behavioral pharmacology

Welcome to UChicago...

A quiet college campus where the sky is grey, the air is still and cold and every morning, raven black monsters fly from tree to tree cawing, as we all huddle closer for warmth in the Regenstein library-bunker.

Welcome to UChicago.

The sun forgot to rise this past week, causing the temperature to drop to an all time low of -60 degrees, not that any one noticed, since it is a mere 20 degrees colder than the usual temperature of our ice-wastes. The University secret police has announced that classes, are not, in fact, cancelled. Any one who fails to show up to class will be executed, or worse, expelled

A look at our community calendar: The quarterly Humans vs. Zombies game has kicked off today. The Moderators would like to remind you that attendance is MANDATORY. All students without the proper armaments are to report to the center of the Quad to receive their $5 HvZ set which includes: a Smith & Wesson .44 Magnum Revolver, 2 bags of hollow-tipped rounds and several hand grenades with an accompanying launcher. Students who pay one dollar more will also receive an entirely useless but very cool looking crossbow. The Moderators would also like to remind you that this is just a game and that guns do not actually kill zombies. In fact, guns do not even kill people. Zombies are not even real, say The Moderators. Nothing is real. We are all immortal and it’s a miracle! The Moderators concluded their statement with this: all humans who claim that they have been irreversibly turned into a zombie after being bitten by one are merely hallucinating or suffering from a particularly virulent strain of Ebola. Please disregard these people. In fact, don’t even go near them, Ebola is very contagious, you know….

And now, a word from our sponsors: Do you like ipecac? Do you like illicit narcotics? Do you like vomiting uncontrollably….for science? Of course you do! You’re a college student. The DeWitt Laboratory of Human Behavioral Pharmacology of the Department of Psychiatry and Behavioral Neuroscience would like to recruit YOU to be their next study subject! Applicants must be old enough to make poor life choices and be of able and healthy constitution. All interested applicants should stand in the center of the Science Quad, facing GCIS and wave around a bag of illicit narcotics, shouting, “We want more drugs!”

Update on the sun that is failing to rise. University administrators are scrambling arrange an emergency Kuvia at the point in the hopes that the annual blood magic of sacrificing a first year in the firepits and the ritualistic “sun salutations” from the local students of the University will succeed in convincing the sun to rise again. The students of Dodd Mead are protesting this motion, as they claim they have not been given sufficient time to prepare their annual propaganda and indoctrination of their first years, and thus run the risk of losing the trophy filled with unrefined uranium traditionally awarded to the house with the greatest attendance. 

And now for some news: The Math Department, in an attempt at expanding their department’s dedication to theory over practice, have relinquished all earthly ties this last Tuesday. Several of the department’s faculty were last seen transcending their earthly bonds and transforming into strange nebulous masses of pure logic and reason. The department’s building, Eckhart Hall, has also decided to join this massive exodus from our spectral plane by becoming entirely translucent and then disappearing all together. Students trying to reach their classes in Eckhart, can still reach the building through the bridge from Ryerson or by praying in their dorm’s bloodstone circle, sacrificing a first year and writing out the proof of the Fundamental Theorem of Calculus in their blood if they do not wish to face the cold of the ice-wastes. The Philosophy Department has gone on record criticizing the Math Department for being entirely unoriginal, as the Philosophy Department had also left behind their earthly bonds several years prior. 

 The University Secret Police called a press conference today to remind people that Greek life does not exist. They stood outside Saieh Chapel and vehemently denied the existence of these so-called “fraternity” and “sorority” organizations. They continued this denial for several minutes and through a lengthy period of questioning from the gathered press which mostly consisted of pointing at the building directly connected to the Saieh Chapel and raising an eyebrow. “Greek Life is not real” they said, “Nu-uh. What is this ‘Panhellenic’ thing you keep talking about?  Show me a fraternity! Show me one of these so-called “frat-bro” students! You are not a frat bro. What’s a frat? Who let you in here?” They then ended the press conference with the customary rounding up, arrests and filing of restraining orders against dissenting members of the press.

