**2. The link between drug action, intracellular signaling, and epigenetic changes**

Both endogenous neurotransmitters and drugs interact with neuronal proteins, such as neurotransmitter receptors, proteins involved in synaptic homeostasis (e.g., neurotransmitter metabolic enzymes, transporters, etc.), and proteins involved in intracellular signaling pathways. These intracellular signaling pathways can propagate to the cell nucleus, leading to changes in gene expression [6]. Often, the first change observed in the cell nucleus following an environmental perturbation (e.g., drug use, stress, novelty, etc.) is the expression of immediate early genes (IEGs). Common IEGs encode transcription factors that increase expression of other target genes by binding to the genes' promoter region, which is a sequence in the DNA that signals the cell to initiate transcription [7, 8]. IEGs are rapidly induced and are often used as a marker of changes in neuronal signaling activity [9]. Both IEGs and target genes may undergo epigenetic modifications that regulate their expression. Thus, either natural signaling in response to environmental stimuli or drug-induced changes in signaling can invoke epigenetic mechanisms that alter gene expression. The dynamics of the epigenetic changes may be specific to the degree and phase of drug exposure, where particular epigenetic marks may only arise (or disappear) following acute or chronic drug administration, or during a period of withdrawal from drug use [10].
