Monoamine neurotransmission occurs at the synapse; the space between the end of one neuron and the start of the next. Monoamine transmitters are released from vesicles where they are stored at the synapses when they are stimulated by an action potential; an electrical signal which has been transmitted down the axon of the neuron. The molecules diffuse across the synapse and then bind with receptor sites on the target neuron. Each monoamine has a specific receptor on the target neuron, in fact some have several receptors which control different effects, for example some dopamine receptors influence emotion and others vomiting.
The immediate effect of neurotransmitters on the target neuron is to change the behaviour of ion channels; some neurotransmitters have an excitatory effect which means that they let in positively charged ions to the synapse which leads to a burst of firing as the negative charges which can move are more likely to enter and lead to a burst of electricity in the neuron; in order to neutralise the charge. However if the neurotransmitter has an inhibitory effect then the ion channels will let in more negatively charged ions and hence there is less likelihood that the neuron will fire.
Several factors affect the action of neurotransmitters. These include the extent to which neurotransmitters are ‘synthesised, stored, released, metabolised and recaptured’ (Gainetdinov & Caron, 2003 p. 2) by neurons in the brain. These functions are mediated by instructions expressed by genes. The relationship between release and control of levels of neurotransmitter in the synapse determines the intensity and duration of the signal which is transmitted. Hence influences on any one of these factors affect neurotransmission.
After the release of the transmitter the signal must be attenuated by a removal of the chemical. Enzymes break down some of the chemicals. Also important are perisynaptic reuptake transporters, situated on the original neuron. These transporters hoover up excess neurotransmitters floating around in the synapse and recycle it. Gainetdinov & Caron (2003) bred mice without these reuptake transporters in order to reveal the effects of excesses of certain neurotransmitters. Many of the psychotropic drugs are effective because they influence neurotransmitter reuptake, hampering the function of the transporters. For example, cocaine hampers the reuptake of the monoamine transmitter norepinephrine and hence leads a small signal to last for a long time. This corresponds with a massive increase in positive mood. The drug lithium, used in the treatment of bipolar disorder produces more rapid reuptake; the logic being that limiting the highs will also reduce the lows.
Dopaminergic transmission in the limbic system is responsible for functions including motor control, reward learning and emotion. Excesses of dopamine in the limbic system due to neurotransmitter dysregulation or dysfunction have been implicated as the cause of positive symptoms of schizophrenia, which include hyperactivity and hallucinations. Davis et al. (1991) argue that there may also be a deficit of dopamine in the cortex which is involved in cognition and attention; therefore schizophrenia is the result of an imbalance of dopamine transmission; known as the dopamine hypothesis. Supporting evidence for this idea comes from the finding that the dose of antipsychotics which inhibit dopamine transmission is negatively correlated with positive symptoms (Seeman, 2002).
A deficit of dopamine transmission is associated with the symptoms of Parkinson’s disease, and is believed to result from the death of dopamine neurons. This hypothesis has been supported by the presence of schizophrenic like psychotic symptoms in a percentage of Parkinson’s patients treated with L-Dopa, a dopamine substitute.
However the relationship between dopamine and schizophrenia appears to be more complex than just an abundance of neurotransmitters; as schizophrenic symptoms are increased in people who take amphetamines and have schizophrenia relative to normal people. It appears that people with psychotic tendencies are more likely to respond more intensely to or increase dopamine transmission in certain circumstances, where a slight increase occurs naturally, relative to normals.
Individuals using psychotropic drugs which increase dopamine transmission may also report delusions and hallucinations, as well as pleasurable feelings which result from an excess of dopamine, due to its association with reward and desire. Mice bred without the dopamine reuptake transporter underwent behavioural changes, becoming more hyperactive and displaying cognitive and sensorimotor changes and sleep dysregulation (Gainetdinov & Caron, 2003). Furthermore due to high levels of dopamine transmission they experienced changes in gene regulation which resulted in reduced storage of dopamine, as well as reduced receptor sensitivity of the post-synaptic receptors. The effect of neurotransmitters in gene expression will be discussed further. This finding has implications for addiction; with the down-regulation of dopamine receptors more and more dopamine is required to elicit the same response. This highlights a possible mechanism of addiction.
