Study reveals central role of endocannabinoids in habit formation

National Institutes of Health (NIH) - Turning Discovery into Health

“Daily activities involve frequent transitions between habitual behaviors, such as driving home, and goal-directed behaviors, such as driving to a new destination on unfamiliar roads. An inability to shift between habitual and non-habitual behaviors has been implicated in obsessive-compulsive disorder (OCD), addiction, and other disorders characterized by impaired decision-making.

In a new study conducted with mice, scientists report that endocannabinoids, natural messengers in the body that are chemically similar to the active compound in marijuana, play an important role in how the brain controls this fundamental process.

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institutes of Health, funded the study.

“The new findings point to a previously unknown mechanism in the brain that regulates the transition between goal-directed and habitual behaviors,” said George F. Koob, Ph.D., NIAAA director. “As we learn more about this mechanism, it could reveal how the brain forms habits and, more specifically, how both endocannabinoids and cannabinoid abuse can influence habitual behavior pathophysiology.” A report of the findings is now online in the journal Neuron.

Previous work in NIAAA’s Laboratory for Integrative Neuroscience suggested that reduced activity in the brain’s orbitofrontal cortex (OFC) underlies habit formation. Endocannabinoids are known to generally reduce the activity of neurons. In the current study, the authors, hypothesized that endocannabinoids in the OFC could be playing a key role in habit formation. The researchers used a newly developed procedure that allowed them to probe the brain mechanisms involved when a mouse shifts from goal-directed to habitual actions. By chemically inhibiting the activity of neurons in the OFC, they disrupted goal-directed behaviors and the mice relied on habitual actions instead. David Lovinger, Ph.D., chief of the NIAAA Laboratory for Integrative Neuroscience, Rui Costa, Ph.D., D.V.M., from the Champalimaud Centre for the Unknown in Lisbon, Portugal, and first author Christina Gremel, Ph.D. from NIAAA and the University of California, San Diego led the research team.

“Mice were trained to receive a food reward in two different ways,” said Dr. Lovinger. “One way required the animal to respond out of habit, while the second way demanded it to perform behaviors that were goal-directed.”

When Dr. Lovinger and his colleagues selectively deleted a particular endocannabinoid receptor, called cannabinoid type 1 (CB1), from OFC neurons, they found that mice that lacked these receptors did not form habits, but used goal-directed responses to receive the food reward. Animals with intact CB1 receptors preferentially used habitual responses to obtain the food reward. The authors say the new study points to a molecular mechanism through which endocannabinoids promote the formation of habits by reducing the flow of information in the OFC.

“Endocannabinoids appear to act as a brake in the OFC, allowing for habit formation,” said Dr. Gremel, an assistant professor of psychology and affiliated with the Neurosciences Graduate program at UCSD. “Our results suggest that alterations in the brain’s endocannabinoid system could be blocking the brain’s capacity to ‘break habits’ as observed in disorders that affect switching between goal-directed and habitual behaviors.”

The authors concluded that their findings demonstrate the existence of parallel brain circuits that mediate goal-directed and habitual behaviors. Drugs of abuse and neuropsychiatric disorders can affect decision-making by changing the balance between habitual and goal-directed actions. In particular, these mechanisms could help explain how cannabis drugs such as marijuana affect memory and decision-making.

The new findings suggest that strategies that target the brain’s endocannabinoid system might restore this balance and alleviate suffering in disorders involving these processes.”

https://www.nih.gov/news-events/news-releases/study-reveals-central-role-endocannabinoids-habit-formation?source=acsh.org

The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain.

 

“Trigeminal neuralgia is a disorder of paroxysmal and severely disabling facial pain and continues to be a real therapeutic challenge.

At present there are few effective drugs. Here we have evaluated the effects of the synthetic cannabinoid WIN 55,212-2 on mechanical allodynia and thermal hyperalgesia in a rat model of trigeminal neuropathic pain produced by a chronic constriction injury (CCI) of the infraorbital branch of the trigeminalnerve (ION).

Taken together, these results suggest that cannabinoids may be a useful therapeutic approach for the clinical management of trigeminal neuropathic pain disorders.”

The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

“Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal.

There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the “so-called” cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients’ prognosis.

In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other.

The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes.

First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed.

In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27456243

Refractory trigeminal neuralgia responsive to nabiximols in a patient with multiple sclerosis.

“Nabiximols is a cannabinoid compound approved for the treatment of multiple sclerosis (MS)-related spasticity.

However, additional symptoms, such as pain, urinary urgency and sleep disturbance, may benefit from treatment.

CASE REPORT:

The present report describes a patient with secondary progressive MS and severe lower limbs spasticity who was started on treatment with nabiximols. The patient also suffered from trigeminal neuralgia, which he was not treating due to inefficacy or side effects of all previously tried medications. After nabiximols initiation the patient experienced a marked benefit on trigeminal neuralgia, which completely resolved, while spasticity responded only partially to treatment.

