Behavioral sensitivity to stress increases as alcohol dependence evolves, and stress is a relapse trigger in alcoholism. Up-regulation of corticotropin-releasing hormone (CRH) signaling in extrahypothalamic brain sites contributes to these dependence-induced changes, but other stress-related neurotransmitters may also play a role. One such neurotransmittor is substance P (SP), which together with its preferred neurokinin 1 receptor (NK1R) is highly expressed in brain areas involved in stress responses and drug reward, including the hypothalamus, amygdala, and nucleus accumbens. In rodents, genetic deletion or pharmacological blockade of NK1R inhibits the associated behavioral responses, whereas psychological stressors induce release of SP in the amygdale (Holmes et al., 2003). In humans, the NK1 antagonist GR205171 reduces symptoms of social anxiety and suppresses brain responses to the Trier Social Stress Test (TSST) (Furmark et al., 2005). Together, these findings suggest that blockade of NK1Rs might modulate stress-related processes of importance for excessive alcohol use and relapse. To our knowledge, however, NK1 antagonism has not been examined in relation to alcoholism. In our recent studies we have therefore examined the role of the NK1 receptor system
