**4. Limbic regions: the prefrontal cortex, the amygdala, and the hippocampus**

#### **4.1 Controlling behavior, memory, and mood**

While the addiction theories have traditionally focused on the interaction among the mesolimbic system and the dorsal striatal regions, the limbic brain regions such as the prefrontal cortex, the hippocampus, and the amygdala—have gained increased attention in addiction [27, 104, 105]. As exposed before, the prefrontal cortex, the hippocampus, and the amygdala are mainly glutamatergic structures all

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

reciprocally interconnected [33] that are closely integrated into the reward brain circuit by receiving direct dopaminergic inputs from the VTA and, conversely, by regulating accumbens and VTA activity (Section 2.1; **Figure 1B**).

The limbic system is classically defined as the brain substrate of "emotion" [106]. The limbic regions modulate the stress response, which is generally stimulated by the amygdala but suppressed by the hippocampus and the prefrontal cortex by inhibitory feedback mechanisms [107]. The amygdala also plays a pivotal role in triggering "unpleasant" emotions and responses such as anxiety and fear [108, 109], though it is also involved in positive emotions and it is activated after either appetitive or aversive stimuli, to evaluate their motivational value [110]. The limbic regions also hold cognitive functions. The prefrontal cortex has a key role in behavioral control, by guiding the dorsal striatum to select appropriate actions through the abovementioned cortico-striatal circuit [88] (Section 3) and by inhibiting or updating inappropriate behaviors (reviewed in [15]). Accordingly, the prefrontal cortex is responsible of higher cognitive process such as planning, reasoning, behavioral flexibility, or decision-making (executive functions), and it holds the "working-memory" capacity that allows to manipulate information that is stored in the short-term (reviewed in [15]). The hippocampus is involved in the acquisition, long-term storage, and further processing (extinction, retrieval, updating, etc.) of declarative memory [111]. Declarative memory includes the semantic memory (verbal information, facts, and concepts), the episodic memory (life events), as well as the spatial memory (contexts and places), so a loss of hippocampal function drives severe anterograde amnesia [111]. Moreover, the hippocampus is important for integrating events that are separated in time or space (thus being crucial for associative learning [112]), and it participates in novelty detection that contributes to recognize previously presented stimuli, allowing to lead exploration and/or cognitive resources to the novel ones [113]. Regarding the amygdala, this region also holds a role in cognition, such as in fear memories [114] or in facilitating the emotional modulation of declarative memory, since emotionally arousing experiences are more strongly consolidated and remembered than neutral ones [115] (**Table 1**).

The initial experiences with drugs would use the regular learning mechanisms in the limbic regions to be acquired and stored in memory [116]. In this way, the prefrontal cortex guides the dorsal striatum and acts as an "ON/OFF switch" for drug-seeking, deciding when this behavior should be allowed or inhibited [105]. Regarding the hippocampus and the amygdala, they interact with the prefrontal cortex and the accumbens for the learning of drug-stimuli associations; and these limbic regions collaborate for the subsequent retrieval, extinction, or reinstatement of the drug-related memories (being the reinstatement, a form of "relapse," that in preclinical models is elicited by drug-associated cues, by stress, or by a low dose of the drug—*priming*) (reviewed in [15, 27, 116]). Since the drug-related experiences are rewarding and emotionally arousing, they activate neurobiological pathways involved in the emotional enhancement of associative memory, which may potentiate their acquisition and subsequent long-term maintenance [116, 117].

#### **4.2 Affective and cognitive alterations are concomitant to drug addiction**

After repeated drug exposure, the limbic regions are highly vulnerable to undergo neuroplastic and/or neurodegenerative changes (**Figure 2**). A reduced gray matter volume is often found in the prefrontal cortex, hippocampus, and amygdala of chronic drug users [7, 10, 12, 59, 118], together with a dysregulated expression of genes including those involved in GABA and glutamate neurotransmission