Today, the Hunchback that lives in the tower above Rockefeller chapel played the Star Wars theme on the bells again, followed by a series of anime theme songs and several songs made popular by the internet, Including, but not limited to “Nyan Cat” and “Darude Sandstorm” When reached for comments, he only said “I did it for Scav” and “Lol I’m so quirky lol” before scurrying back up to his nest on a gargoyle overlooking University Ave.“ 

More to come…

Small DNA modifications predict brain's threat response

The tiny addition of a chemical mark atop a gene that is well known for its involvement in clinical depression and posttraumatic stress disorder can affect the way a person’s brain responds to threats, according to a new study by Duke University researchers.

The results, which appear online August 3 in Nature Neuroscience, go beyond genetics to help explain why some individuals may be more vulnerable than others to stress and stress-related psychiatric disorders.

The study focused on the serotonin transporter, a molecule that regulates the amount of serotonin signaling between brain cells and is a major target for treatment of depression and mood disorders. In the 1990s, scientists discovered that differences in the DNA sequence of the serotonin transporter gene seemed to give some individuals exaggerated responses to stress, including the development of depression.

(Image caption: An artist’s conception shows how molecules called methyl groups attach to a specific stretch of DNA, changing expression of the serotonin transporter gene in a way that ultimately shapes individual differences in the brain’s reactivity to threat. The methyl groups in this diagram are overlaid on the amygdala of the brain, where threat perception occurs. Credit: Annchen Knodt, Duke University)

Sitting on top of the serotonin transporter’s DNA (and studding the entire genome), are chemical marks called methyl groups that help regulate where and when a gene is active, or expressed. DNA methylation is one form of epigenetic modification being studied by scientists trying to understand how the same genetic code can produce so many different cells and tissues as well as differences between individuals as closely related as twins.

In looking for methylation differences, “we decided to start with the serotonin transporter because we know a lot about it biologically, pharmacologically, behaviorally, and it’s one of the best characterized genes in neuroscience,” said senior author Ahmad Hariri, a professor of psychology and neuroscience and member of the Duke Institute for Brain Sciences.

“If we’re going to make claims about the importance of epigenetics in the human brain, we wanted to start with a gene that we have a fairly good understanding of,” Hariri said.

This work is part of the ongoing Duke Neurogenetics Study (DNS), a comprehensive study linking genes, brain activity and other biological markers to risk for mental illness in young adults.

The group performed non-invasive brain imaging in the first 80 college-aged participants of the DNS, showing them pictures of angry or fearful faces and watching the responses of a deep brain region called the amygdala, which helps shape our behavioral and biological responses to threat and stress.

The team also measured the amount of methylation on serotonin transporter DNA isolated from the participants’ saliva, in collaboration with Karestan Koenen at Columbia University’s Mailman School of Public Health in New York.

The greater the methylation of an individual’s serotonin transporter gene, the greater the reactivity of the amygdala, the study found. Increased amygdala reactivity may in turn contribute to an exaggerated stress response and vulnerability to stress-related disorders.

To the group’s surprise, even small methylation variations between individuals were sufficient to create differences between individuals’ amygdala reactivity, said lead author Yuliya Nikolova, a graduate student in Hariri’s group. The amount of methylation was a better predictor of amygdala activity than DNA sequence variation, which had previously been associated with risk for depression and anxiety.

The team was excited about the discovery but also cautious, Hariri said, because there have been many findings in genetics that were never replicated.

That’s why they jumped at the chance to look for the same pattern in a different set of participants, this time in the Teen Alcohol Outcomes Study (TAOS) at the University of Texas Health Science Center at San Antonio.

Working with TAOS director, Douglas Williamson, the group again measured amygdala reactivity to angry and fearful faces as well as methylation of the serotonin transporter gene isolated from blood in 96 adolescents between 11 and 15 years old. The analyses revealed an even stronger link between methylation and amygdala reactivity.

“Now over 10 percent of the differences in amygdala function mapped onto these small differences in methylation,” Hariri said. The DNS study had found just under 7 percent.

