Francisco Corvalan Hopp

The latest DA research has well established the important role played by the nucleus accumbens (NAc) in the neuroregulation of DA with paths coming mostly from PFC, Amygdala and Hyppocampus competing for attention from the NAc, whereas NAc discriminates which stimulus will be preferred: 1. “Emotions” coming from Amygdala, 2. “Context” coming from Hyppocampus and 3. Rationality (goal-directed) coming from PFC. Interestingly both Amyg and HypoC have better chance to be heard, since they influence the DA phasic release (250 nM) overwhelming the cell with their input, while PFC works continuously like a “pacemaker” enabling the dopamine release in small amounts (from 0.01 to 0.04 nM) in

the synaptic channel like in a steady state (Grace 1995, 2001). The adaptation of this finding to ADHD came pretty soon: Söderlund a.al. refers to ADHD as the fight between goal-directed vs. stimulus-response behavior, proposing that cronic low levels of DA in ADHD upregulate the efficiency of the phasic response,

with an hypersensivity to environment stimuli. He suggests that for low DA levels, more external “noise” is needed for higher cognitive performance, in order to a. reduce the importance of emotional/contextual stimuli, b. in order to let the neurons release sufficient DA in the synaptic channel to get attention to PFC’s directions (Sikström/Söderlund 2007).

Psychopharmacology Hopp

Dr. Beate Schrank

Jan 2014

It is the Nucleus Accumbens, …!I N S I D E T H I S A R T I C L E :

Advances: Neurobiology of ADHD

Regrets of ADHD experts in NYT 29-12-13http://www.nytimes.com/2013/12/30/health/adhd-experts-re-evaluate-studys-zeal-for-drugs.html

“My belief based on the science is that symptom

reduction is a good thing, but adding skill-building is a better thing,” said Stephen Hinshaw, a psychologist at the University of California, Berkeley, and one of the (DSM) study researchers. “If you don’t provide skills-

based training, you’re doing the kid a disservice. I wish we had had a fairer test.”

Note: Caveats are rising to the use of MPH, AMP so far the main and side effects in the long-term reduce the ability of the person to manage him/herself.

Nucleus Accumbens 1

Regrets of ADHD experts 1

NE and the Locus Coeruleus 2

MPH’s influence on DA 2

Noise improves performance 2

Avoiding DA depletion 3

Drugs addressing NE-LC 3

Choice: DA or NE for ADHD? 3

While Grace researched the DA system, Aston-Jones did the same with the NE neurons, in that he also differentiated two processes in the NE cells: phasic and tonic, both of them related to the attention processing and to the discrimination of task-relevant stimuli, dismissal of distractors, selective attention, filtering, i.e. cognitive functioning. From his

NE and the locus coeruleus => Impact on attention research he concluded

that the Locus Coeruleus plays a central role in regulating the balance between focused vs. flexible responding, or selective vs. scanning attention. All brain areas associated with attentional processing are densely innervated with NE neurons, not only giving the NE neurotransmitter the “arousal” role, but also performance role for

attention task, discriminating distracters, etc.

Some of the ADHD experts have soon integrated the new NE role in the action of MPH, since MPH is a dual DA & NE reuptake inhibitor, postulating a new “catecholamine” ADHD theory vs. the old one DA-ADHD theory (Biederman 2005, Devilbiss 2011). See Aston-Jones in Brain Norepinephrine (Ordway, 2007).

