Dr. Robert Malenka, MD, Ph.D., is a professor of psychiatry and behavioral sciences at Stanford School of Medicine. He has made numerous seminal discoveries of how the brain changes (neuroplasticity) in response to learning and in response to rewarding and reinforcing experiences
In this episode of Huberman Lab, Andrew Huberman and Robert Malenka discuss neuroplasticity as it relates to the brain’s reward systems and how they motivate us to seek out specific behaviors, substances, and social connections.
Host: Andrew Huberman (@hubermanlab)
Dopamine is the substrate from which adrenaline is made (or epinephrine in the brain) which allows us to get into action
Dopamine is a neuromodulator in the brain whose main function is in reward circuitry
Mesolimbic pathway AKA reward circuitry: ventral tegmental area (VTA) + nucleus accumbens
Reward circuitry: tells us something in our environment or some stimulus feels good (driving us toward) or bad (driving us away)
  • Think about Thanksgiving or holiday meals: before you eat, the smell of food is stimulating and you enjoy it – when you’re full, those same smells are almost aversive
Prefrontal cortex: important in setting rules and understanding appropriate responses given context
Dopamine is highly plastic and highly contextually dependent – the dopamine system is in communication with memory systems in the hippocampus
If you get excited or anticipate something, the rate of dopamine firing increases 30-40x and pushes you to action
Examples of activities and associated dopamine increases: sex doubles dopamine levels; nicotine increases dopamine by 150%, cocaine and amphetamine increase dopamine by approximately 1000%, video games can release dopamine somewhere between nicotine and cocaine
The rate and amount of dopamine increase are related to the addictive property of a drug or behavior
  • The route of administration influences the reward circuitry and speed of dopamine release – the effect of snorting cocaine is different than injecting
  • A single administration can cause temporary changes in the brain that extend beyond the experience (e.g., one use of cocaine can induce changes in the brain lasting for a day/week, etc.)
Addiction is a continuum – there are different degrees of addictive liability; caffeine has addictive properties and causes tolerance, but you’re unlikely to engage in harmful behavior to pursue
“It’s impossible to become addicted to a substance if you’ve used it.” – Dr. Robert Malenka
Addiction makes a broader array of experiences (drugs, substances, etc.) attractive to us so we’re more likely to engage, further feeding addiction problems
A common experience of addictive disorder: I hate it and I can’t wait to do it again
  • Drugs or stimulus trick the reward circuitry – this is the underlying cause of addiction
  • Not everyone who uses a substance will become addicted but you can’t predict ahead of time, again because you can’t become addicted to something you’ve never used
Whether you develop a problem with addiction is related to other parts of your life – do you have other healthy outlets (e.g., exercise)?
Things that are reinforcing are not always rewarding  
  • Reinforcing: the behavior that led to the stimuli makes you want to do that behavior again
  • Rewarding: the behavior felt ‘good’
The addictive liability of opioids and psychostimulants release massive amounts of dopamine via very different mechanisms
Psychostimulants (cocaine and methamphetamines) bind to protein in the brain responsible for sucking up the dopamine in the brain so you release more dopamine
Opiates work where the dopamine lives and increase activity in dopamine neurons themselves, causing massive release
Even when talking about one category of drugs (like opioids), they’re not all created equal in impact on the brain or in subjective experience
  • Fentanyl has a much greater addictive liability because of how it interacts in the brain
Talking about autism: individuals living with autism spectrum disorder are on a wide continuum ranging from highly functioning to maladaptive – but most have some social impairment
  • The term ‘autistic’ is becoming used less because of the highly heterogeneous nature of autism spectrum disorders
  • There is evidence that the reinforcing component of social interaction is reduced or lacking in individuals with autism spectrum disorder
  • It’s possible that some aspects of serotonergic systems may not be functioning in some individuals with autism spectrum disorder
Pro-social, non-sexual experiences are highly reinforcing and modify the reward circuitry
  • Why? It’s highly evolutionary – you’re protected from predators in groups, it’s enjoyable and energizing, it buffers against loneliness, increases the likelihood of reproducing, etc.
  • Oxytocin is evolutionarily conserved and is released during bonding, promoting sociability as well
The nucleus accumbens and related circuitry play an important role in which behaviors you choose to participate in and pursue
Dopamine is released in the nucleus accumbens and VTA during positive, non-aggressive social interactions (and maybe negative ones if you like to fight)
  • Serotonin is also released – remember, dopamine and serotonin are not released in isolation, it’s a weighting of inputs
Social media has a high addictive liability – it’s capitalizing on primitive, neurocognitive mechanisms; there’s something stimulating about knowing someone is thinking about you
A key component of positive, prosocial interactions is empathy (influence by the emotional state of another member of species)
  • Ongoing mouse research: will one mouse behave in a generous or compassionate way so another receives a reward or experiences pain relief?
  • Dopamine and serotonin may influence empathic behaviors
Social buffering of pain: in social settings, you actually experience some level of pain relief
MDMA is an amphetamine derivative
The major molecular targets of MDMA are the molecules that inhibit dopamine and serotonin (in other words, MDMA spews out dopamine and serotonin release)
MDMA gives people a different effect than other methamphetamines because of its ability to favorably release serotonin more than dopamine
The addictive liability of MDMA is mediated by its effects on the dopamine system and the prosocial effect is likely mediated by serotonin
Serotonin neurons in a different region than the nucleus accumbens of the brain influence dopamine neurons
Distinct neural mechanisms for the prosocial and rewarding properties of MDMA (Science Translational Medicine)
Oxytocin receptor is not required for social attachment in prairie voles (Neuron)
Gating of social reward by oxytocin in the ventral tegmental area (Science)
Anterior cingulate inputs to nucleus accumbens control the social transfer of pain and analgesia (Science)
Social reward requires coordinated activity of nucleus accumbens oxytocin and serotonin (Nature)
Selective filtering of excitatory inputs to nucleus accumbens by dopamine and serotonin (Proceedings of the National Academy of Sciences)
Serotonin receptor regulation as a potential mechanism for sexually dimorphic oxytocin dysregulation in a model of Autism (Brain Research)
5-HT modulation of a medial septal circuit tunes social memory stability (Nature)
MapLight
Multidisciplinary Association for Psychedelic Studies (MAPS)
MindMed