Taking the study one step further, the group also analyzed patterns of methylation in the brains of dead people in collaboration with Etienne Sibille at the University of Pittsburgh, now at the Centre for Addiction and Mental Health in Toronto.

Once again, they saw that methylation of a single spot in the serotonin transporter gene was associated with lower levels of serotonin transporter expression in the amygdala.

“That’s when we thought, ‘Alright, this is pretty awesome,’” Hariri said.

Hariri said the work reveals a compelling mechanistic link: Higher methylation is generally associated with less reading of the gene, and that’s what they saw. He said methylation dampens expression of the gene, which then affects amygdala reactivity, presumably by altering serotonin signaling.

The researchers would now like to see how methylation of this specific bit of DNA affects the brain. In particular, this region of the gene might serve as a landing place for cellular machinery that binds to the DNA and reads it, Nikolova said.

The group also plans to look at methylation patterns of other genes in the serotonin system that may contribute to the brain’s response to threatening stimuli.

The fact that serotonin transporter methylation patterns were similar in saliva, blood and brain also suggests that these patterns may be passed down through generations rather than acquired by individuals based on their own experiences.

Hariri said he hopes that other researchers looking for biomarkers of mental illness will begin to consider methylation above and beyond DNA sequence-based variation and across different tissues.

Placebo analgesia: A review

Time to rehash my fall term paper for the Behavioral Pharmacology course. -

Abstract: Our understanding of the neurophysiological and psychological mechanisms of placebo analgesic effects has expanded considerably over the last 20 years owing to the developments in brain mapping and imaging techniques. We have now identified a number of neural circuits in the brain involved in the modulation of pain perception based on emotional and cognitive factors. Numerous studies have shed light on the role of specific receptors and neurotransmitters involved in these circuits and how they regulate each other in different areas of the brain resulting in modulation of placebo analgesia. We also now understand the importance of environmental factors, learning, memory, emotional state, gender, personality traits, pre-notions and non-specific factors in pain interpretation. The identification of the clinical implications of placebo-nocebo effects will enable us to design better clinical studies and provide absolute data for new analgesic drugs. It is important to understand the ethical consequences of implementing psychosocial strategies based on placebo effects in conjunction with traditional treatments to improve pharmacotherapy.  Further studies in this field could provide new treatment strategies in disease conditions like chronic idiopathic pain, Parkinson’s disease and Alzheimer’s disease.

Introduction – What is Pain?
The origin and mechanism of pain has fascinated various philosophers and scientists over a number of centuries. Charles Darwin described pain as a ‘homeostatic emotion,’ which is essential for the survival of a species1. Over the years, our understanding of this phenomenon has improved remarkably. Today, the International Association for the Study of Pain (IASP) defines Pain as – “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”2. From the evolutionary and behavioral stand point, pain reflex is a part of the body’s defense mechanism that alerts the individual from harmful stimuli and prevents from reinjuring a wound.

The general mechanism of pain reflex has been well studied over the years. Noxious stimuli of various modalities are sensed by a specialized set of nerve fibers (unmyelinated C fibers and thinly myelinated A fibers). These nerve fibers with the help of Purinergic channels and receptors convert the physiochemical stimuli into electrical signals (Action potential). These sensory inputs are then integrated at the spinal dorsal horn and transmitted to specific areas of the brain through numerous neural pathways. The thalamus and limbic areas are believed to mediate the emotional and aversive components of pain. The cortex is identified to perceive the pain and accordingly relay back motor signals through the efferent nerve fibers to the spinal cord, which enables the withdrawal from the noxious stimuli. This general mechanism may not be true in case of chronic pain, which is usually idiopathic and serves no clear biological purpose.

