NIDA Program Project Grant on Drug Addiction at UT-Southwestern

Introduction to Brain Signaling

The brain contains roughly 100 billion nerve cells (or neurons), with each neuron forming connections (called synapses) with up to thousands of other neurons. The specificity of this staggering number of synaptic connections underlies all aspects of brain function and illustrates the remarkable complexity of the brain.

Communication between neurons is a combination of electrical and chemical processes. Electrical processes are involved because each nerve cell is a tiny battery. When an electrical impulse is generated in one nerve cell, it is transmitted to other nerve cells. However, a chemical process is required for this transmission, because nerve cells do not physically connect with one another (Figure 4). Rather, small gaps exist between nerve cells at synapses. Information crosses this gap through a chemical process, whereby the electrical impulse in the first nerve cell triggers the release of a neurotransmitter which crosses the synapse and binds to specialized receptor proteins on the second nerve cells. This neurotransmitter-receptor interaction then regulates other proteins, called ion channels, which create electrical impulses in that second nerve cells. Virtually all drugs of abuse produce their effects on the brain via initial interactions with protein targets at the synapse (Figure 4).

The binding of a neurotransmitter to its receptor also activates a cascade of biochemical events inside the nerve cell, which alters all aspects of that neuron’s function. This occurs through the regulation of signaling molecules called G proteins, second messengers, protein kinases, and protein phosphatases, among many others (Figure 5). Regulation of these signaling pathways ultimately causes long-lived changes in gene expression in the neuron’s nucleus. Repeated exposure to a drug of abuse would, therefore, be expected to produce molecular and cellular adaptations as a result of repeated perturbation of these intracellular pathways. We believe that these adaptations are ultimately responsible for many features of drug addiction.

Regulation of Gene Expression in the Brain

Regulation of gene expression is one molecular mechanism that would be expected to lead to relatively stable changes within neurons. According to this scheme, repeated exposure to stress, by causing repeated perturbation of intracellular signaling pathways, would lead eventually to changes in nuclear function and to altered rates of transcription of particular target genes. Altered expression of these genes would lead to altered activity of the neurons in which those changes occur and, ultimately, to changes in the neural circuits in which those neurons operate. The result would be stable changes in behavior.

The rate of expression of a particular gene is controlled by its location within nucleosomes and by the activity of the cell’s transcriptional machinery. A nucleosome is a tightly wound span of DNA that is bound to histones and other nuclear proteins. Transcription of a gene requires the unwinding of a nucleosome, which makes the gene accessible to a transcription complex. This complex is comprised of RNA polymerase (which transcribes the new RNA strand) and numerous regulatory proteins (some of which unwind nucleosomes via histone acetyl transferase activity). Transcription factors are proteins that bind to specific sites (response elements; also called promoter or enhancer elements) present within the regulatory regions of certain genes and thereby increase or decrease the rate at which those genes are transcribed. Transcription factors act by enhancing (or inhibiting) the activity of the transcription complex, in some cases by altering nucleosomal structure through changes in histone acetyl transferase or histone deacetylase activity of the complex.

Regulation of transcription factors is the best-understood mechanism by which changes in gene expression occur in the adult brain. Most transcription factors are regulated by phosphorylation. Accordingly, repeated exposure to a drug of abuse, by causing repeated perturbation of synaptic transmission and hence of protein kinases or protein phosphatases, would lead eventually to changes in the phosphorylation state of particular transcription factors. This would lead to altered expression of target genes for these transcription factors. Among such target genes are those for additional transcriptional factors, which—via alterations in their levels—would alter the expression of still additional target genes and so on. Stress could conceivably produce stable changes in gene expression via regulation of many other types of nuclear proteins, but such actions are just now being explored for the first time. Two transcription factors of great interest to this PPG are CREB and ∆FosB.

NIDA Program Project Grant on Drug Addiction at UT Southwestern

Basics of Brain Function

Related Links

Introduction to Brain Signaling

Regulation of Gene Expression in the Brain