Cobbers on the Brain

Sleep 

When sitting in class and finishing work many individuals look forward to a specific time of the day. This is the time in which we can snuggle into our beds and fall asleep. However, is sleep more important than we think? Sleep provides healing and restoration and promotes good health and recovery from illness. Sleep is a cyclical physiological process that alternates with long periods of wakefulness. It influences physiological function and behavioral responses. This is controlled by your internal clock called your circadian rhythm. The part of your brain that controls the circadian rhythm is the suprachiasmatic nucleus (SCN) nerve cells in the hypothalamus control the rhythm of the sleep-wake cycle and coordinate this cycle with other rhythms. 

Sleep Disturbance  

There are some symptoms of the sleep cycle that cause disturbances and result in lack of sleep. These include anxiety, restlessness, irritability, and impaired judgement. However, is lack of sleep really that big of a problem? Lack of sleep can have serious potential problems for one’s health including high blood pressure, diabetes, heart attacks, and heart failure. The previous list of health problems relates to that of physical health, but what about the physiological perspective of the brain? When making memories it is important to note that there are three types of ways in which something can become a memory. This includes acquisition-learning or experiencing something new, recall-having the ability to access the memory in the future, and consolidation-the memory becomes stable in the brain.  The first two are through to be done while an individual is awake, however, consolidation requires an individual to be asleep.  This is because adequate sleep aids in the health of your hippocamps and neocortex within the brain. These areas while sleeping are believed to replay the events of the day and review/process memories and move them into an area where they can be stored as long-term memories.  

Are there medical ways to help insomnia?  

GABA are inhibitory neurotransmitters of the central nervous system that aids in sleep. GABA inhibitors are broken down into three different generations of hypnotics based on the GABA receptor mediated inhibitory process. These include the first- and second-generation hypnotics being barbiturates and benzodiazepines, while the third generation of hypnotics being imidazopyridines and cyclopyrrolones. The first- and second-generation hypnotics decrease waking, increase slow-wave sleep and enhance paradoxical sleep. Slow-wave sleep is the third phase of sleep which is the deepest phase of non-rapid eye movement sleep. During this time dreaming and sleepwalking can occur. This stage is also important for memory consolidation, which is a process where recently learned experiences are transformed into long-term memory. When paradoxical sleep is reached intense brain activity in the forebrain and midbrain occur. It differs from slow wave sleep due to the absence of motor function except for eye muscles and the diaphragm. An individual is unable to sleepwalk but is still dreaming during this time. The third generation of hypnotics is like that of the first- and second-generation hypnotics on waking and slow wave sleep but has a decreased paradoxical sleep during the first few hours of sleep.  

How do benzodiazepines work?  

By Hannah P.

Benzodiazepines are a class of drugs named for their chemical structure that are commonly used to treat anxiety disorders and sleep-related disorders. They include well-known drugs like valium, Xanax, and klonopin. There are dozens of drugs in the benzodiazepine class, but the mechanism by which they all exert their effects is thought to be similar. The sedating and anxiety-reducing effects of benzodiazepines are believed to be attributable to the drugs’ actions at receptors for the neurotransmitter gamma-aminobutyric acid (GABA). In particular, benzodiazepines act at a subtype of GABA receptors called the GABAa receptor; GABAa receptors that also bind benzodiazepines are sometimes called benzodiazepine receptors. When benzodiazepines bind, or attach, to the GABA receptor, they bind at alocation separate from where GABA itself binds and exerts an influence over GABA binding. This type of action is called an allosteric effect, and in the case of benzodiazepines it results in increased action at the GABA receptor. There is not complete consensus on exactly how benzodiazepine binding affects activity at the GABA receptor but there is evidence to suggest that it increases the likelihood that GABA binding will activate the receptor and/or increases the effect that GABA has when it binds to the receptor. That effect is to open an ion channel and allow the passage of negatively charged chloride ions into the neuron. This influx of negatively charged ions pushes the membrane potential further from zero, or hyper polarizes it, and makes it less likely the neuron will fire an action potential.This type of neural inhibition is the basis for the effects of benzodiazepines, for by inhibiting the activity of neurons that make up networks involved with anxiety and arousal, the drugs are able to produce calming effects. 

By Hannah P.

How do we feel pain? 

When we feel pain sensory receptors in our skin send a message via nerve fibres, A-delta fibres and C fibres, to the spinal cord and brainstem and then onto the brain where the sensation of pain is registered, the information is processed and the pain is perceived. Fast pain is transported from A delta fibers while slow pain from C fibers.Examples of A delta fiber pain are sharp, prickling and acute pain and C fibers are slow, throbbing, aching chronic pain.