Molecular physiology of Nociception:
The most important advances in pain and analgesia research have come through our understanding of basic molecular neurophysiology involving specific endogenous neurotransmitters and receptors. The peripheral sensory network mainly involves glutamate acting on ionotropic and metabotropic glutamate receptors, Substance P acting on TrkA tyrosine kinase receptors and Lectin analogues acting on P2X3 receptors1. The phosphorylation of Ionotropic glutamate receptors (NMDA and AMPA receptors) lead to biophysical changes and results in central sensitization, which is characterized by hyperalgesia, allodynia and chronic pain. This central sensitization can also be modulated by the metabotropic glutamate receptors and also through dis-inhibition of GABAergic signals3. Cannabinoid receptors have also been discovered to show anti-nociception action by inhibiting signals from periphery, through their interaction with opioid receptors and PAG, a neural analgesic substrate. Numerous other receptors and proteins are also currently being discovered that have implications in pain signal relay along the spinal chord to the brain.

The nociceptive processing in the supra-spinal sites is mainly carried out at the thalamic relay nuclei. They play a key role in pain modulation and further relay of signals to the cerebral cortex. It has been discovered that few descending inhibitory systems combine together at the brainstem rostral ventro-medial medulla (RVM) and modulate the spinal transmission1. These modulatory signals are controlled through the endogenous opioid system and are of evolutionary significance as they enable the organism to ignore pain in critical situations of stress and recovery. This relay system between the frontal cortex, limbic systems and thalamus enables cognitive and emotional control respectively over nociception and therefore plays a major part in placebo-based analgesia4,5.

Placebo and Nocebo effects:
Placebo effects are the psychobiological effects in the brain and/or body that occur following an inert treatment or procedure that has no direct pharmacological actions6. When these observed effects are harmful or undesirable they are termed as Nocebo effects. Numerous studies have confirmed that modulation of pain perception can be controlled by ‘expectation’ alone and that both placebo and nocebo effects can change when pre-conditioned6,7. Brain imaging and radiotracer studies have identified that all subtypes (μ, κ, and δ) of Opioid receptors are involved in placebo analgesic effects and that Cholecystokinin (CCK) system opposes this effect (therefore are usually involved in nocebo effects)7. These opioid-based effects were primarily discovered in specific brain regions - prefrontal cortex, Pre-aquaductal grey area and amygdala1.

Other systems have also been identified to be involved in placebo analgesia. Nucleus accumbens is a major area of the brain that is involved in placebo analgesia and features numerous dopamine neurons. It is considered that Dopaminergic responses to placebo interventions interact with downstream opioid signaling8. Another study has identified that central Serotonergic and Noradrenergic neurons also modulate the descending pain modulatory circuitry that mediates analgesia induced by opioids, which explains the analgesic effects of certain tricyclic antidepressants9.

Behavioral and Clinical Implications of placebo analgesia:
It has been confirmed that placebos have better effect than ‘no treatment’, in case of subjective continuous outcomes and for treatment of pain10.  We now understand that positive and negative expectations can be used to manipulate pain perception and thereby behavior11. It has been observed that under the expectation of high pain, the anxiety mechanisms are stimulated in the hippocampus and brain stem regions and thereby stimulating CCK systems resulting in nocebo effects12. Also both cognitive and emotional systems are involved in the modulation of pain perception through various mechanisms such as learning, memory, reward, beliefs, personality, psychological traits etc. The most well studied mechanisms involved in placebo analgesia are expectancy and conditioning. Pavlovnian conditioning which involves pairing an unconditioned stimulus (drug) with a conditioned stimulus (shape, color, flavor, taste, of the pill or route of administration of the drug) leads to a conditioned response (analgesia), even when only the conditioned stimulus is administered. The magnitude of the effect depends on the duration of the acquisition phase and the effect of the conditioning procedure13.

Reward expectation has also been shown to effect placebo analgesia perception through dopaminergic mechanisms14. This could have significant implications in clinical trial patient selection. The expectation created based on past experience and learned memory also influence perception of drug effect and is called cognitive reappraisal. This explains why red placebo pills are more likely to act as stimulants compared with blue placebo pills as red is associated with ‘danger’ or ‘hot’. Also more expensive placebo treatments produce higher analgesic effects than less expensive ones15. Personality traits also influence placebo analgesic effects through dopaminergic pathways and using this data, patients can be selected based on expected placebo analgesia16.

