Scientists identify connection between dopamine and behavior related to pain and fear
New research illuminates crucial links between avoidance behavior and key brain chemicals
April 19, 2018
Science Daily/University of Maryland School of Medicine
Scientists at the University of Maryland School of Medicine have for the first time found direct causal links between the neurotransmitter dopamine and avoidance -- behavior related to pain and fear.
Researchers have long known that dopamine plays a key role in driving behavior related to pleasurable goals, such as food, sex and social interaction. In general, increasing dopamine boosts the drive toward these stimuli. But dopamine's role in allowing organisms to avoid negative events has remained mysterious.
The new study establishes for the first time that dopamine is central in causing behavior related to the avoidance of specific threats. The work was published today in the journal Current Biology.
"This study really advances what we know about how dopamine affects aversively motivated behaviors," said Joseph F. Cheer PhD, a professor in the UMSOM Department of Anatomy & Neurobiology and the study's corresponding author. "In the past, we thought of dopamine as a neurotransmitter involved in actions associated with the pursuit of rewards. With this new information we can delve into how dopamine affects so many more kinds of motivated behavior."
To better understand the role that dopamine plays in this process, Dr. Cheer and his colleagues, including principal author Jennifer Wenzel, PhD, a fellow in Dr. Cheer's laboratory, studied rats, focusing on a particular brain area, the nucleus accumbens. This brain region plays a crucial role in linking the need or desire for a given reward -- food, sex, etc. -- with the motor response to actually obtain that reward.
To study the animals under natural conditions, they used optogenetics, a relatively new technique in which specific groups of neurons can be controlled by exposure to light. In this case, Dr. Cheer's group used a blue laser to stimulate genetically modified rats whose dopamine neurons could be controlled to send out more or less dopamine. In this way, they were able to see how dopamine levels affected the animals' behavior. The principal advantage of this approach: he could control dopamine levels even as the animals moved freely in their environment.
The researchers subjected the animals to small electric shocks, but also taught the animals how to escape the shocks by pressing a small lever. Using optogenetics, they controlled the amount of dopamine released by neurons in the nucleus accumbens. Animals with high levels of dopamine in this brain region learned to avoid a shock more quickly and more often than animals that had a lower level of dopamine in this region.
Dr. Cheer says that this indicates that dopamine causally drives animals to avoid unpleasant or painful situations and stimuli. The results greatly expand the role that dopamine plays in driving behavior.
The researchers also examined the role that endocannabinoids play in this process. Endocannabinoids, brain chemicals that resemble the active ingredients in marijuana, play key roles in many brain processes. Here, Dr. Cheer and his colleagues found that endocannabinoids essentially open the gate that allows the dopamine neurons to fire. When the researchers reduced the level of endocannabinoids, the animals were much less likely to move to avoid shocks.
Dr. Cheer argues that the research sheds light on brain disorders such as post-traumatic stress disorder and depression. In depression, patients feel unable to avoid a sense of helplessness in the face of problems, and tend to ruminate rather than act to improve their situation. In PTSD, patients are unable to avoid an overwhelming sense of fear and anxiety in the face of seemingly low-stress situations. Both disorders, he says, may involve abnormally low levels of dopamine, and may be seen on some level as a failure of the avoidance system.
In both depression and PTSD, doctors already sometimes treat patients with medicine to increase dopamine and there are now clinical trials testing use of endocannabinoid drugs to treat these conditions. Dr. Cheer suggests that this approach may need to be used more often, and should certainly be studied in more detail.
https://www.sciencedaily.com/releases/2018/04/180419131108.htm
Cannabis reduces creativity, but user generally not aware
October 4, 2016
Science Daily/Leiden, Universiteit
Regular users of cannabis are less aware of their own mistakes, and they are not good at creative thinking. This is the conclusion drawn by psychologist Mikael Kowal from his research on the effects of cannabis. PhD defence 6 October.
Dopamine
Kowal conducted experiments on 40 regular users of cannabis. The control group of 20 non-users were given a placebo. Kowal studied the direct and chronic effects of cannabis on dopamine-related functions, such as creative thinking and the ability to recognise one's own mistakes. The brain chemical dopamine is important for the proper working of the brain and also plays a role in learning performance.
Less good at brainstorming
Kowal's research showed that cannabis users were less able to brainstorm, a mental process that is crucial for creative performance: 'There is a widespread belief among users that these drugs enhance creativity. This experiment disproves that belief.'
