Interview with Professor Kent C. Berridge
The man who broke the "Dopamine High" myth, and showed the world why we can "like" things we don't "want", and "want" things we don't "like".
One of my personal scientific heroes is the incomparable, indomitable, Professor Kent C. Berridge, currently based at the University of Michigan's very own Berridge Lab, and currently holds the very long (but well deserved) appointment as the James Olds Distinguished University Professor of Psychology and Neuroscience. For many decades, he's been a prolific producer of studies, research papers, theoretical and experimental works on the subjects of dopamine, and is perhaps best known for the Incentive Salience theory, and identifying "liking" and "wanting" as two separate processes in the brain; though he has done much more throughout his highly productive career to date, showing no signs of slowing down!
He's also a really nice person, happy to answer questions from laymen like myself, will happily jump on Zoom to talk all about the new research going on at the Berridge lab on optogenetically stimulating areas of the brain that handle liking, wanting, fear, disgust, and so on.
Recently I asked Prof Berridge if he might be interested in answering a few questions for an article, and to my delight, he agreed! I sent him 6 questions, and received some truly fascinating and in-depth responses which I'm sure you will all appreciate as much as I did.
I've kept the text fairly verbatim, only with minor edits regarding formatting.
Here goes!
Q: You've been the major driving force in the development of Incentive Salience, where did it first begin? What made you decide to go down that particular path, especially considering the orthodoxy at the time?
A: It was not anything we went looking for. In the beginning, around late 1980s, I was convinced by Roy Wise's evidence an that dopamine mediated pleasure 'liking'. His evidence was based on 'anhedonia' (loss of pleasure) apparently induced by drugs that blocked dopamine receptors: they caused rats to gradually abandon pursuit and consumption of food reward, brain stimulation reward, drug reward, etc. The 'dopamine blockade anhedonia' logic was that rats no longer wanted rewards because they no longer liked them after dopamine blockade. That was plausible, and my first dopamine study was a collaborative pilot with Roy Wise to add one more piece of evidence to the dopamine pleasure pile. We tried his blocking drugs in my lab to see if they would reduce 'liking' for sweetness.
I was measuring 'liking' in a different way from Roy Wise's pursuit/consumption tasks. Our facial expression measure was more like how human parents ask if their infants like the taste of the family's food: by giving a taste and watching affective facial expression. This measure was developed for human infants, but also can be applied to animals including rats. I expected that dopamine blocking drugs would reduce facial 'liking' reactions elicited by sugar infusions into a rat's mouth.
So I was very disappointed to find in my lab that taste-elicited 'liking' reactions to sucrose were not at all reduced by dopamine blocking drugs, or even by dopamine brain lesions that left only 1 or 2% of dopamine remaining.
The incentive salience hypothesis was initially a post hoc attempt to explain this failure, and reconcile why dopamine blockade produced anhedonia evidence in traditional choice/pursuit/consumption tests, but failed to reduce sweetness 'liking' reactions at all. It was a very tentative hypothesis at first. It was a possibility, but I didn't really begin to believe in incentive salience until a couple years later, when we began to stimulate brain dopamine systems and found it increased 'wanting' for sweet rewards but again failed to increase 'liking' reactions to the same rewards. That provided confirmation, and helped identify signature features of incentive salience in behavior, and so was more convincing to me.
Q: Since liking and wanting are their own processes, what about disliking, avoidance, fear? Are there any insights into what could be going on with clinical anxiety disorders?
A: Yes, I think 'disgust' and 'fear' are related, but still distinct processes. For example, we can produce 'fearful' reactions (e.g., avoidance and active antipredator defensive burying reactions) without 'disgust' in rats through microinjections in posterior nucleus accumbens that weakly suppress neural activity (i.e., an AMPA glutamate antagonist drug that blocks excitatory glutamate signals). But if we use a different drug that more strongly inhibits the neurons (a GABA agonist that hyperpolarizes neurons), we produce both the fearful reactions but also bitter-like 'disgust' gapes, etc., to the taste of normally pleasant sugar. The fact that both are produced at the same brain site suggests fear and disgust are related, but the fact that excessive disgust requires stronger neural inhibition suggests there are different neural modes involved in 'fear' vs 'disgust'.
