Angiotensin-Converting Enzyme Inhibitors Modulate Brain Opioids
Post by Shireen Parimoo
The takeaway
Angiotensin-converting enzyme (ACE), an enzyme that normally regulates blood pressure in the body, is also important for reward processing in the brain. Inhibition of ACE in the nucleus accumbens may be a viable option for treating addiction and substance use disorders.
What's the science?
The nucleus accumbens (NAc) is a key region of the reward circuit in the brain and is implicated in addiction. Two types of NAc neurons – DS1 and DS2 neurons – are important in reward processing but are difficult to study separately because they receive similar inputs and express many of the same genes. This, in turn, makes it difficult to develop pharmacological treatments for addiction that specifically target DS1 or DS2 neurons. Interestingly, only DS1 neurons express angiotensin-converting enzyme (ACE), which is thought to modulate excitatory transmission within the NAc by acting on opioid receptors and may be important in reward processing. This week in Science, Trieu and colleagues sought to identify the exact mechanism by which ACE regulates synaptic transmission in the NAc and to elucidate its role in the reward pathway.
How did they do it?
The authors conducted a series of ex vivo and in vivo experiments. First, they quantified ACE expression in slices of NAc neurons and applied captopril (an ACE inhibitor) and naloxone (an opioid receptor antagonist). Recording mEPSPs (miniature excitatory postsynaptic potentials) from both DS1 and DS2 neurons in those slices allowed them to determine whether ACE affected synaptic transmission in the NAc through opioid signaling. Next, they used liquid chromatography-tandem mass spectrometry to examine the effect of NAc stimulation on the concentration of different enkephalins (e.g., Leu-enkephalins, MERF, etc.). Enkephalins are opioid peptides released by DS2 neurons and except for MERF, most enkephalins can be degraded by ACE. The authors assessed how ACE inhibition and optogenetic stimulation affected enkephalin levels, as well as the subsequent impact of elevated enkephalin levels on synaptic transmission in the NAc. They then applied captopril and MERF to NAc slices along with opioid receptor antagonists to identify the specific opioid receptors that are involved in ACE inhibition.
The authors also investigated the effect of ACE inhibition on excitatory transmission in vivo by administering captopril and optogenetically stimulating medial prefrontal neurons that provide excitatory input to the NAc. Finally, they used a place conditioning paradigm to study the impact of ACE inhibition on reward learning in mice. In this paradigm, mice typically prefer a context that is paired with a reward compared to a control context. The authors examined the impact of captopril on preference for a context paired with fentanyl, an opioid drug that normally has an excitatory effect on NAc neurons.
What did they find?
There was a higher concentration of ACE in DS1 compared to DS2 neurons in the NAc. Inhibition of ACE led to long-term depression (a form of synaptic plasticity) in the DS1 neurons but had no impact on synaptic transmission in DS2 neurons. Naloxone – an opioid receptor antagonist – prevented long-term depression in DS1 neurons when it was applied together with captopril. However, applying naloxone after captopril did not reverse LTD. These findings demonstrate that ACE inhibition triggers synaptic plasticity by acting on opioid receptors in the NAc.
Extracellular concentrations of all enkephalins increased following NAc stimulation, including MERF. However, inhibiting ACE increased MERF but had no impact on other enkephalins. Moreover, stimulating DS2 neurons increased MERF levels even in the presence of captopril, which indicates that MERFs are released by DS2 neurons. Applying enkephalins to both DS1 and DS2 neurons decreased the frequency (but not amplitude) of mEPSPs in the NAc, with the strongest effects resulting from MERF application. In DS1 neurons, captopril and MERF alone did not affect mEPSPs but applying them together reduced mEPSP frequency. Additionally blocking the mu opioid receptor prevented the reduction in mEPSP frequency, which suggests that ACE inhibition triggers synaptic plasticity changes in DS1 neurons by acting on the mu opioid receptors. Finally, medial prefrontal input to the NAc typically increases excitatory transmission in DS1 neurons, but this sensitivity was reduced in the presence of captopril. Similarly, mice who underwent place conditioning showed a strong preference for the fentanyl-associated context, but this preference was smaller when captopril was administered. Thus, ACE inhibition reduced NAc activity in vivo and modulated reward learning in mice by dampening the impact of reward at the neural level.
What's the impact?
This study is the first to demonstrate how ACE inhibitors modulate synaptic transmission in specific types of neurons in the nucleus accumbens. Given the crucial role of the nucleus accumbens in reward processing, ACE inhibitors hold considerable potential for the development of targeted drugs for treating addiction and substance use disorders.