**5. Conclusion**

chronic alcohol‐induced neuroadaptations in other receptor subtypes like the GABA‐A receptors facilitate the anxiolytic effects of alcohol [171]. Increasing the activity of 5‐HT on GABA‐A receptors on BLA principal cells may contribute in reducing withdrawal‐induced

**Figure 2. Changes in 5‐HT signaling and BLA output following acute and chronic alcohol exposure or withdrawal**. Acute alcohol increases 5‐HT release in the BLA which is regulated by a feedback loop through 5‐HT1A autoreceptors expressed on 5‐HT neurons in the DRN. Increased BLA‐5‐HT levels enhance the inhibition of BLA activity through postsynaptic 5‐HT1A receptors expressed on principal neurons. Increased 5‐HT signaling also activates 5‐HT2A/2C recep‐ tors expressed on GABAergic interneurons in the BLA that further increase the inhibition on BLA principal cells through increased GABAergic tone. The net result of this inhibition is decreased BLA principal neuron excitability and BLA activity, which has been shown to reduce anxiety and may explain the anxiolytic effect of acute alcohol. Chronic alcohol/withdrawal increases the expression of 5‐HT1A autoreceptors in the DRN which decreases 5‐HT levels in the BLA. This reduces 5‐HT1A‐mediated inhibition on BLA principal cells. Chronic alcohol‐induced withdrawal downregu‐ lates the expression of 5‐HT2A/2C receptors on GABAergic interneurons to further decrease the inhibitory GABA tone on BLA principal cells, increasing excitability. Chronic alcohol also upregulates GABA receptors on principal cells. This

results in a net increase in BLA activity causing anxiety that may contribute to alcohol‐seeking and relapse.

Furthermore, cross‐modulation of synaptic transmission in the BLA by 5‐HT1A/1B receptors and *β*‐ARs dictates BLA output [159] that may affect behavioral outcomes like stress, anxiety, and drug dependence. In support of this, we have shown that pindolol, a drug having dual pharmacological activity on 5‐HT1A/1B receptors and *β*1/*β*<sup>2</sup> ARs, decreases alcohol consump‐ tion in mice following long‐term alcohol exposure. Our electrophysiological experiments also indicate that the BLA may mediate the effects of pindolol on alcohol consumption [172].

anxiety and alcohol‐seeking.

124 Recent Advances in Drug Addiction Research and Clinical Applications

Research in the past few decades has significantly increased our understanding of the neurobiological basis of alcohol dependence. Recent research has targeted pathways that mediate more than just the reinforcing properties of alcohol. However, despite these concert‐ ed efforts, effective pharmacological interventions for the management of AUDs remain elusive.

Chronic alcohol consumption causes maladaptive changes in brain regions like the extended amygdala that cause sensitization to negative emotional states of withdrawal. These changes disrupt the signaling of many neurotransmitters including those involved in stress. Dysregu‐ lation of NE and 5‐HT signaling has been widely implicated in the development of affective disorders andalcohol addiction. Specifically, NEand/or 5‐HTimpairments in theBLA, a region involved in stress, emotional processing, and reward‐seeking have been suggested to play a major role in the development of alcohol dependence (**Figures 1** and **2**).

In addition to the growing evidence in animal models of alcohol addiction, pharmacological compounds that target NE and 5‐HT receptors have also shown promise as potential treat‐ ment strategies for AUDs in human patients [173, 174]. Noradrenergic compounds like propranolol [175, 176] and atenolol [174] have been shown to attenuate alcohol‐seeking behavior and reduce craving in human alcoholics. Similarly, serotonergic compounds like buspirone show efficacy to reduce anxiety‐induced consumption in alcoholics [177, 178]. Moreover, our research indicates that pindolol, the FDA‐approved antihypertensive drug having activity on both 5‐HT and NE receptors, may have a similar mechanism of action to more effectively reduce alcohol consumption following chronic intake [172].

Since the BLA plays a vital role in affective disorders and stress‐induced maladaptive behavioral conditioning, drugs that selectively modulate NE and 5‐HT signaling in the BLA offer great promise in the treatment of AUDs. With the increasing need for improved pharmacotherapeutic strategies for the management of AUDs combined with the modest efficacy of current treatments, putative compounds that target 5‐HT and NE receptors may prove useful for the development of more effective treatment strategies for alcohol depend‐ ence.
