By Gigi Sage
It would be an understatement to say that alcohol is widely used and abused in society. There is a constant debate as to what the legal age should be; have we got it right in the UK or should it be 21 as in the US? There is no doubt that alcohol affects our bodies in many more ways than one however its effects on the brain are by far the most complex. In this article I will scratch the surface on the neuropharmacology of alcohol and the physiology behind its changes to our behaviour. Neurotransmitters are the signalling molecules that allow neurons to communicate across synapses and the effects of alcohol on our behaviour are largely explained by its effects on such endogenous chemicals (i.e. Chemicals synthesized by the body itself). There are two main neurotransmitters in the brain; GABA (inhibitory) and Glutamate (excitatory). In this article we will see how alcohol enhances the effects of GABA whilst simultaneously inhibiting the effects of glutamate. We will also see the effects on neuromodulators* such as opioids and on maintenance cells named neuroglia.
As mentioned above glutamate is the main excitatory neurotransmitter in the brain and alcohol inhibits both such ionotropic and metabotropic receptors. Ionotropic receptors, when activated, open an ion channel pore. In terms of glutamate such type of receptor includes NMDA and AMPA. Both of these receptors allow the movement of calcium and sodium ions to flow through the synaptic cleft to the post-synaptic terminal, causing depolarisation. Respectively glutamate metabotropic receptors activate secondary messengers within the post-synaptic terminal of which, again, cause depolarisation in the post-synaptic neuron. For both types of receptors alcohol acts as a non-competitive antagonist, inhibiting depolarization and subsequent excitation of such neurons. This helps us to understand how we develop tolerance. When alcohol is consumed chronically the body compensates to increase the number of glutamate receptors on postsynaptic terminals as well as reducing the rate of glutamate reuptake back into the presynaptic terminal. This supports the body to survive when ethanol is inhibiting these receptors. Therefore, chronic alcohol abusers may experience seizures if they suddenly stop drinking because the brain has an increased number of receptors and the concentration of glutamate is higher in the synaptic cleft (higher frequency of neuronal depolarisation).
In respect of the inhibitory neurotransmitter GABA there are two main receptors; GABAa (ionotropic) and GABAb (metabotropic). Alcohol acts as a positive allosteric modulator on GABAa receptors of which allow the movement of chloride ions from the synaptic cleft to the post-synaptic terminal. Therefore, when activated the concentration of negative ions in the post-synaptic terminal increases and the membrane becomes hyperpolarised (membrane potential is more negative). This reduces the chance of an action potential. Not only does this help to explain the slow movement and speech associated with alcohol consumption but helps us to understand the side effects that can be seen following withdrawal in those that have abused alcohol chronically. If alcohol is abused chronically the body reduces the sensitivity of GABA receptors as well as physically moving them away from the synapse (extrasynaptically). Therefore, these receptors are less frequently activated and the chance of seizures increases by the reduction of inhibitory receptors.
This means that alcohol stimulates inhibitory transmission and inhibits excitatory transmission. To put it simply this slows down the brain; explaining why those intoxicated slur their words and have low reaction times. Such physiology underpins the reasoning behind drink driving limits as alcohol inhibits us from reacting quickly to stimuli.
Concerning opioids, alcohol increases the endogenous synthesis and release of these molecules. Within the central nervous system opioids are neuromodulators of which act via G-protein coupled receptors. They can be classified into 4 main groups (Delta, Kappa, Mu and NOP) of which are all inhibitory. Opioids are known for their high abuse potential , especially in medicine where they are used in the treatment of pain and have caused a lot of controversy surrounding their lead to drug abuse (especially in the US). Alcohol increases the release of opioids onto opioid receptors, present on GABAergic neurons. Such neurons inhibit GABAergic interneurons of which inhibit dopamine neurons and the subsequent release of dopamine (feed-forward inhibition). Therefore, when GABAergic interneurons are inhibited we see the disinhibition of dopamine neurons and release of dopamine. This leads to positive reinforcement via the association of alcohol with the effects of dopamine in the brain. Chronic alcohol abuse will reduce the number of opioid receptors in brain, leading to dysphoria following withdrawal. A helpful picture to explain this concept can be found below:
Figure 1
Finally, I wanted to delve a little further into the brain and talk about the effects of alcohol on glial cells. 70% of the brain are made up for neuroglia of which are supporting cells of the nervous system. Different types of these cells are found between the central and peripheral nervous system. To retain our focus on the brain we find 4 different types of these cells in the central nervous system (made up of the brain and spinal cord): Astrocytes, Oligodendrocytes, NG2 cells and ependymal cells. These cells perform different roles to regulate and maintain our neurons, without them our neurons would cease to exist. Glial cells are directly affected by alcohol, particularly astrocytes. One of the main roles of astrocytes is the uptake of neurotransmitter from the synaptic cleft. Alcohol increases the activity of glutamate (excitatory) transporters on the surface of these cells (GLAST or GLT-1). This decreases the concentration of glutamate in the synaptic cleft, reducing the activation of glutamate receptors. This, in fact, reduces the effects of alcohol on our brain.
I think it’s fair to say that alcohol does change our brain in many more ways than one. It is important to note that the effects listed above are very general to the human brain and we never know how an individual may respond to the acute/chronic intake of alcohol. As is common with neuroscientific research, we must carry out further investigations as to the interaction between such a widely used substance and the chemicals in our brain. Furthermore, although integrated and accepted into our society, it is a substance that should be treated with respect.
*Neuromodulators are chemicals that modulate neurons and the way that they communicate. The main difference between them and neurotransmitters is their tendency to affect a large group of neurons as opposed to a single post-synaptic terminal.1
Neurotransmitters VS Neuromodulators - The Revisionist [Internet]. The Revisionist. 2020 [cited 24 August 2020]. Available from: https://www.therevisionist.org/bio-hacking/neurotransmitters-vs-neuromodulators/#:~:text=Generally%20speaking%2C%20a%20neurotransmitter%20is,a%20whole%20group%20of%20neurons.
Figure 1: Heilig, Markus & Goldman, David & Berrettini, Wade & O'Brien, Charles. (2011). Pharmacogenetic approaches to the treatment of alcohol addiction. Nature reviews. Neuroscience. 12. 670-84. 10.1038/nrn3110. https://www.researchgate.net/figure/An-alcohol-endogenous-opioid-dopamine-cascade-is-the-target-of-naltrexoneSchematic-of_fig5_51730536
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