The role of the amygdala in modulating opioid withdrawal is of particular interest; this was one of the nuclei showing prominent opioid modulation of Htr3a expression in our studies. The expression of Htr3a is particularly high in the amygdala [56]. It has long been recognized that this structure is involved in various physiological aspects of the opioid withdrawal syndrome in rodents. For example, microinjection of naloxone and its derivatives into the amygdala precipitates jumping behavior in morphine-dependent rats [57,58]. Additional experiments have identified the periaqueductal gray matter as a key center mediating the signs of opioid withdrawal [57]. This was the area showing the greatest degree of Htr3a modulation of opioids in our experiments. Moreover, the amygdala is one of the structures at the center of the neuroadaptive changes supporting the larger syndrome of addiction to opioids and other substances of abuse [59]. Although not tested for opioids specifically, ondansetron microinjection into the mouse amygdala (and dorsal raphe) blocked an aversive behavior (light/dark exploration) exhibited by rodents during withdrawal from nicotine, cocaine, benzodiazepines, and ethanol [38].