The fact that some researchers are going deeper into the mechanism of motivation, attention and executive functions, help others to explain how Methylphenidate MPH works, since its action is not clear enough. It impacts both DA and NE systems, and it seems that its action be not specific enough. Grace’s discovery means that DA

MPH’s questionable influence on DA is not only important for the tonic firing (triggered from PFC) but also during the phasic DA release (provoked by the input from Amygdala and Hyppocampus), reason why some explain the MPH mechanism as highly context-dependent, since this more DA will enable the person to be more attentive to the context, like in the school

environment where the patient taking MPH will be more sensitive to the teacher than those w/o MPH => because of the “overrepresentation of the limbic influence in the Nac” (Grace,2007)

A second aspect being currently discussed around MPH is the down-regulation of post-synaptic D1 receptors in the presence of DA in the channel, leading to less receptors what in turns tend to be a vicious circle (similar to the danger of tolerance and substance abuse)

Researchers in Stockholm found that background “white noise” is beneficial for children with ADHD, since this background noise raises the dopamine level and allow them to “generate” more available dopamine that will be then used by the focusing job

“Noise” improves cognitive performance to ADHDin the Locus Coeruleus

instead of creating phasic releases of DA when environmental stimuli show up (thus distracting them). They explain this with the “stochastic resonance” model, that means that the signal-to-noise-ratio SNR is being

increased when “white noise” is being added to the channel, allowing the receptor to filter out the significant signal, in this case the focus task (Söderlund et.al 2007).

“The noradrenergic system has been intimately associated with the modulation of higher cortical functions including attention, alertness, vigilance and executive function. Noradrenergic activation is known to

Neurobiology of ADHDPage 2

There are many similarities between the LC-NE anddopamine (DA) systems, but the relationships betweenthese systems and how they interact have remained unclearAston-Jones, 2005

Research applied to ADHD treatment Page 3

.Another interesting topic has been the Dopamine Depletion studies, which have demonstrated the role of DA in goal-directed behavior and self-control. It is just enough to deplete DA through nutrition to be able to destabilize the normal functioning of a healthy individual, shifting or falling back from goal-directed behavior to habitual, long-learned behavior. This could imply

Avoiding DA depletionIMHO this investigation could be enhanced: First you might deplete dopamine through its precursors to deteriorate the focus on goals AND/OR secondly you might increase DA the inverse way thus improving goal-directed behavior. Since tyrosine is the main precursor for DA (together with phenylanaline and tryptophan), there are

several “natural” recipes to provide tyrosine to ADHD, even directly, although this second part of the investigation is still on progress and without further results. There are some evidence that tyrosine work the first weeks, but this is still been regarded as alternative treatment and only suggested for Adult ADHD. Only case studies have been reported.

Since the side-effects of MPH and AMP are some times devastating for individuals, in special young people, there is currently a trend to become more accurate with drugs that have shown less side-effects and address specifics. One of them is clonidine, a blood-pressure treatment medicine, that inhibits the tonic release of NE at the Locus

More specific drugs addressing NE-LC neurons Coeruleus, thus improving

the focusing and attention to task (discrimination). The other one is guanfacine, that also acts directly to the NE cells in the LC and PFC. Both drugs have been 2009 and 2010 by the FDA for treatment of ADHD in children and adolescents. There are still few studies on these 2 drugs, mostly case studies regarding weight gain and

sedation /hypotensive occurrences. Also stopping clonidin causes the blood pressure to raise suddenly, while guanfacine might behave better in relationship to sedation occurrences. Both drugs should be taken at bed time to reduce the tiredness during the day experienced in the first days of treatment.

Faraone, 2010

As a short summary, it seems that ADHD is a multiple disorder that implies different brain systems. ADHD’s with hyperactivity, impulsiveness and distraction seem to be more related to the DA system and NACC:

Do we have to choose DA or NE for ADHD? “stimulus-directed” behavior

vs. goal-directed (see Grace tonic and phasic DA release, and “noise” SNR effect). ADHD more type III “sluggishness” seems to be more related to the NE systems located in LC and PFC, which controls arousal, vigilance, learning (and motivation). We would

need to differentiate these 2 systems properly to give an adequate treatment according to the diagnosed ADHD type. Traditional medications are currently being discussed due to their heavy side-effects and habituation and new drugs are being included “officially” as drugs-of-choice for ADHD.