The central pathways of addiction and their associated neurochemical systems. A. Sagittal rat brain section depicting the systems involved in reward/aversion and addiction. B. Medium spiny neurons (MSN) are the primary sites of synaptic integration in the DS/NAc, which regulate locomotion and reward processes. Striatonigral MSN (DYN), are essential for the reinforcing effects of drugs, whereas striatopallidal MSN (ENK) oppose the actions of striatonigral MSN and promote aversion. Cholinergic interneurons provide ACh in the DS/NAc, which is critical for regulating the balance between striatonigral and striatopallidal MSN (among other functions). The CeA/BST contain several neuron types expressing neuropeptides (and other neurotransmitters). CRF and DYN neurons contribute to negative affect, whereas ENK neurons contribute to positive affect. DA neurons in the SN/VTA send projections throughout the forebrain, which convey motivational salience and value, as well as providing an alerting signal for stimuli with potential significance. NE neurons in the LC/NTS send projections throughout the forebrain, which enhance attention and arousal and modulate systems critical for maintaining homeostasis. C. The cycle of drug abuse/withdrawal alters the balance of signaling in the DS/NAc and CeA/BST. Individuals initiating drug use primarily for “sensation-seeking” (refer to Figure 1) or “self-medication” (refer to Figure 5) have different neurochemical profiles in the basal state and during acute intoxication and the post-drug “crash.” The relative size of the pie pieces (e.g., DYN, ENK and CRF) indicates the predominance of each system, whereas the shading density (e.g., DA and NE) indicates the relative extracellular monoamine concentrations. Neurochemical profiles are further altered during dependence, with plasticity mechanisms in the DS/NAc potentiating striatonigral circuits driving compulsive drug-seeking behavior (indicated by the raised pie wedge). The collective neurochemical changes and their associated effects on DS/NAc and CeA/BST neurotransmission contribute to more frequent cycles of abuse and relapse that are the hallmarks of the spiral to addiction (refer to Figures 1 and 5).