#### **Figure 3.**

*Reduced adult hippocampal neurogenesis as an example of drug-induced neuroplasticity. Photographs show the hippocampus (dentate gyrus) of mice treated either with saline or ethanol for 8 days (protocol published in our previous work [22]). Young neurons expressing the immature neuron marker doublecortin were stained by immunohistochemistry. Arrow points young neurons showing horizontally disposed nuclei and underdeveloped dendritic tree in the ethanol-treated animal. Scale bar: 100 μm.*

[119, 120] and alteration in LTP or LTD processes [121–124]. Particularly, alcohol is associated with severe brain damage and neurotoxicity in the limbic system [12], and sufficient exposure may precipitate severe neurocognitive syndromes such as lasting dementia [125]. Other limbic neuroadaptations induced by addictive drugs involve a reduction of adult hippocampal neurogenesis, as evidenced by a recent *postmortem* study in persons that abused alcohol [126]. The generation, maturation, and functional integration of new neurons in the adult brain—where the dentate gyrus of the hippocampus is a main neurogenic niche—has been extensively described in rodents, for which the new hippocampal neurons participate in many forms of hippocampal-dependent learning and emotional regulation [127]. While the existence and functional implications of adult hippocampal neurogenesis in humans still generate controversy [128], there is currently a wide preclinical evidence supporting that drugs of abuse modulate—mainly reduce—the adult-born hippocampal neurons (**Figure 3**), which has raised interest on the potential involvement of this neuroplastic phenomenon in addiction [27, 116, 129, 130].

Damage of the limbic regions generates the "cognitive" symptoms in drug addiction. The drug-induced neuroplasticity in prefrontal areas involved in the corticostriatal circuit contributes to the "loss of control" over drug-seeking behavior that becomes further governed by the dorsal striatal habits [105, 131, 132] (Section 3; **Table 1**). The prefrontal "disinhibition" may affect other behavioral domains, promoting impulsivity, impaired decision-making, and more involvement in risky behaviors [133] which, in turn, may contribute to further engagement in drug use (**Figure 1A**). Since the limbic regions are required for associative memory, memories for drug-stimuli associations may become engrained in addiction, being resistant to extinction and forgetting but prone to reinstatement [117, 134, 135]. Therefore, a potentiated function of the limbic regions at the initial experiences with drugs may facilitate their storage in memory; but their impoverished function after repeated drug exposure may impede these memories to be subsequently extinguished. As explained before (Sections 2 and 3), the memories for drug-stimuli associations are relevant in addiction, since they trigger drug craving and habitual drug use responses.

Furthermore, limbic system malfunction in addiction yields a variable degree of cognitive decline that may affect both prefrontal- and hippocampal-dependent domains, including attention, working memory, declarative memory, and executive functions, as evidenced in both drug-exposed animals and in persons with

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

SUDs (**Table 1**; reviewed in [15]). Cognitive impairment may last for months or years after ceasing drug use, and, in the most severe cases, it may be irreversible (e.g., [18, 125, 136–138]). The cognitive decline has relevant clinical implications, since it is a consistent predictor of addiction treatment dropout and relapse (reviewed in [15]). In this way, it is possible for cognitive impairment to act as an indirect indicator of the extent of malfunction of the limbic regions that are implicated in key behavioral processes that lead to drug use such as behavioral disinhibition or drug craving (**Table 1**). Another possibility is that cognitive impairment may directly compromise the follow-up of addiction treatments by burdening the acquisition of new adaptive information, such as the contents of behavioral therapies that usually require a considerable cognitive effort to be apprehended [139].

Finally, at the emotional level, malfunction of limbic regions during drug withdrawal may curse with a "negative affect" involving stress and anxiety in addition to "loss of reward" (Section 2; **Table 1**) that may trigger drug use by negative reinforcement (i.e., using drugs to escape the aversive emotional state) [78, 140] (**Figure 1A**). In fact, the stress response is frequently dysregulated in persons with SUDs [141] that are vulnerable to stressful experiences, which are a powerful cause of relapse in drug use [81, 142]. Furthermore, SUDs have a high psychiatric comorbidity (~40%) with mood and anxiety disorders [143–145]. Dual pathology complicates the treatment of drug addiction, since an integrative therapeutic approach that involves both the SUD and the comorbid psychiatric disorder may be necessary for these patients [146].
