A series of studies suggest that repeated low doses of d-amphetamine can lead to a progressively greater behavioral response in some people.
This phenomenon, known as “behavioral sensitization,” has been observed in animal models and hypothesized to contribute to addiction in humans.
However, few controlled human studies have directly tested this idea.
A new double-blind, placebo-controlled trial provides further evidence that specific subjective effects progressively increase with repeated d-amphetamine exposure, particularly in women.
At the same time, tolerance developed to other amphetamine effects such as drug liking.
These findings point to the potential to establish a human model of behavioral sensitization that could unlock insights into the development and treatment of drug addiction.
Key Facts:
- Repeated low doses of d-amphetamine led to greater increases over time in energy, euphoria and vigor ratings in healthy volunteers, especially women.
- But drug liking decreased from the first to later amphetamine doses, indicating tolerance.
- Different amphetamine effects may be mediated via separate neurobehavioral mechanisms.
- A human sensitization model could enhance understanding of processes underlying addiction and inform new treatments.
Source: Neuropsychopharmacology
The Animal Model of Behavioral Sensitization
Behavioral sensitization refers to a progressively greater behavioral response that develops with repeated exposures to a stimulant drug.
This phenomenon was first characterized in animal studies, where rodents demonstrate enhanced locomotor activity and stereotyped behaviors when given a stimulant they have previously received compared to animals receiving the drug for the first time.
For instance, rats given repeated injections of amphetamine over days or weeks exhibit greater hyperactivity and repetitive sniffing and licking behaviors when challenged with amphetamine again later on.
Sensitization has also been shown across drug classes – animals pretreated with nicotine, cocaine, alcohol and opiates display an amplified reaction when re-exposed to those substances.
Importantly, sensitization outlasts the presence of the drug in an animal’s system, persisting for weeks, months or even over a year after the initial repeated drug dosing.
Repeated Stimulant Administration Alters Neurobiology
What accounts for this progressive and enduring enhancement of behavioral responses to repeated stimulant administration?
Research points to lasting adaptations in brain dopamine systems.
All drugs of abuse acutely increase dopamine levels in the nucleus accumbens and other reward pathways.
But repeated exposure leads to additional longer-term changes in dopamine neurotransmission.
For one, elevated extracellular dopamine persists beyond the direct pharmacological effects of the drug.
Alterations also occur in dopamine receptors, transporters and intracellular signaling pathways.
Together these neuroadaptations are thought to underlie the enhanced behavioral reactivity to subsequent drug exposures i.e. sensitization.
Some evidence also indicates structural remodeling of dopamine circuitry with repeated stimulant administration.
Sensitization & Addiction Link
Sensitization has been hypothesized to contribute to human drug addiction in two key ways:
- It may explain the transition from casual to compulsive patterns of drug use. As individuals become sensitized with repeated exposures, they experience greater incentive and motivation to take the drug, which drives escalating use.
- Sensitization may also account for why addicted persons relapse easily even after long periods of abstinence. The persistently hyper-reactive dopamine systems render individuals highly vulnerable to the effects of stimulant exposure, precipitating renewed intensive use.
So behavioral sensitization in animals provides a model for elucidating core neurobiological processes that lead to the development and persistence of addiction.
But direct parallels in humans have been less clear.
Prior Human Studies of Behavioral Sensitization
Can behavioral sensitization be demonstrated in people?
Only a handful of controlled studies have attempted to address this question by examining responses to repeated stimulant administration.
In three separate trials, Strakowski and colleagues gave healthy volunteers two or three low oral doses of d-amphetamine (0.25 mg/kg) versus placebo over a several day period.
They observed progressively greater effects over time on measures like eye blink rate, energy, mood and talkativeness.
Personality traits like novelty seeking were linked to enhanced progression of drug responses.
Another study found cocaine addicts did not exhibit further amplification of cocaine effects with repeated intravenous injections over several weeks.
This suggests prior sensitization from abuse histories, so additional progression would not occur.
However, a trial by Wachtel and de Wit failed to detect any progression in amphetamine’s behavioral effects when healthy volunteers were given two 20 mg oral doses several days apart.
D-Amphetamine (0.25 mg/kg) & Behavior Study
These early human studies had limitations like small samples, potential unblinding of subjects and raters to drug versus placebo conditions, and reliance on observer-rated measures.
To address these issues, Strakowski et al. conducted a larger parallel-groups, randomized, double-blind, placebo-controlled trial.
58 healthy men and women were assigned to:
- 3 placebo doses over 5 days (PPP)
- 2 placebo + 1 amphetamine dose on day 5 (PPA)
- 3 amphetamine doses over 5 days (AAA)
0.25 mg/kg oral d-amphetamine was used.
Subjects and staff were blind to group assignments.
Main outcomes were self-reported subjective drug effects, including vigor, euphoria and drug liking visual analog scales.
Eye blink rate was an objective measure collected via videotaping.
Findings: Behavioral Sensitization & Tolerance
On the final test day, vigor and euphoria ratings increased progressively in the AAA group compared to the single dose and placebo conditions.
However, drug liking was highest after the first amphetamine dose and declined with repeated administration.
Women exhibited more robust sensitization-like effects than men across measures.
But eye blink rate did not differ between groups.
Subjects’ ability to correctly guess if they had received amphetamine was no better than chance.
These results provide new evidence that specific behavioral responses may become enhanced with repeated stimulant exposure in humans, particularly women.
But other effects like drug liking demonstrate tolerance.
Different amphetamine effects appear to be mediated via distinct neurobehavioral mechanisms.
Some show sensitization, while others follow an opposing adaptation.
Conclusion: Amphetamine & Behavioral Effects
These findings point to the potential to establish a human experimental model of behavioral sensitization.
Such a model could provide unique opportunities to:
- Elucidate brain mechanisms driving sensitization versus tolerance
- Clarify how sensitization processes precipitate addiction in at-risk individuals
- Explore whether sensitization underlies compulsive drug use and relapse
- Inform the development of new behavioral and pharmacological treatments
- Study the role of sensitization in psychiatric conditions like schizophrenia and bipolar disorder
However, more research is still needed to replicate these observations and resolve inconsistencies across studies.
Potential moderators like drug doses, intervals between exposures and individual traits should be explored.
Larger sample sizes will help confirm effects and clarify sex differences.
It will also be important to test this model with other stimulant drugs like cocaine and nicotine.
Can sensitization be generalized across classes, or does it represent a specific adaptation to amphetamines?
Finally, longer-term follow-up will determine if behavioral enhancement persists after repeated dosing stops.
This will help assess parallels to the enduring sensitization observed in animal models.
While not definitive, these recent findings represent an exciting step toward developing a human experimental model of stimulant-induced behavioral sensitization.
Such a model could provide unprecedented opportunities to elucidate core mechanisms of addiction and new directions for treatment.
Further rigorous research is warranted to realize these potential benefits.
References
- Study: Human response to repeated low-dose d-amphetamine: evidence for behavioral enhancement and tolerance
- Authors: S M Strakowski et al. (2001)
