Stimulants: Therapeutic actions in ADHD
PSYC 8705 Neuropharmacology
Presented by XXXXXX
General Roadmap
 Therapeutic actions of stimulant administration both for
animal and human subjects
 Highlight the importance of prefrontal cortex as an area of
pharmacological intervention for individuals suffering from
ADHD
 Similarities between studies on animal subjects and
humans
Extending the literature: Kuczenski and Segal’s
(2002): Rodent model
 Old assumption: Animals and humans differ in their
responses to stimulants
 Rats: When administered with high doses of stimulants,
dopamine was released in the ventral and dorsal striatum
of the rat’s brain and resulted in locomotor hyperactivity.
 Human: Subjects who were being treated for ADHD using
stimulant medication responded with reduced locomotor
activity and an ability to better concentrate.
Clients with ADHD vs. ‘normal’
 Old assumption: Differences between the effects of
stimulants on ADHD and ‘normal’ individuals.
 Paradoxical calming effects on ADHD patients.
 ‘Normal’ individuals taking the same dose reported
simulating effects.
It’s the dose not the species
 Kuczenski and Segal’s (2002) significantly extended the
literature by directing a greater attention to the dose of
stimulants that was administered to rodents and
humans.
 Doses administered to rodents far exceeded the
equivalent doses administered to humans with ADHD
 Given lower doses, both rodents and humans responded
with the same behaviors (e.g. decreased locomotion;
little effect on dopamine release).
Norepinephrine I: Release
 NE: Enhances cognitive functioning in PFC by acting on
postsynaptic α2A receptors
 Kuczenski and Segal (2002): Release of norepinephrine
in the hippocampus (-> greater research attention on
NE).
 Berridge et al (2006): High levels of catecholamine
release in the prefrontal cortex
 ADHD medications most commonly affect the pre-frontal
cortex rather than the subcortical areas.
 Significant because neither PET nor SPECT ligands
were able to detect catecholamine release in the cortex.
Norepinephrine II: Blocking
Monkeys: Blocking α2A receptors in the PFC erodes
delay-related cell firing and creates symptoms similar to
those of individuals with ADHD.
 Conclusions:
1. Genetic mutations in NE synthetic enzymes (DBH) or
the α2A receptors may contribute to ADHD by
weakening the endogenous noradrenergic α2A
adrenoceptor signaling.
2. High levels of NE release (e.g. during stress) impair
prefrontal functioning through action at the α1 receptors

Prefrontal cortex
 Prefrontal cortex: Attention, working memory, planning,
impulse control, inhibition of responses to distractions,
mental flexibility, and the ability to monitor actions
 Lesion studies:
1. Ventromedial prefrontal cortex:
Emotion dysregulation (Anderson et al., 1999)
Distractability (Godefroy & Rousseaux, 1996)
Decreased inhibition of unimportant stimuli (Yamaguchi
& Knight, 1990)
Decreased concentration and organization (ThompsonSchill et al, 2002)
2. Dorsolateral prefrontal cortex:
Inability to shift attention (Manes et al, 2002),
3. Superior prefrontal cortex
Inability to divide attention.
Prefrontal cortex: Sensitive to genetic mutations &
developmental abnormalities ?

1.
Structural imaging studies:
Smaller volume of PFC, right hemisphere, cerebellum,
caudate, and corpus callosum among ADHD patients
(Sowell et al, 2003; Seidman et al, 2005).

1.
2.
Functional imaging studies:
Reduced blood flow and metabolism in PFC
Impairments of associated cognitive functioning in PFC
Receptor sites?
 Dopamine D1, D4, D5 receptors, dopamine beta
hydroxylase (DBH), and the α2A adrenoceptor gene are
associated to ADHD (Park et al, 2005)
 Polymorphism: Ineffective/excessive catecholamine
receptor stimulation can result in severe cognitive
impairments associated with the PFC (Arnsten &
Robbins, 2005).
 Dopamine (D1 and D5):
1. Humans: Greater DA release during stress impairs
memory and attention regulation in humans (Arnsten et
al, 2005)
2. Monkeys: Stimulation of D1/D2 receptors during a
spatial working memory task
Moderate: Improved inhibition + enhanced spatial tuning
High: Suppressed inhibition + eroded spatial tuning
 Conclusion: Mutation/impairment of DA receptors ->
impairments in behavior regulation.
Critical Review I
 Pervasive lack of information: Research questions or
research purpose are missing, which makes a
purposeful review difficult.
 Little information about the studies supporting the
author’s argument (sample size, participant variables,
and empirical or not).
 Little discussion of the reviewed studies which makes a
critical analysis of the author’s research rationale very
difficult
 No exploration of alternate explanations (Better: Present
why the proposed theory seems more plausible than
alternate explanations).
 No statement describing the relevance of the findings for
the treatment of ADHD
Critical Review II
 Causality (see p. 2378). : Author implies causality
without the proper support (For example, just because
individuals with ADHD are impaired on the same tasks
as patients with prefrontal lesions, ADHD is not
automatically associated with prefrontal dysfunction).
 Reduced volume (see p. 2378): It is not mentioned
whether the reduced volume of those brain regions is
relative to the remaining brain regions or can be
attributed to an overall smaller sized brain. Compare to
gender studies: The size does not necessarily increase
functioning.
 Better: Investigate whether those smaller portions of the
prefrontal cortex still maintain their intended function.
Critical Review III

1.
Unrelated information:
α1 receptor blockers such as Prozosin are used in the
treatment of PTSD (p.2380).
Unclear: How are the actions of NE on α1 receptors,
as seen in PTSD treatment, related to the actions of
the same neurotransmitter on a different kind of
receptor, even if that receptor belongs to the same
receptor family.
2.
ADHD and bipolar disorder are often confused during
diagnosis (p.2380): It is unclear how this information
relates to ADHD.
Conclusion
 Despite the lacking discussion of the research findings and
a missing research purpose, the arguments presented in
the article appear to follow each other logically and provide
a good overview of the effects stimulants have on
prefrontal function and catecholamine receptors.
 Using lesion studies to simulate developmental
abnormalities and genetic mutations might be too
unspecific but those studies provide important indicators
for the effects of the simulated receptor dysfunction for
cognitive abilities among both human and animal research
subjects.