Focus on: neurotransmitter systems

Abstract

Neurotransmitter systems have been long recognized as important targets of the developmental actions of alcohol (i.e., ethanol). Short- and long-term effects of ethanol on amino acid (e.g., γ-aminobutyric acid and glutamate) and biogenic amine (e.g., serotonin and dopamine) neurotransmitters have been demonstrated in animal models of fetal alcohol spectrum disorders (FASD). Researchers have detected ethanol effects after exposure during developmental periods equivalent to the first, second, and third trimesters of human pregnancy. Results support the recommendation that pregnant women should abstain from drinking-even small quantities-as effects of ethanol on neurotransmitter systems have been detected at low levels of exposure. Recent studies have elucidated new mechanisms and/or consequences of the actions of ethanol on amino acid and biogenic amine neuro-transmitter systems. Alterations in these neurotransmitter systems could, in part, be responsible for many of the conditions associated with FASD, including (1) learning, memory, and attention deficits; (2) motor coordination impairments; (3) abnormal responsiveness to stress; and (4) increased susceptibility to neuropsychiatric disorders, such as substance abuse and depression, and also neurological disorders, such as epilepsy and sudden infant death syndrome. However, future research is needed to conclusively establish a causal relationship between these conditions and developmental dysfunctions in neurotransmitter systems.

Figure 1

Potential sites of action of developmental ethanol exposure on neurotransmitter systems. A) Shown in the upper panel is a schematic representation of the components of a neuron, including the cell body and the ends of projections (axons and axon terminals) that release neurotransmitter onto branch-like projections (dendrites) in adjacent neurons. Note that the axons make synaptic connections with dendrites from three adjacent neurons. Shown in the lower panel is a synapse in more detail. In axonal terminals, neurotransmitters are synthesized and packaged into synaptic vesicles. Release of the neurotransmitter is triggered by influx of Ca²⁺ via voltage-gated Ca²⁺ channels. Neurotransmitter release can be modulated by neurotransmitter-gated ion channels and G protein–coupled receptors expressed in axonal terminals. Neurotransmitters act by activating neurotransmitter-gated ion channels and G protein–coupled receptors expressed in target neurons (either at postsynaptic or extrasynaptic locations). One mechanism by which the action of the neurotransmitter can be terminated is by reuptake into the axonal terminal or neighboring glial cells via neurotransmitter transporters. B) Upper panel: developmental ethanol exposure could affect a given neurotransmitter system by decreasing the number of neurons, dendrite and axonal length and/or number, and/or modifying the number and/or efficacy of synapses. Lower panel: developmental ethanol exposure can affect any of the components involved in neurotransmission. In this hypothetical example, ethanol exposure decreased neurotransmitter release, and this led to a compensatory increased in the levels of postsynaptic and extrasynaptic neurotransmitter receptors in the target neuron.

Figure 2

γ-Aminobutyric acid (GABA)_A receptors stimulate immature neurons and inhibit mature neurons. A) In immature neurons, intracellular Cl⁻ concentrations are higher than in mature neurons. This is a consequence of low expression of a Cl⁻ exporter (potassium/chloride cotransporter type 2; KCC2) and high expression of a Cl⁻ importer (sodium/potassium/chloride cotransporter type 1; NKCC1). Activation of GABA_A receptors causes Cl⁻ flux out of the cell, which makes the membrane potential more positive, leading to activation of Ca²⁺ channels. B) In mature neurons, intracellular Cl⁻ concentrations are low. This is a consequence of high expression of a Cl⁻ exporter and low expression of a Cl⁻ importer. Activation of GABA_A receptors causes Cl⁻ flux into the cell, which makes the membrane potential more negative. Ca²⁺ channels are not activated under these conditions. The unique properties of GABA_A receptors during development make them especially vulnerable to ethanol (see text).

Figure 3

Examples of brain regions where chemical neurotransmitter system alterations have been demonstrated in models of fetal alcohol spectrum disorders (FASD). Shown is a schematic representation of the mature human brain. The potential FASD-linked conditions that could be explained by neurotransmitter system alterations are given under the label for each region. Anxiety and abnormal stress responses (serotonin) apply both to hypothalamus and pituitary. Examples of neurotransmitters that could potentially be involved in these deficits are given in parenthesis.

Figure 4

Diagram illustrating the potential role of neurotransmitter system alterations in fetal alcohol spectrum disorders (FASD). Ethanol exposure during development, acting in conjunction with genetic susceptibility factors (for instance, variations in the serotonin transporter gene) and environmental factors (for example, coexposure to nicotine), disrupts the actions of neurotransmitter systems (i.e., biogenic amines, etc) that normally interact in a complex manner to regulate the key processes involved in brain development (i.e. proliferation, etc). Disruption of these processes results in persistent alterations in synaptic transmission/plasticity and neuronal network function. These alterations likely underlie the deficits associated with FASD (i.e., learning and memory deficits). The precise chain of events leading from developmental ethanol exposure to these deficits remains to be determined.