Researchers have found that repeated low doses of amphetamine can alter reward and motivation circuits in the human brain.
The changes mirror what is seen in addiction and schizophrenia.
Key Facts:
- Healthy volunteers received 4 doses of a low 20mg dose of amphetamine or placebo, spaced 2 days apart.
- Those getting amphetamine showed enhanced subjective responses over time indicating sensitization.
- During a gambling task in an MRI scanner, amphetamine group showed altered brain responses in regions linked to motivation and reward.
- Effects were seen in the caudate nucleus and amygdala after amphetamine sensitization.
- Changes correlated with the degree of sensitization to the drug’s effects.
- May provide insights into development of addiction and schizophrenia.
Source: PLOS One
Low Dose Amphetamine (20 mg) & Brain Sensitization
Researchers from King’s College London have uncovered evidence that repeated low doses of amphetamine can alter reward processing in the human brain, inducing sensitization effects.
In a study published in PLOS One, the team showed that four spaced doses of 20mg of amphetamine produced sensitization – progressive amplification of various subjective effects of the drug over time.
The researchers also found that this sensitization was accompanied by changes in how the brain responds to rewards, with altered functioning in key regions linked to motivation, learning and emotion regulation.
This is the first time anyone has been able to induce sensitization in humans and show definitively that it changes reward processing in the brain.
The findings provide new insights into how repeated stimulant exposure can disrupt normal reward circuits and drive maladaptive behaviors, as seen in addiction and schizophrenia.
Inducing Sensitization in Humans
Sensitization refers to the progressive increase in drug effects seen with repeated intermittent drug dosing.
It is a phenomenon well established in animal studies, where rodents given repeated stimulants like amphetamine or cocaine show amplified behavioral and neurochemical responses over time.
Sensitization is believed to underlie aspects of addiction, conferring increased motivation and craving for the drug. It may also contribute to dopamine abnormalities implicated in schizophrenia.
Recreating these effects in humans has proven challenging.
But the researchers previously developed a safe protocol for inducing sensitization in people using a low 20mg dose of amphetamine.
In their latest work, they examined how this sensitization affects brain systems involved in reward processing and motivated behavior.
Effects of Amphetamine on Reward Circuits (Study)
22 healthy male participants were given either amphetamine or placebo across 4 sessions spaced 2 days apart.
In between the 3rd and 4th doses was a 2 week washout period.
Those getting amphetamine showed enhanced subjective effects over successive doses indicative of sensitization.
For example, they reported greater amphetamine-like experiences, euphoria, alertness and activity.
During the 4th session, subjects underwent fMRI brain scanning while performing a gambling task where they could win or lose money.
This assessed neural responses during decision-making, reward anticipation and reward outcomes.
In the amphetamine group, key differences emerged in two regions – the caudate nucleus and amygdala – compared to the placebo group.
The caudate showed decreased activation during decision-making but increased activity during reward anticipation after sensitization.
The amygdala showed a blunted response to reward outcomes.
Importantly, the degree of change correlated with the extent of sensitization to the drug’s effects. The greater the sensitization, the larger the neural changes.
Insights Into Addiction and Schizophrenia
The caudate nucleus and amygdala are central components of the brain’s reward system.
The caudate is involved in linking actions to outcomes and habitual behaviors.
The amygdala assigns emotional significance to events.
Disruption of these regions points to sensitized effects on motivation and learning mechanisms that stem from dopamine abnormalities.
Altered caudate signaling may reflect elevated dopamine producing hyper-excitability of neural loops that facilitate compulsive reward-seeking.
Blunted amygdala responses likely indicate sustained dopamine elevation.
This parallels neural effects seen in addiction where enhanced motivation for the drug occurs alongside reduced sensitivity to everyday rewards.
Similar dopamine and reward circuit abnormalities are also well documented in schizophrenia.
Patients show altered associative learning, motivation deficits, and abnormal reactions to positive and negative outcomes.
The findings demonstrate that sensitization impacts dopamine-dependent processes relevant to both disorders.
This shows the translational value of the model for gaining mechanistic insights.
Takeaways: Amphetamine & Reward System Effects
By inducing sensitization in a controlled manner, scientists can better understand how stimulants remodel reward circuits in the brain.
This could aid efforts to develop medications and behavioral treatments for addiction and schizophrenia.
Examining genetic influences on vulnerability to sensitization may be informative.
Interactions between genes and sensitization likely confer risk for mental illnesses.
The researchers hope to explore this gene-environment interplay in future studies.
The researchers also aim to trace sensitization effects over longer timescales and characterize their persistence once stimulant exposure stops.
Knowing whether sensitization-related neural changes are transient or enduring will reveal their true disease relevance.
Overall, this groundbreaking research provides a framework for studying how stimulant-induced neuroplasticity contributes to compulsive behaviors and dopamine dysfunction.
Uncovering these mechanisms in humans moves the field closer to novel ways of treating and preventing addiction and schizophrenia.
References
- Study: Amphetamine sensitization alters reward processing in the human striatum and amygdala
- Authors: Owen G. O’Daly et al. (2014)
