**3. The BLA: role in alcohol addiction**

The amygdaloid complex is made up 13 distinct nuclei which are divided in three groups: the deep or basolateral group, the superficial or cortical‐like group, and the centromedial group [104]. These nuclei have been proposed to be located in such a way to maximize the amygdala's connections with other limbic, cortical, and subcortical regions of the brain to help facilitate its function in emotional processing, learning, and fear memory [105–107]. The basolateral amygdalar complex, comprising of lateral amygdala (LA), basal and basomedial nuclei [108, 109] controls behavioral expressions like emotional arousal, fear, and stress that are linked to traumatic incidents, stressful environmental stimuli, or pharmacological stressors, and consolidates them as memories [70]. The BLA communicates through excitatory efferents to the prefrontal cortex and structures of the limbic system involving the hippocampus, NAc, dorsomedial striatum (DMS), and BNST [110–114], while it receives feedback from these structures through glutamatergic afferents [115, 116], majority of which converge with the cortical inputs [114] running toward the BLA.

pivotal role in processing of information from emotional and rewarding stimuli. Chronic alcohol abuse alters the activity of these brain areas, resulting in changes in motivational and goal‐directed behaviors, which further drive alcohol‐seeking behavior [76, 77]. For instance, studies have shown that behavioral sensitization to alcohol is mediated by accumbal 5‐HT2C receptors [76], and blockade of 5‐HT3 receptors especially in the VTA attenuates alcohol consumption [77]. The 5‐HT receptors, 5‐HT1A, 5‐HT1B, 5‐HT2A, and 5‐HT2C, [78–80] have been widely implicated in alcohol consumption in animal models with new evidence also impli‐

NE has been shown to play a significant role in negative emotional states which contribute to alcohol consumption [60, 83, 84]. Acute alcohol decreases [85], while chronic alcohol and withdrawal increases the activity of neurons in the locus coeruleus (LC), a region that provides the majority of NE in the brain [86]. Activation of the *α*2‐adrenergic autoreceptors has been shown to attenuate the overall negative effects of withdrawal [87], and blocking *α*1‐adrener‐ gic receptors (ARs) using prazosin reduced alcohol consumption in dependent rats [88] and human alcoholics [89]. Likewise, treatment with the *β*‐AR antagonist, propranolol, reduced drinking in dependent rats [60]. Evidence also suggests that *β*‐ARs may also contribute in

Furthermore, CRF is a regulating factor in the activation of the hypothalamus–pituitary– adrenal (HPA) axis to stress [90–94]. Chronic alcohol consumption affects CRF signaling in the central nucleus of amygdala (CeA) and BNST, as evidenced by alterations in CRF transmis‐ sion during withdrawal [95]. Interestingly, NE and 5‐HT have been shown to interact with the neurotransmitter CRF in neuroanatomical sites like the LC, DRN, CeA, and BNST [96–100] to influence addictive behaviors. For instance, yohimbine, a pharmacological agent used to promote stress in rats, has effects on NE, 5‐HT, and CRF signaling to potentiate alcohol drinking and reinstatement [101, 102], suggesting possible mutual regulatory roles of these neurotransmitters in alcohol dependence and relapse. This was further evidenced by CRF antagonism in the DRN to attenuate yohimbine‐induced alcohol‐seeking behaviorin rats [100]. Also, CRF and NE antagonism has been shown to be effective in reducing stress‐induced

The amygdaloid complex is made up 13 distinct nuclei which are divided in three groups: the deep or basolateral group, the superficial or cortical‐like group, and the centromedial group [104]. These nuclei have been proposed to be located in such a way to maximize the amygdala's connections with other limbic, cortical, and subcortical regions of the brain to help facilitate its function in emotional processing, learning, and fear memory [105–107]. The basolateral amygdalar complex, comprising of lateral amygdala (LA), basal and basomedial nuclei [108, 109] controls behavioral expressions like emotional arousal, fear, and stress that are linked to traumatic incidents, stressful environmental stimuli, or pharmacological stressors, and consolidates them as memories [70]. The BLA communicates through excitatory efferents to

cating 5‐HT3 and 5‐HT6 receptors in alcohol addiction [81, 82].

120 Recent Advances in Drug Addiction Research and Clinical Applications

mediating the anxiolytic effects of alcohol [58].

reinstatement in human alcoholics [88, 103].

**3. The BLA: role in alcohol addiction**

The role of the BLA in fear, memory consolidation, and emotional learning along with its contribution in associative learning for appetitive conditioning is well documented [70, 105, 117, 118]. Since the BLA can impart incentive salience to a previously neutral stimulus in response to a motivational or a goal‐directed task [119], recent efforts have now focused on the role of the BLA in drug‐seeking, including cocaine [120], morphine [121], and alcohol [122– 124].

Alcohol has been shown to increase neuronal activity and glucose utilization in the BLA [125]. Additionally, long‐term alcohol exposure alters glutamate transmission in the BLA [126] and NAc [127], which is implicated in increased alcohol self‐administration in rodents [128]. Furthermore, alcohol‐induced withdrawal stress increases presynaptic glutamatergic func‐ tion in thalamic afferents to the BLA that may explain the increased emotional dysregulation during withdrawal [129]. It has also been shown that altered neuropeptide S function in the BLA following long‐term alcohol exposure may contribute to relapse [130]. Furthermore, a recent study has shown thatIL‐1 receptor signaling in the BLA contributes to binge‐like alcohol consumption in mice [131].

There is growing body of evidence that supports the role of the BLA in conditioned–cued relapse [132] and context‐induced reinstatement [133] for alcohol and a variety of other drugs [134–137]. It was shown that the BLA may play a significant role in cue‐induced alcohol reinstatement [138], following exposure to previously alcohol‐paired environmental cues [123]. Research has also shown that BLA–glutamatergic signaling attributes salience to conditioned cues that are related to alcohol‐seeking [132], while the opioidergic system of the BLA may play a role in context‐induced alcohol‐seeking [140]. Indeed, since the BLA exten‐ sively communicates with the NAc, alcohol withdrawal‐induced changes in glutamatergic function in the BLA get perpetuated in structures of the reward system that may contribute to craving and relapse [141].

It is well documented that repeated and chronic stress leads to adverse behavioral outcomes, and many studies support the reinforcing effects of chronic stress in drug addiction in animal models [86, 142–144]. Stress alters the morphology of BLA principal cells and impairs fear extinction memory [145] that may have implications in the development of affective disor‐ ders like PTSD and depression. It has been shown that the BLA modulates chronic stress‐ induced learning and memory deficits in the hippocampus, suggesting that dysregulation of BLA–hippocampal signaling may affect memory storage, retrieval, and extinction of fear memory that may contribute to emotional disorders and drug dependence [146]. Further‐ more, early life stress causes increased excitability of pyramidal cells in the BLA [147], while chronic restraint stress in adolescent and adultrats increases BLA activity [148]. Increased BLA excitability has been positively correlated with increased anxiety and increased alcohol‐ seeking behavior [141, 147, 149, 150].

Long‐term exposure to alcohol simulates chronic stress‐like conditions [130] that have a profound effect on fear memory consolidation [151]. Alcohol withdrawal‐induced stress has been shown to increase conditioned fear [152] and impair extinction of fear memory [153]. A recent study also showed that repeated alcohol exposures enhance retrieval of previously consolidated fear memories and augments activity in BLA and other brain regions involved in fear memory retrieval [154].