CONCLUSION:

Nabiximols mechanism of action is based on the interaction with CB1 and CB2 receptors, which are expressed by central nervous system neurons and are known to modulate pain among other effects. The present case indicates that nabiximols and other cannabinoids need to be further tested for the treatment of trigeminal neuralgia.”

http://www.ncbi.nlm.nih.gov/pubmed/27456876

“Therapeutic potential of cannabinoids in trigeminal neuralgia. Considering the pronounced antinociceptive effects produced by cannabinoids, they may be a promising therapeutic approach for the clinical management of trigeminal neuralgia.”  http://www.ncbi.nlm.nih.gov/pubmed/15578967

Should we care about sativex-induced neurobehavioral effects? A 6-month follow-up study.

“Sativex® is an exclusive cannabinoid-based drug approved for the treatment of spasticity due to Multiple Sclerosis (MS).

The most common side effects include dizziness, nausea, and somnolence. However, it is still under debate whether the drug could cause negative cognitive effects.

The aim of our study was to investigate the effect of Sativex® on functional and psychological status in cannabis-naïve MS patients.

After the treatment, we did not observe any significant neurobehavioral impairment in all the patients, but one.

Our findings suggest that Sativex® treatment does not significantly affect the cognitive and neurobehavioral functions.”

http://www.ncbi.nlm.nih.gov/pubmed/27460745

Blockade of Cannabinoid CB1 receptor attenuates the acquisition of morphine-induced conditioned place preference along with a downregulation of ERK, CREB phosphorylation, and BDNF expression in the nucleus accumbens and hippocampus.

“Cannabinoid CB1 receptor (CB1R) is highly expressed in the mesocorticolimbic system and associated with drug craving and relapse.

Clinical trials suggest that CB1R antagonists may represent new therapies for drug addiction.

Collectively, these findings demonstrate that 1) Repeated morphine with context exposures but not merely the pharmacological effects of morphine increased CB1R expression both in the NAc and hippocampus. 2) CB1R antagonist mediated blockade of ERK-CREB-BDNF signaling activation in the NAc and hippocampus may be an important mechanism underlying the attenuation of morphine CPP.”

http://www.ncbi.nlm.nih.gov/pubmed/27461790

Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia.

“Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes.

Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection.

Cannabidiol could be a good candidate.

Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets.

Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio.

The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone.

The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult.”

http://www.ncbi.nlm.nih.gov/pubmed/27462203

Deficient Adolescent Social Behavior Following Early-Life Inflammation is Ameliorated by Augmentation of Anandamide Signaling.

“Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function.

The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence.

We investigate the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS.

These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.”

http://www.ncbi.nlm.nih.gov/pubmed/27453335

The CB1 Antagonist, SR141716A, Is Protective in Permanent Photothrombotic Cerebral Ischemia.

“Modulation of the endocannabinoid system has been shown to have a significant impact on outcomes in animal models of stroke.

We have previously reported a protective effect of the CB1 antagonist, SR141716A, in a transient reperfusion mouse model of cerebral ischemia. This protective effect was in part mediated by activation of the 5HT1A receptor.

Here we have examined its effect in a mouse model of permanent ischemia induced by photoinjury.

The CB1 antagonist was found to be protective in this model.

As was the case following transient ischemia reperfusion, SR141716A (5mg/kg) resulted in smaller infarct fractions and stroke volumes when utilized both as a pretreatment and as a post-treatment. In contrast to the effect in a transient ischemia model, the pretreatment effect did not depend on the 5HT1A receptor.

Neurological function correlated favorably to the reduction in stroke size when SR141716A was given as a pretreatment.

With the incidence of stroke predicted to rise in parallel with an ever aging population, understanding mechanisms underlying ischemia and therapeutics remains a paramount goal of research.”

http://www.ncbi.nlm.nih.gov/pubmed/27453059

Cannabinoid Receptor 1 (CNR1) Gene Variant Moderates Neural Index of Cognitive Disruption during Nicotine Withdrawal.

 

“Nicotine withdrawal-related disruption of cognitive control may contribute to the reinforcement of tobacco use.

Identification of gene variants that predict this withdrawal phenotype may lead to tailored pharmacotherapy for smoking cessation.

Variation on the cannabinoid receptor 1 gene (CNR1) has been related to nicotine dependence, and CNR1 antagonists may increase attention and memory functioning.

The current findings suggest potential efficacy of cannabinoid RECEPTOR antagonism as a pharmacotherapy approach for smoking cessation among individuals who exhibit greater nicotine withdrawal-related cognitive disruption.”

http://www.ncbi.nlm.nih.gov/pubmed/27453054