Q: I recently posted my response to a question on Parkinsons Disease and have since had quite a few more people reach out to me on the subject; do you have any thoughts on where we might one day find solutions to neurodegeneration?
A: The molecular and cellular mechanisms that kill dopamine neurons in Parkinson's disease are still a bit controversial, but are gradually becoming better understood. So there is hope that when the cell death mechanisms are eventually pinpointed, there may be ways to disrupt those processes and save the neurons. That's still probably quite a way in the future, but there's hope in the long run.
Q: Regarding the hedonic hotspots, is it limited to just opioids, endocannabinoids and GABA?
A: There are a few other neurotransmitters that may work to enhance 'liking' in hedonic hotspots, such as orexin. But never dopamine. Also, aside from neurochemical enhancement, we now have some unpublished evidence from our lab that optogenetic stimulation of neuronal firing in a hedonic hotspot can also enhance 'liking' reactions, at least in orbitofrontal, insula and ventral pallidum hotspots.
Q: I get asked quite often "If Dopamine doesn't cause euphoria, why does Amphetamine have that effect?" Are drugs like Amphetamine activating those hotspots somehow, in addition to their effects on dopamine?
A: Yes, there are two ways amphetamine or cocaine can produce euphoria. First, via incentive salience itself, those drugs can make the whole world, people, events, seem more attractive and inviting. That's a 'wanting' type of euphoria. However, its not necessarily always pleasant: incentive salience can flip to fearful salience in some individuals at high doses, producing amphetamine or cocaine psychosis with paranoia.
The second way amphetamine/cocaine produces euphoria is more related to your suggestion that hotspots become activated. Even though increased dopamine, the direct effect of amphetamine and cocaine, fails to enhance 'liking' in the hotspots, there is some evidence that the drugs can secondarily cause increases in endogenous opioid release in the nucleus accumbens. If an endogenous opioid neurotransmitter, such as enkephalin or endorphin, were released in the hedonic hotspot of NAc, that could plausibly contribute a pleasurable 'liking' component to the psychostimulant euphoria.
Q: What is next for the mind of KCB? What are the next great questions you're most interested in? (Yes, KCB. That’s his official name now, I’ve decided.)
A: I think neuroscience now has lots of ways to change the intensity of 'wanting', but we don't yet have much understanding of what controls the directional target and focus width of 'wanting'. That is, you 'want' food when hungry, a drink when thirsty, different things at other times. In addiction, one set of things may be intensely and narrowly 'wanted', while other life rewards become relatively less 'wanted'. We need to understand how this happens.
That's why my lab is recently using optogenetic stimulations of amygdala to recruit and guide mesolimbic dopamine systems, to control the target and intensity of 'wanting'. Using optogenetic stimulation of amygdala, for example, we let rats choose between sugar and intravenous cocaine. Normal rats choose both relatively equally. But by pairing brain stimulation with a particular target, we can arbitrarily create a 'sugar addict' rat that intensely pursues sugar but completely ignores cocaine. Or make a different rat into a 'cocaine addict' that pursues cocaine but ignores sugar. With the same brain stimulation, we can even make a rat 'want what hurts': that is, to seek out a target that gives no pleasure at all, but only a painful electric shock. This is giving us some insight into mechanisms that control the target and focus of incentive salience.
There are other questions too. For example, regarding pleasure, all the hedonic hotspots cause gain of function, enhancing 'liking' when stimulated. But there is only one site in the brain that, if lesioned, eliminates normal 'liking' so that even sweetness then elicits 'disgust'. That site is the hedonic hotspot of the ventral pallidum. What makes the ventral pallidum hotspot so uniquely crucial to normal 'liking'? I wish I knew...
Once again, I'd like to thank Prof Berridge for taking the time to share his profound knowledge and expertise with us. I've been working on setting up a Dopaminergic podcast as a companion to the blog, and hopefully once that's up and running, I'd love to have him on as a guest sometime!
I hope to be able to do interviews with neuroscientists as a semi-regular feature, so keep an eye out for more of these. I'm also very much looking forward to the new research Prof Berridge mentioned regarding the optogenetic stimulation, and once that's out, I'll probably do an article about it as well.
Stay tuned to the blog, I’ve got lots more coming this weekend, and a big one about Consciousness to be published very soon.