What is the pathway for pain? 

In short form pain starts at nociceptors –> Primary afferent sensory fibers –> Dorsal root ganglion –> Na channels allow depolarization through axons –> Dorsal Horn of spinal cord –> Second order neurons –> Brain.

The General Pain Pathway

Within the pain pathway there are 3 orders of neurons that carry action potentials, signalling pain. First-order neurons are pseudounipolar neurons which have cell bodies within the dorsal root ganglion. They have one axon which splits into two branches, a peripheral branch (which extends towards the periphery) and a central branch (which extends centrally into the spinal cord/brainstem). Second-order cell bodies of these neurons are found in the rexed laminae of the spinal cord, or in the nuclei of the cranial nerves within the brain stem. These neurons then decussate in the anterior white commissure of the spinal cord and ascend cranially in the spinothalamic tract to the ventral posterolateral (VPL) nucleus of the thalamus. Third-order the cell bodies of third-order neurons lie within the VPL of the thalamus. They project via the posterior limb of the internal capsule to terminate in the ipsilateral postcentral gyrus (primary somatosensory cortex). The postcentral gyrus is somatotopically organised. Therefore, pain signals initiated in the hand will terminate in the area of the cortex dedicated to sensations of the hand.

How do we react to pain? 

This can lead to two different responses, fight or flight. In response to the pain stimulus the brain overall increases in “fight or flight” arousal.

– increased sympathetic tone

– increased catecholamine release

– increased metabolism & oxygen consumption (via hypothalamus)

How can you treat pain? 

There are many ways an individual can help reduce pain and manage it. Some people will say to get plenty of rest, distract yourself, or participate in light exercise. However, what happens when these tips don’t help with the pain? Many people reach for pharmaceutical mechanisms to treat what they are experiencing from ibprohpen to different opioids. This occurs by inhibiting nociceptors and dorsal horn pain transmission. 

What are CB1 and CB2? 

CB1 are receptors found primarily on the presynaptic membrane of neurons, ubiquitous. It is coupled to G proteins, causing inhibition of adenylyl cyclase, influencing numerous transcription factors and potassium channels. While CB2 are receptors which are more localized, specifically to immune cells. Both CB2 and CB1 receptors on mast cells participate in the anti-inflammatory mechanism of action of cannabinoids.

How is CB1 involved in pain management? 

The CB1 receptor is distributed throughout the nervous system. It mediates psychoactivity, pain regulation, memory processing and motor control. CB1 is a presynaptic heteroreceptor that modulates neurotransmitter and neuropeptide release and inhibits synaptic transmission. Activation of CB1 results in the activation of inwardly rectifying potassium channels, which decrease presynaptic neuron firing, and in the inhibition of voltage-sensitive calcium channels that decrease neurotransmitter release. Allosteric modulators of the CB1 receptor bind to a distinct site apart from the orthosteric site and produce conformational changes in the receptor, thereby altering the potency of the ligand when it binds to the receptor. No effect in the absence of ligand binding. So, CB1 positive allosteric modulators would be expected to enhance the pain relieving effects of endocannabinoids, but with limited side effects. ZCZO11 reduced neuropathic pain and inflammatory pain without development of tolerance or occurrence of psychoactive side effects.

Overview of the circadian rhythm

The circadian rhythm regulation plays a crucial role in people’s healthy lives affected by factors consisting of cosmic events related to the universe and earth, environmental factors, and lifestyles. The circadian rhythm is affected by the circadian clock, which is an internal regulator in cells of organisms, coordinates physiological and behavioral activities with daily environmental variations within 24-hour cycles (Charrier et al., 2017). That’s just a quick explanation of the circadian rhythm but how does adenosine affect this.

Adenosine overview

Adenosine is linked to metabolism of cells. In the central nervous system, an increase in neuronal activity enhances energy consumption as well as extracellular adenosine concentrations. In the brain, adenosine antagonists affects A1 receptors which decreases neuronal activity which is why you have more energy (Porkka- Heiskanen et al., 2002).

Adenosine and sleep

Out of the many articles I have been reading it seems like the main area of adenosine activity is the cholinergic basal forebrain. It is important in this function because it is an essential area for mediating the sleep-inducing effects of adenosine by inhibition of wake-promoting neurons via the A1 receptor (Basheer et al., 2004). Their evidence finds that a cascade of signal transduction induced in A1 receptor activation in cholinergic neurons leads to increased transcription of the A1 receptor. They believe that this is the reason behind sleep-deprivation.

