitter, as it "activates" the target neuron, while **GABA** has an inhibitory role; **dopamine** is critical in the mesolimbic reward system regulating reward and arousal.

**Preclinical models of addiction:** Paradigms or "tasks" that are designed to assess addiction-related behaviors in animals, usually rodents (i.e., "preclinical" refers to laboratory research—animal or in vitro previous to clinical studies in humans). For example, the **drug-induced conditioned place preference** assesses drug reward and the learning of drug-stimuli associations, by examining how much the rodent prefers to stay in a maze compartment where the drug was previously administered (which is distinguishable from a neutral maze compartment as they have different contextual cues). The **drug self-administration** paradigm assesses motivation for the drug, by examining how much the rodent presses a level that results in drug delivery (or how much the rodent keeps insisting in pressing the lever even when the drug is no longer provided). Pressing the lever is considered as a drug-seeking (or taking) behavior. There are other models such as the "voluntary drinking" paradigms used for ethanol.

**Preclinical models of learning:** There are a wide variety of tasks to assess different forms of learning and memory in rodents. For example, in the **spatial navigation** tasks, the animal learns to orientate in the surrounding space to find a particular place in a maze (e.g., the maze exit, or hidden food rewards). In **novelty-based** tasks, the animal prefers to explore a novel object or place as long as it remembers the familiar one(s). Tasks based on **associative learning** require the animal to associate stimuli; for example, in fear conditioning, a compartment of the maze where an electric shock is provided is discriminated by its contextual cues (shock-cue association). In **instrumental learning tasks** (operant conditioning), the animal learns to perform a specific response, such as pressing a lever, to obtain a reward, such as food.

**Psychiatric comorbidity:** Different psychiatric disorders that occur simultaneously in the same individual, usually worsening the therapeutic outcome. Drug addiction is often associated to high psychiatric comorbidity, including mood and anxiety disorders (depression, generalized anxiety, phobias, etc.) and personality disorders.

**Relapse:** Resuming drug use after a period of abstinence.

**Reward:** A stimuli or outcome that is pleasurable and/or beneficial for the individual. **Primary rewards** are those stimuli intrinsically pleasurable (e.g., a delicious food), while **conditioned rewards** are those that have gained their reinforcing value by being associated with a rewarding stimuli (e.g., the sound of a bell that rings when the food is ready to serve becomes rewarding).

**Substance use disorder (SUD), drug addiction:** A chronic and highly relapsing disorder which its main characteristic is an uncontrollable (and usually excessive) drug intake. Furthermore, addiction frequently carries a socioeconomic and health burden for the individual, including motivational, emotional, and cognitive impairment. Unfortunately, these symptoms induced by drugs contribute to further drug use, generating a "vicious cycle."

**Stress:** A physiological response generated by a stimulus perceived as threatening or aversive. The stress response is dysregulated by addictive drugs, and experiencing stress contributes to relapse in drug use.

**Synapse:** It is the region where chemical or electrical information is transmitted from one neuron to another. A typical chemical synapse uses neurotransmitters that are synthetized by the presynaptic neuron and released through the axon terminals (**Figure 2**); and then they bind with specific neurotransmitter receptors in the postsynaptic neuron that may be located in the dendritic spines but also in the axon or soma.

**Vulnerability:** Referred to addiction, "vulnerability" entails both biological features and behavioral (personality) traits that predispose the individual to initiate and maintain drug use or to generate a SUD. For example, exacerbated impulsivity and reduced inhibition of behavior, inclination to take risks, preference for experiencing novel stimuli or seeking sensations, or an anxious personality are associated to increased risk for drug abuse. Importantly, the behavioral attributes are assumed to be a reflection of a particular pattern of brain functioning (i.e., they entail a biological-brain-correlate).

**Working memory:** It is a short-term memory capacity for concepts or stimuli that do not need to be remembered in the long-term, but they should be processed (i.e., mentally manipulated or "worked with") for a short period of time. For example, working memory is needed for reasoning, planning, and solving problems or mathematical operations.

#### **Box 1.**

*Definitions.*

of VTA GABAergic interneurons opioids and cocaine [50, 51]. According to the accumbens' role for experiencing rewards, the accumbens is involved in enjoying the recreational feelings induced by drugs [52], in their "activating" psychomotor effects [53, 54], and in learning the stimuli that are predictive of the drug's effects or its availability (i.e., drug-stimuli associations [43, 55]). In this way, rodents with lesions in the accumbens will reduce the expression of drug-seeking or drug-taking behaviors when they are tested in common preclinical models for addiction-like responses, such as conditioned place preference or self-administration paradigms [54, 56–58].

*Aberrant Brain Neuroplasticity and Function in Drug Addiction: A Focus on Learning-Related… DOI: http://dx.doi.org/10.5772/intechopen.85280*


*Behavioral functions and addiction symptoms are linked to the main brain region(s) that supports them, but it should be noted that these reward and learning-related brain systems act in close synchrony (***Figure 1B***) to support behavior.*

#### **Table 1.**

*Impaired function of learning-related brain regions in drug addiction.*
