The Hippocampus as a Neural Link between Negative Affect and Vulnerability for Psychostimulant Relapse
The Hippocampus - Plasticity and Functions
Psychostimulant dependence (including cocaine, amphetamine, and methamphetamine) is a chronic relapsing disorder with significant personal, health, and financial burdens. Attempts at abstinence produce a severe and protracted withdrawal syndrome characterized by stress hypersensitivity that can facilitate drug craving, anxiety, and dysphoria. These negative withdrawal symptoms can induce relapse, maintaining the addiction cycle. The hippocampus mediates cognitive, emotional, and endocrine
... ses to stressors. The ventral hippocampus is in a pivotal position to regulate the mesoaccumbal dopamine reward system, and interacts with serotonergic and glucocorticoid systems that mediate anxiety and stress responsiveness. Psychostimulant actions on the hippocampus induce long-term changes to these systems and impact the process of adult neurogenesis in the hippocampus, which may facilitate drug dependence by altering drug-cue learning and emotional regulation. Multiple studies indicate that psychostimulant-induced hippocampal neuroadaptations heighten hippocampal-mesoaccumbal activity to amplify drug-and drug-cue responses while persistent dysregulation of hippocampal emotional systems potentiate negative affect. Understanding how psychostimulants modulate the hippocampus to alter hippocampal-mesoaccumbal activity-and how hippocampal neurogenesis influences drug-related memories and reward-is important for identifying novel treatment strategies that can ameliorate negative affect and relapse vulnerability in psychostimulant addiction. Abuse of psychostimulants such as cocaine and amphetamines affects millions of people worldwide, as psychostimulants are the second most widely abused class of illicit drug globally behind marijuana      . In general, drug addiction and subsequent relapse vulnerability are thought to occur through counter-adaptive neurochemical changes within brain circuits that normally conserve an emotional homeostasis    . Dysregulation of the homeostatic system-through genetics, environment (stress), history of drug taking, or current emotive states-produces susceptibility to become dependent and to relapse during long-term abstinence [9, 10]. Psychostimulants produce a severe and protracted withdrawal syndrome which includes symptoms of stress hypersensitivity, intense drug craving, anxiety, and dysphoria . These symptoms are reproduced in animal models , and can induce craving and relapse in humans [13, 22, 23], thus maintaining the addiction cycle . The underlying mechanisms that enable stress-sensitive and dysphoric states in withdrawal to induce relapse are thought to involve alterations to the mesolimbic dopamine reward system and anti-reward/stress systems [9, 26, 28] that include the hippocampus . Currently, no medications have proven effective for treating psychostimulant withdrawal [13, 16, 31]. Thus, understanding the neurobiology underlying the aversive states during psychostimulant withdrawal is an essential component of relapse prevention . The hippocampus, stress and addiction The hippocampus, a brain region associated with spatial learning and memory, has been established as a critical region for reward-and stress-associated responses and drug-seeking behaviors [30,. Exposure to conditioned contextual cues and aversive or stressful stimuli are powerful triggers of drug cravings  and are associated with activation of limbic brain regions, including the hippocampus, in both human and rodent models . Dorsal and ventral subdivisions of the rodent hippocampus have been proposed based on anatomical connectivity and behavioral output . The rodent dorsal hippocampus, analogous to the human posterior hippocampus, receives exteroceptive information from the entorhinal cortex and has a major role in rapid spatial learning (Figure 1) . The ventral hippocampus, analogous to the human anterior hippocampus, receives interoceptive information through reciprocal connections to limbic regions that modulate motivational and affective states; the other limbic brain regions involved include the nucleus accumbens, amygdala, medial prefrontal cortex, and hypothalamus (Figure 1 ) . Notably, both regions of the hippocampus are involved in memory formation ; dorsal neurons form contextual representations of specific single events while ventral neurons form representations of multiple events (related by a distinct context) over time . The subiculum, the major output structure of the hippocampus, provides projections to the nucleus accumbens, which also receives input from ventral tegmental area (VTA) dopamine terminals [34,. The nucleus accumbens integrates affective and motivational information The Hippocampus -Plasticity and Functions 128 to produce goal-directed behavioral output . Thus, the hippocampus is poised to play an important role in mediating the effects of drugs of abuse (e.g., psychostimulants) through its interactions with the mesoaccumbal dopamine system. Importantly, the dorsal and ventral hippocampus may differentially regulate accumbal activity [60, 63], since the ventral subiculum projects to the medial shell of the nucleus accumbens while the dorsal subiculum projects to the more lateral accumbens and core (Figure 1) [51, 54, 64]. The dorsal and ventral hippocampus also influences accumbal activity indirectly, via multi-synaptic projections to the VTA (Figure 1 ) . Consequently, glutamatergic output from the hippocampus facilitates dopaminergic activity in the mesolimbic dopamine pathway [34, 57, 68, 69]. In the nucleus accumbens shell, this communication is vital for forming place-reward associations  and mediating reward salience . Thus, context-related processing within the hippocampus may drive reward-related processes mediated by the nucleus accumbens. The hippocampus also regulates anxiety and avoidance behaviors. Anxiety is an innate response coordinated to protect an animal from potential harm, which is linked to maximizing chances of reward in approach-avoidance conflict situations. The hippocampus has been proposed to underlie anxiety behaviors by detecting novelty or uncertainty [73, 74] and then increasing attention and behavioral inhibition [75, 76] . However, maladaptive changes to the circuits underlying this response can constrain normal functioning and lead to a disruptive pathological state. The ventral hippocampus in particular plays a predominant role in mediating anxiety/avoidance behaviors. For example, glutamatergic activation of the ventral hippocampus is important for expressing anxiety-like behaviors [77, 78] and lesioning the ventral-but not dorsal-hippocampus reduces innate avoidance behavior in unconditioned anxiety tests, and reduces Figure 1. Schematic of afferent/efferent connections and functions of the dorsal and ventral hippocampus related to reward and stress processes. Abbreviations: Cx, cortex; HPA, hypothalamic-pituitary-adrenal; PFC, prefrontal cortex; PVN, paraventricular nucleus of the hypothalamus; VTA, ventral tegmental area. The Hippocampus as a Neural Link between Negative Affect and Vulnerability... http://dx.doi.org/10.5772/intechopen.70854 The Hippocampus as a Neural Link between Negative Affect and Vulnerability... http://dx.doi.org/10.5772/intechopen.70854 The Hippocampus -Plasticity and Functions 132 The Hippocampus as a Neural Link between Negative Affect and Vulnerability...