The influence of the study design, verbal suggestions and other environmental factors can indirectly affect the perception of pain due to placebo analgesia. It has been identified that the pharmacodynamics and efficacy of the drug can also be altered based on Expectation18. In a ‘hidden-open’ placebo-nocebo intervention study, patients perceived pain relief only after informing them that the drug infusion had began even though they had already begun the administered. Similarly, the patients stopped perceiving analgesia upon informing them that drug was stopped even though it wasn’t and the neuroimaging data confirmed this effect. The placebo/nocebo effect due to the Expectation was able to overcome the actual pharmacodynamics effect of the drug.18

Placebo analgesia study models:
While designing studies for placebo-analgesia, the confounding factors such as natural history, personal biases and co-interventions should be taken into consideration and minimized so that the absolute pharmacological effect of the drug can be determined. Most analgesia studies use standardized pain intensity rating systems to obtained psychological details from patients directly. The common designs used are - Balanced placebo design, Double blind versus deceptive design, Open-hidden paradigm and Brain mapping using PET, fMRI and ECG17.

Balanced placebo design involves the comparison of the responses in patients to the informed amount of drug with the informed amount of placebo and between the actual doses of drug and actual doses of placebo. This design enables the study of the effects of verbal suggestions on placebo analgesia.

Double blind versus deceptive design compares the therapeutic outcome of a double-blind administration of an active drug with a deceptive one. The option of getting either a placebo or drug, during the double blind study, results in less placebo analgesia than when administering only the placebo, but disguised as a potent drug, during the ‘deception’ study.

Open-hidden paradigm is used to identify the placebo effect in context to specific instructions. The administration of active drug is hidden from patient initially and changes in the analgesia perception once informed are studies. Similarly, the cessation of the administration of the drug is hidden and informed later to observe changes in perception. This design has been used in studying placebo analgesia in case of anxiety, Alzheimer’s disease and Parkinson’s disease.

Brain mapping techniques enable the identification of the brain area and circuits involved in placebo analgesia under different physiological and pathological conditions. There are some drawbacks of using brain mapping techniques in that the brain patterns that predict placebo analgesia might differ among individuals as this does not take into account the affective information (Information on which aspects of pain that were actually judged by the patient). Data obtained from Pain intensity ratings includes this factor and therefore may differ from conclusions obtained from brain images.

Importance of placebo analgesia:
Most analgesic drugs show different efficacy and potency in different patients due to variability in the patients’ prior beliefs, personality traits, other environmental factors and study design factors19. Unexplained variability due to placebo analgesia makes it a challenge to control non-pharmacological responses in clinical trials and capitalize on them in clinical care. Clear understanding of placebo analgesia should provide new insight into development of efficient screening procedures for pain medication.

Placebo analgesia could also be harnessed either as a solitary treatment strategy or in conjunction with pharmacologically active drugs to improve the end-effects in patients. Better understanding of the effects of physician-patient interactions, clinical practices, verbal suggestions, patient expectations and classical conditioning techniques may pave way for new strategies for placebo-based analgesic therapy. Numerous brain-mapping studies have established that placebo effects of analgesia can be clinically implemented owing to its considerable magnitude and long duration of action. But, further large-scale clinical studies establishing these concepts are required for the wide-scale use of deception or non-deception-based strategies for placebo analgesia in the clinical environment.

Although the primary molecular neurophysiology of placebo analgesia is complicated and involves a variety of receptor systems, it is irrefutable that it plays a major role in the efficacy of a number of drug classes such as Tricyclic antidepressants, opioid analgesics, etc. Comprehensive understanding of these mechanisms is crucial for the development of not just new drugs but also better treatment strategies. The use of placebo analgesic effects as a treatment using deception models are strictly prohibited due to obvious ethical reasons19. A recent study of the influence of placebo effects in IBS patients, at Harvard Medical School, highlights a new argument that placebo treatment can work even without deception20. Although further clinical studies are required to confirm this phenomenon and understand the underlying mechanism, it can potentially open new doors for the use of clinical placebo analgesia based therapies. For now, we can try to put into practice our knowledge of the positive effects of expectation and belief in the form of better clinical practices and patient care along with improving the patient-physician interactions.

