Neurotransmitters

Neurotransmitters are endogenous chemical messengers that allow the communication between a releasing neuron that sends signals across a synapse onto a target neuron, a gland/muscle cell. They may have an excitatory (contributing to trigger an action potential) or inhibitory effect (those inhibiting or preventing action potentials).

Neurotransmitters are stored in synaptic vesicles in the pre-synaptic neuron. They are released into and diffused across the synaptic cleft (gap between neuron and target cell). They bind to receptors at the post-synaptic cell.

In response to an action potential, a neurotransmitter is released at the pre-synaptic terminal. The released neurotransmitter may then move across the synapse and bind with receptors in the post-synaptic neuron, causing changes in the membrane potential. Binding of neurotransmitter may influence the post-synaptic neuron in either an excitatory or inhibitory way.

A released neurotransmitter is typically available in the synaptic cleft for a short time before it is either metabolised by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a post-synaptic receptor.

Ionotropic receptors: ion channels to which neurotransmitters bind directly to, in order to open them

Metabotropic receptors: do not have a channel that opens or closes. Instead they are linked to a small chemical called a G-protein. A neurotransmitter binds to the metabotropic receptor. The receptor then activates the G-protein. This protein activates another molecule. The secondary messenger may then bind to and open ion channels located somewhere else on the membrane.

Neurotransmitter actions can be stopped by 4 mechanisms:

• Diffusion: neurotransmitter drifts away, out of the synaptic cleft where it can no longer act on a receptor
• Enzymatic degredation: a specific enzyme changes the structure of the neurotransmitter so its not recognised by the receptor. (E.g acetylcholinesterase is the enzyme that breaks acetylcholine into choline and acetate)
• Glial cells: astrocytes remove neurotransmitters from the snyaptic cleft
• Reuptake: neurotransmitter is taken back into the axon terminal that released it

There is no one-to-one relationship between a neuron and a neurotransmitter. Instead, there is a large number of combinations of neurotransmitters and receptors on neurons. A single neuron may use one neurotransmitter at one synapse, and another at another synapse, and different neurotransmitters may coexist in the same synapse.

There are 4 main neurotransmitter systems in the central nervous system

• Cholinergic system: acetylcholine - implicated in arousal, emotion and mood, learning, motor function, motivation, short-term memory, and reward
• Serotonergic system: serotonin - implicated in arousal, body temperature regulation, emotion and mood, feeding and energy homeostasis, reward, and sensory perception
• Dopaminergic system: dopamine - implicated in arousal, aversion, cognitive control, emotion and mood, motivation, motor function, positive reinforcement, reward, sexual arousal, ****** and refractory period
• Noradrenalergic system: noradrenaline - implicated in anxiety, arousal, circadian rhythms, cognitive control, feeding and energy homeostasis, and reward

Cholinergic system: system is made up of nerve cells that are activated by or contain and release acetylcholine. ACh system has 2 branches: basal forebrain, projecting to the neocortex and hippocampus - important for a form of arousal called vigilance and for enhancing signal-to-noise ratios which enables detecting targets with great fidelity. This has an impact of attention, memory encoding, and working memory processes. Brain stem - important for sleep/waking cycle.

Serotonergic system: serotonin is the "feel good" chemical. Its functions in a healthy brain are - mood balance and social behaviour, appetite, sleep, cognitive functions including memory and learning, and inhibition. In pathology, it may play a part in depression, aggression, impulsive behaviour, alcohol abuse, ADHD, and schizphrenia. Serotonin may have a role in moral judgement (Crockett et al, 2010): emotion regulation - serotonin promotes the effortful control of violent impulses. Harm aversion - serotonin amplifies the aversiveness of personally harming others. Serotonin enhances aversive emotional reactions to harm. The concentrations of serotonin is reduced in brains of suicide victims. Higher traits of callous-unemotional were associated with low serotonin, and vice versa.

Dopaminergic system: dopamine is synthesised in nerve cells mainly originating in the midbrain's substantia nigra and the ventral tegmental areas (TGA). These nerve cells send their axons to 3 main parts of the forebrain: frontal cortex, striatum, and limbic system. Dopamine is highly implicated in reward. Dopamine levels increase when animals or humans are exposed to enjoyable stimuli. Electric stimulation of some dopamine-related brain areas produced rewarding effects (Olds & Olds, 1963). Lesion studies in animals to areas rich in dopaminergic neurons showed altered preferences for rewarding stimuli.

Drugs can enhance the release of dopamine or block its reuptake, e.g cocaine blocks dopamine transports which means reuptake is inhibited. The effects of dopamine are prolonged.

Dopamine and memory: the hippocampus is required to encode memories for new events or episodes. Hippocampal activity corresponds to dopamine release to keep memory of new events. Dopaminergic enhancement may improve duration of episodic memory trace. Study found that dopamine was associated to an increase in remembered stimuli (Chowdhury et al, 2013).