Norepinephrine and serotonin neurotransmission are implicated in mood disorders as their transmission has a demonstrable effect on mood. This could result from a lack of sensitivity, or oversensitivity to neurotransmitters by the receptors; as the actual levels of the neurotransmitters in the synapses appear to be normal (Stahl, in press). One biological precursor of depression and bipolar disorder involves reduced number or sensitivity of post synaptic receptors for norepinephrine and serotonin in areas of the mesocortex and thalamus which are implicated in emotional regulation (McBride et al., 1994). The observation that depressed individuals frequently display low physiological arousal is conducive to the view that neurotransmission is for some reason suppressed.
Many antidepressants work by increasing neurotransmission of the monoamines serotonin and noradrenaline by preventing reuptake of the neurotransmitters from the synapse (hence the name for the drug Prozac, which is a ‘Selective Serotonin Reuptake Inhibitor’). However antidepressants do not work immediately despite the fact that the effect on neurotransmitters should be immediate; as is evidently the case with recreational psychotropic drugs such as cocaine which prevents the reuptake of norepinephrine, and leads to an immediate high.
The biological explanation of the delay in action is related the second major effect of monoamine neurotransmission: its effect on gene expression. The monoamine hypothesis of depression provides a clear explanation of this and accounts for the delayed onset of antidepressant medications. It is not a deficit in neurotransmission which causes depression but a problem with the sensitivity of the receptor sites for the critical monoamines. The sensitivity is mediated by genetic instructions. Over time when patients are administered a course of antidepressants, the increased presence of the neurotransmitters leads to changes in gene expression in the neurons, which affects the receptor sites. Genes which have lain dormant may be activated by the increased presence of neurotransmitters and lead to an increase in the density of receptor sites. The overall result is that patients become more receptive to monoamine neurotransmitters and hence mood is boosted overall (Stahl, 2000).
‘First messenger’ neurotransmitters are released and bind to their corresponding receptors on the receiving neuron. These cause a change in the receptor of the neuron, which then allows the G protein within the cell to bind to the receptor site as well. The G-protein and an enzyme then bind together which releases a ‘second messenger’ neurotransmitter; which allows the signal to enter the neuron. The second messenger leads to activation of a protein kinase enzyme. Enzymes influence transcription factors and consequently which of the genes contained in the DNA of the cell are transcribed. Hence the regulation of genes is influenced by neurotransmitters. Different genes are activated in the presence of different, or varying levels of neurotransmitters. These genes direct protein synthesis and hence have a direct influence over how the neuron works (Stahl, 1999)
Hence neurotransmission has both a short term effect on behavioural or psychological response through the conveyance of signals and a long term effect on gene transcription. Different genes are transcribed over time. For example, early onset genes are transcribed minutes after the neurotransmitter has been received, whereas other genes are only transcribed over a long period of time. Hence cellular changes may not be immediate.
In conclusion the effects of monoamine neurotransmitters on the brain are crucial to many aspects of functioning and drugs which interfere with transmission in the short term may have long term effects through changes in gene expression. The consequences of this may be positive; in the case of antidepressants; or negative in the case of addiction to cocaine.
References:
Davis et al. 1991. Dopamine in schizophrenia: a review and reconceptualization
American Journal of Psychiatry. 148: 1474-1486
Gainetdinov, R. R. & Caron, M. G. 2003. MONOAMINE TRANSPORTERS: From Genes to Behaviour. Annual Review of Pharmacology and Toxicology, 43, 261-284
Stahl, S. M. Essential Psychopharmacology. 2nd ed. New York, NY: Cambridge University Press. In press
Stahl, S. M. 1999. Molecular neurobiology for practicing psychiatrists, part 2: how neurotransmitters activate second messenger systems. Journal of Clinical Psychiatry 1999; 60 647-648
Stahl, S. M. 2000. . Journal of Clinical Psychiatry; 62 77-78
Torres, G. E., Gainetdinov, R. R. & Caron, M, G. 2003. Plasma membrane monoamine transporters: structure, regulation & function. Nature Reviews Neuroscience 4, 13-25