Coffee and sleep

The information I found on the effects of adenosine on sleep made me wonder if the time that one drinks caffeine has an effect on certain stages of sleep. A study monitored the effects of drinking caffeine at 0, 3, and 6 hours before going to sleep. The results of this study suggest that 400 mg of caffeine taken 0, 3, or even 6 hours prior to bedtime significantly disrupts sleep. Even at 6 hours, caffeine reduced sleep by more than 1 hour (Drake et al., 2013). This isn’t that crazy since 400 mg is a lot of caffeine but even 6 hours seems like it should be long enough. The caffeine however, only reduced the time between stage 1 and 2 sleep and had no effect on REM sleep. The results did conclude though that this degree of sleep loss, if experienced over multiple nights, may have detrimental effects on daytime function (although more research is needed).

Works cited

Basheer, R., Strecker, R. E., Thakkar, M. M., & McCarley, R. W. (2004). Adenosine and sleep–wake regulation. Progress in Neurobiology, 73(6), 379–396. https://doi.org/10.1016/j.pneurobio.2004.06.004

Charrier, A., Olliac, B., Roubertoux, P., & Tordjman, S. (2017, April 29). Clock genes and altered sleep-wake rhythms: Their role in the development of psychiatric disorders. International journal of molecular sciences. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454851/.

Drake, C., Roehrs, T., Shambroom, J., & Roth, T. (2013). Caffeine effects on sleep taken 0, 3, or 6 hours before going to bed. Journal of Clinical Sleep Medicine, 09(11), 1195–1200. https://doi.org/10.5664/jcsm.3170

Porkka-Heiskanen, T., Alanko, L., Kalinchuk, A., & Stenberg, D. (2002). Adenosine and sleep. Sleep Medicine Reviews, 6(4), 321–332. https://doi.org/10.1053/smrv.2001.0201

Cannabinoids in the brain

Cannabinoids are popular in both recreational and medical use. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). Psychoactive cannabinoids cause enhancement of sensory perception, difficulties in concentration, impairment of memory, along with an extensive list of other symptoms. Recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus (Ameri et al., 1999). The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N and P-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. Interestingly, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system (Ameri et al., 1999). This might explain why people call it a ‘gateway drug.’

THC long-term effects studies

A study found that, cognitive impairments in adult rats exposed to THC during adolescence are associated with structural and functional changes in the hippocampus (NDA et al., 2021). They also found that when that animal is exposed to THC, there is an increased likelihood that the animal will target and self-administer other drugs that effect the same reward system. The studies referenced by the NDA found that some users developed altered connectivity within the brain leading to different cognitive impairments, while other studies found no significant structural differences in the brain. Basically, they have no idea if there is a negative long-term effect in general. However, they do believe that the age that you start using at is a determining factor.

Gateway drug?

So, if no conclusive results were found on the structure of the brain long-term, what about long term effects on usage. They found that, early exposure to cannabinoids in adolescent rodents decreases the reactivity of brain dopamine reward centers later in adulthood. Although this does not directly conclude the results of a human brain, this could help explain the increased vulnerability for addiction to other substances of misuse later in life. These findings naturally would suggest that marijuana is a gateway drug, however, most people who use marijuana do not go on to use other, “harder” substances. They found that there is also a cross sensational effect within alcohol and other drugs. This means that simply drinking alcohol also heightens your responses to other drugs (NDA et al., 2021).

What to draw out of this

To say that marijuana has no negative effect on the brain would be disingenuous. However, just because the evidence is inconclusive at this point does not mean that it is entirely safe to use. If you use marijuana, cool, but just know there could be risks of future cognitive development in store.

Works Cited

Ameri, A. (1999). The effects of cannabinoids on the brain. Progress in Neurobiology, 58(4), 315–348. https://doi.org/10.1016/s0301-0082(98)00087-2

National Institute on Drug Abuse. (2021, April 13). What are marijuana’s long-term effects on the brain? National Institute on Drug Abuse. Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana/what-are-marijuanas-long-term-effects-brain.

National Institute on Drug Abuse. (2021, May 24). Is marijuana a gateway drug? National Institute on Drug Abuse. Retrieved from https://www.drugabuse.gov/publications/research-reports/marijuana/marijuana-gateway-drug.