Poor at recognising mistakes
Kowal also demonstrated that for chronic users the brain processes involved in monitoring mistakes also work less effectively. A high dose of cannabis seems to influence both the unconscious processing of mistakes and also the later and more conscious stages of error processing. Kowal: 'It is important that we gather more knowledge about the effects of cannabis on a person's ability to detect mistakes. This can help with putting together a treatment programme for drug addiction.'
Lower dopamine production
The research also indicated clear long-term effects: cannabis disrupts the activity of dopamine in the brain. With chronic users a significant reduction was seen in the frequency of spontaneous eye blinking, an indication of a reduction in dopamine production.
More research needed
The conclusion from other scientific research is that regular cannabis use does not necessarily have disastrous effects for the take-up of dopamine. It may well be that the age at which cannabis is first used is a crucial factor, Kowal suggests. The type of cannabis and the way neurobiological processes interact with one another can also result in individual differences. Kowal: 'More research is needed on the effects of cannabis and on the individual consequences it can have on mental functions.'
https://www.sciencedaily.com/releases/2016/10/161004125829.htm
Sex, drugs and estradiol: Why cannabis affects women differently
October 26, 2018
Science Daily/Frontiers
Sex differences in cannabis use are beginning to be explained with the aid of brain studies in animals and humans.
Cannabis use is riding high on a decade-long wave of decriminalization, legalization and unregulated synthetic substitutes. As society examines the impact, an interesting disparity has become apparent: the risks are different in females than in males.
A new review of animal studies says that sex differences in response to cannabis are not just socio-cultural, but biological too. Published in Frontiers in Behavioral Neuroscience, it examines the influence of sex hormones like testosterone, estradiol (estrogen) and progesterone on the endocannabinoid system: networks of brain cells which communicate using the same family of chemicals found in cannabis, called 'cannabinoids'.
Animal studies
"It has been pretty hard to get laboratory animals to self-administer cannabinoids like human cannabis users," says study co-author Dr Liana Fattore, Senior Researcher at the National Research Council of Italy and President of the Mediterranean Society of Neuroscience. "However, animal studies on the effects of sex hormones and anabolic steroids on cannabinoid self-administration behavior have contributed a lot to our current understanding of sex differences in response to cannabis."
So how does cannabis affect men and women differently? Besides genetic background and hormonal fluctuations, the paper highlights a number of important sex differences.
Men are up to four times more likely to try cannabis -- and use higher doses, more frequently.
"Male sex steroids increase risk-taking behavior and suppress the brain's reward system, which could explain why males are more likely to try drugs, including cannabis" explains Fattore. "This is true for both natural male sex steroids like testosterone and synthetic steroids like nandrolone."
But despite lower average cannabis use, women go from first hit to habit faster than men. In fact, men and women differ not only in the prevalence and frequency of cannabis use, pattern and reasons of use, but also in the vulnerability to develop cannabis use disorder.
"Females seem to be more vulnerable, at a neurochemical level, in developing addiction to cannabis," explains Fattore.
"Studies in rats show that the female hormone estradiol affects control of movement, social behavior and filtering of sensory input to the brain -- all targets of drug taking -- via modulation of the endocannabinoid system, whose feedback in turn influences estradiol production.
"Specifically, female rats have different levels of endocannabinoids and more sensitive receptors than males in key brain areas related to these functions, with significant changes along the menstrual cycle.
"As a result, the interactions between the endocannabinoid system and the brain level of dopamine -- the neurotransmitter of "pleasure" and "reward" -- are sex-dependent."
Human impact
The inconsistency of conditions in these studies greatly complicates interpretation of an already complex role of sex hormones in the endocannabinoid system and cannabinoid sensitivity.
"The effects varied according the specific cannabinoid studied, as well as the strain of animals tested and duration of hormone exposure," admits Fattore. However, the human data so far are consistent with the idea that estradiol regulates the female response to cannabinoids. As in animals, human males and females are diverse in their genetic and hormonally driven behaviour and they process information differently, perceive emotions in different ways and are differently vulnerable to develop drug addiction.
"Blood levels of enzymes which break down cannabinoids fluctuate across the human menstrual cycle, and imaging studies show that brain levels of cannabinoid receptors increase with aging in females -- mirroring in each case changes in estradiol levels."
Fattore believes that deepening our understanding of the interactions between cannabinoids and sex steroids is crucial in assessing the impact of increasing cannabis use, and tackling the fallout.
"Gender-tailored detoxification treatments and relapse prevention strategies for patients with cannabis addiction are increasingly requested. Optimizing personalized evidence-based prevention and treatment protocols demands further research on the source of sex disparities in cannabis response."
https://www.sciencedaily.com/releases/2018/10/181026102627.htm