Imagine having a child who is so uncontrollably disruptive that going out to eat at restaurants is never an option. With no friends at school, he is just as frustrated as anyone else about his inability to focus. “ADHD [attention deficit hyperactivity disorder] really is a debilitating condition,” says Dr. Amy Arnsten, professor of Neurobiology and Psychology at Yale School of Medicine, “And not just for the children, but for the whole family.” Arnsten’s laboratory recently developed a drug, guanfacine, which provides a new option for the treatment of ADHD.
Like many other mental illnesses, ADHD was not taken seriously by the public for many years. Recent scientific studies, however, have underscored the biological basis of ADHD. ADHD is highly heritable and associated with weakness in the prefrontal cortex (PFC) (figure 1), the most evolved region in the brain. The PFC, located at the forefront of the brain, regulates our attention and actions and is key for judgment and high-order decision-making. For most people, language is governed on the left side of the PFC, while inhibition of inappropriate behaviors is controlled on the right. Children who lack focus or self-control, common symptoms of ADHD, have been found to have deficiencies in their PFC, particularly in the right hemisphere.
The PFC relies on a delicate yet well-balanced system of neurotransmitters to function properly, most notably norepinephrine (NE) and dopamine (DA). The right amount of NE will properly stimulate postsynaptic alpha-2A receptors (figure 2) to inhibit cAMP (cyclic adenosine monophosphate) in PFC dendritic spines, protrusions where neurons communicate. When there is inadequate NE stimulation of alpha-2A receptors, cAMP opens ion channels that weaken neuronal inputs. With sufficient NE, the cAMP pathways are inhibited and the neuronal networks connect more effectively (figure 3)
Arnsten’s laboratory found that guanfacine, which mimics NE at alpha-2A receptors, strengthens PFC regulation of behavior and attention. These basic studies have led to an extended release formulation of guanfacine (figure 4), called Intuniv that has recently been approved by the Food and Drug Administration to treat ADHD. Intuniv helps patients to control their distractibility and impulsivity. “Ours is one of the few examples of a drug coming out of a laboratory in academia,” explains Arnsten, “It took twenty years, but considering ninety-five to ninety-nine percent of compounds produced in drug companies never make it out, it really means a lot for ours to be out there helping people.” Since guanfacine had been used for years to reduce high blood pressure, it was known safe for human use. Hypotension and sedation are its main side effects, but it is not prone to abuse since its effects do not cause addiction.
Treatment for ADHD, which was traditionally limited to methylphenidate, commercially known as Ritalin, now offers more options. “ADHD was largely ignored in the past,” explains Arnsten, “[not only] because people didn’t understand it, but also because life was simpler back then. Having ADHD was sometimes even an advantage, allowing people to make necessary impulsive decisions.” But in the Information Age, ADHD is a greater liability for those diagnosed with the disorder. “We need our PFC more to succeed in our culture as never before.”
Arnsten is inspired knowing that children out there are benefiting from her work; she frequently reads parents’ blogs late at night. “One mother says her young son, now on Intuniv, smiled for the first time in two years,” says Arnsten.
The Arnsten Lab is now looking into better treatments for schizophrenia, bipolar disorder, and post-traumatic stress disorder. The lab hopes to understand how genetic insults weaken PFC circuits and develop treatments to restore normal functioning.
Additional Readings:
Arnsten, Amy. The Emerging Neurobiology of Attention Deficit HyperactivityDisorder: The Key Role of the Prefrontal Association Cortex. The Joumal ofPediatrics 2009; 154: S22-S31.
Robbins TW. Shifting and stopping: fronto-striatal substrates, neurochemical modulation and clinical implications. Philos Trans R Soc Lond B Biol Sci. 2007; 362:917-32.
Wang M, Ramos B, Paspalas C, Shu Y, Simen A, Duque A, et al. Alpha2A- adrenoceptor stimulation strengthens working memory networks by inhibiting cAMP- HCN channel signaling in prefrontal cortex. Cell 2007;129:397-410.