Originates in brain stem structures, such as the locus ceruleus, and also the medulla. Two main brances of the noradrenaline system

• Dorsal ascending system: projects to the forebrain, including the neocortex, and the hippocampus. This doesn't go to the striatum
• Ventral system: projects mainly to the hypothalamus and to other parts of the brain including the limbic system, which is involved in emotion.

Main functions: arousal and processing novelty. The system works fast, however too much stimulation including too much novelty may cause stress.

Addiction is the compulsive seeking, and then obtaining of a substance or object. It is a dependency because biological, psychological, and social behaviours are more and more dominated by the idea of obtaining a drug or the object of addiction (Peele & Degrandpre, 1998). Addiction is therefore a chronic disease of brain reward, motivation, and memory. It can be driven by chemical and non-chemical substances.

Addiction features

• Salience: object of addiction dominates thoughts and actions
• Tolerance: need to increase a dose
• Craving: the "wanting"
• Withdrawal: physical or psychological e.g vomiting or changes in mood
• Conflict: between addicted and other people/situations
• Relapse: use of drugs or other addiction after trying to stop

Drugs achieve their affect by imitating or altering the release or uptake of neurotransmitters. The experiences following drug abuse reflect the functional roles of the particular neurotransmitter whose activity it disrupts.

Some drugs mimic neurotransmitters. Heroin chemically resembles the brain's natural opioids, which affect pain, mood control, immune response, hunger, and thirst. Because heroin stimulates many more receptors than the brain would actually use even more strongly, the result is a massive amplification of opioid activity, producing a euphoric feeling.

Marijuana mimics cannabinoid neurotransmitters, the most important of which is anandamide. Nicotine attaches to receptors for acetylcholine, the neurotransmitter for the cholinergic system

Some drugs interfere with sending and receiving processes of a neurotransmitter. Cocaine attaches to the dopamine transporter which draws free-floating dopamine outside the synapse back into the sending cell. As long as cocaine occupies the transporter, dopamine cannot re-enter the cell by this route. Dopamine therefore builds up in the synapse, stimulating receiving cell receptors more copiously and producing much greater dopamine impact on the receiving cells than what occurs naturally.

Also, some drugs alter neurotransmission by means other than increasing or decreasing the quantity of receptors stimulated. Benzodiazepines (such as diazepam and lorazepam) produce relaxation by enhancing receiving neurons' responses when the inhibitory neurotransmitter GABA attaches to their receptors.

Addiction is thought to be caused by a combination of genetic environmental factors

• Genes: have been linked to certain addictions. There is evidence of a genetic component in addiction through twin studies (Agrawal & Lynskey, 2008). Children of alcoholics have a four-fold increase in the likelihood of becoming alcoholics themselves, comapred to children born to non-alcoholics. Also, a genetic tendency towards a slight imbalance between dopamine, serotonin and noradrenaline is common. The more off-balance the relationship between the neurotransmitters is, the greater the risk of addiction
• Environment: the environment plays a role in initiating and maintaining addictive behaviours. For an addict, even the sight of a place or object related to drugs can release dopamine in the reward/pleasure pathway. Once the response is triggered, the brain seeks to obtain the drug or object of addiction (craving).

Early phase of drug experimentation: neurotransmission normalises as the intoxication wears off and the substance leaves the brain. Associations with context of drug use start to take place. In the wanting-and-liking theory (Robinson & Berridge, 2008) this stage is strongly related to the "liking", especially in a social context. Wanting is based in the mesolimbic pathways, liking is based in the brainstem.

Medium-long term changes (intensive to compulsive drug use): drug tolerance begins - adjustments ar made to compensate for drug-induced increases in the intensity of neurotransmitter signalling. The brain tries to bring stimulation down to a more manageable level by reducing the number of, for example dopamine receptors at the synapse, or increasing the number of dopamine transporters so that dopamine can be cleared from the synapse quicker. These changes make the brain less responsive to the drug, but they also decrease the brain's response to natural rewards. Neuronal changes - repeated abuse of drugs permanently rewires the brain. Connections between neurons may be pruned back or form more. There may be toxic effects on nerve cells, which induce changes in axons.

Most addictive substances cause a change in levels of dopamine, the neurotransmitter in charge of pleasure and reward. Pleasurable experiences result in dopamine release that involves the nucleus accumbens i.e the reward centre, via the dopaminergic pathway. Memories of pleasurable experiences, as well as their context are stored, and the reward pathway is reinforced from highly pleasurable experiences that are repeated. The more pleasurable an experience is, or the more its repeated, the stronger the reward pathway becomes and likelihood for repetition

Drugs may interfere with dopamine by blocking its reuptake, such that dopamine accumulates in the synapse and stimulates receptors further to make the addict feel good. Indirectly, dopamine can be interfered with by inhibiting the release of other neurotransmitters, like GABA which usually regulate dopamine. Therefore is less GABA is present, more dopamine is available.

Experimenting with drugs in the context of abnormal dopamine (as in mania, ADHD and bipolar disorder) is most likely to lead to addiction to stimulants that module dopamine, like cocaine.