1.    Kuner, R. Central mechanisms of pathological pain. Nat Med 16, 1258-1266 (2010).
2.    Part III: Pain Terms, A Current List with Definitions and Notes on Usage (pp 209-214) Classification of Chronic Pain, Second Edition, IASP Task Force on Taxonomy, edited by H. Merskey and N. Bogduk, IASP Press, Seattle, ©1994.
3.    Fields, H.L. & Levine, J.D. Pain—Mechanisms and Management. West J Med 141, 347-357 (1984).
4.    Basbaum, A.I., Bautista, D.M., Scherrer, G & Julius, D. Cellular and Molecular Mechanisms of Pain. Cell 139, 267-284 (2009).
5.    Benedetti, F., Mayberg, H.S., Wager, T.D., Stohler, C.S. & Zubieta, J.-K. Neurobiological Mechanisms of the Placebo Effect. The Journal of Neuroscience 25, 10390 -10402 (2005).
6.    Benedetti, F. Mechanisms of placebo and placebo-related effects across diseases and treatments. Annu. Rev. Pharmacol. Toxicol. 48, 33-60 (2008).
7.    Bingel, U., Colloca, L. & Vase, L. Mechanisms and Clinical Implications of the Placebo Effect: Is There a Potential for the Elderly? A Mini-Review. Gerontology 57, 354-363 (2011).
8.    Scott, D.J. et al. Individual Differences in Reward Responding Explain Placebo-Induced Expectations and Effects. Neuron 55, 325-336 (2007).
9.    Porreca, F., Ossipov, M.H. & Gebhart, G.F. Chronic pain and medullary descending facilitation. Trends Neurosci. 25, 319-325 (2002).
10.    Review: placebo is better than no treatment for subjective continuous outcomes and for treatment of pain. Evidence Based Medicine 7, 11 (2002).
11.    Price, D.D. et al. An analysis of factors that contribute to the magnitude of placebo analgesia in an experimental paradigm. Pain 83, 147-156 (1999).
12.    Benedetti, F. Cholecystokinin Type A and Type B Receptors and Their Modulation of Opioid Analgesia. Physiology 12, 263 -268 (1997).
13.    Siegel S. 2002. Explanatory mechanisms for placebo effects: Pavlovian conditioning. In The Science of the Placebo: Toward an Interdisciplinary Research Agenda, ed. HA Guess, A Kleinman, JW Kusek, LW Engel, pp. 133–57, London: BMJ Books
14.    de la Fuente-Fernández, R. The placebo-reward hypothesis: dopamine and the placebo effect. Parkinsonism Relat. Disord. 15 Suppl 3, S72-74 (2009).
15.    Blackwell, B., Bloomfield, S.S. & Buncher, C.R. Demonstration to medical students of placebo responses and non-drug factors. Lancet 1, 1279-1282 (1972).
16.    Schweinhardt, P., Seminowicz, D.A., Jaeger, E., Duncan, G.H. & Bushnell, M.C. The Anatomy of the Mesolimbic Reward System: A Link between Personality and the Placebo Analgesic Response. The Journal of Neuroscience 29, 4882 -4887 (2009).
17.    Colloca, L., Benedetti, F. & Porro, C.A. Experimental designs and brain mapping approaches for studying the placebo analgesic effect. Eur. J. Appl. Physiol. 102, 371-380 (2008).
18.    Finniss, D.G., Kaptchuk, T.J., Miller, F. & Benedetti, F. Biological, clinical, and ethical advances of placebo effects. The Lancet 375, 686-695 (2010).
19.    Price, D.D., Finniss, D.G. & Benedetti, F. A Comprehensive Review of the Placebo Effect: Recent Advances and Current Thought. Annual Review of Psychology 59, 565-590 (2008).
20.    Kaptchuk, T.J. et al. Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome. PLoS ONE 5, e15591 (2010).