Neurocircuitry associated with the positive reinforcement of drugs of abuse and the negative reinforcement of dependence and how it changes in the transition from nondependent drug taking to dependent drug taking (Modified with permission from ). Key elements of the reward circuit are dopamine (DA) and opioid peptides at both the ventral tegmental area (VTA) and nucleus accumbens, which are activated during initial use and the early binge/intoxication stage of the addiction cycle. Key elements of the stress circuit are corticotropin-releasing factor (CRF) and norepinephrine (NE) neurons that converge on γ-aminobutyric acid (GABA) interneurons in the central nucleus of the amygdala, which are activated during the development of dependence. The hypothesis elaborated here is that in nondependent animals, opioid peptides that preferentially activate μ opioid receptors have a facilitatory effect on the positive reinforcing actions of drugs of abuse but that opioid peptides that preferentially activate κ opioid receptors have an inhibitory effect on the positive reinforcing actions of drugs of abuse. In contrast, in dependent animals, the μ opioid system is compromised via tolerance-like neuroadaptations, and the κ opioid system becomes either activated or sensitized indirectly by drugs of abuse via the dopaminergic–CREB system and via an interaction with the stress system, manifesting its influence on compulsive drug seeking. Mu and κ receptors are distributed across all of these brain regions and the spinal cord. For example, “a high correlation between μ receptor mRNA expression and binding is observed in the striatal clusters and patches of the nucleus accumbens and caudate–putamen, diagonal band of Broca, globus pallidus and ventral pallidum, bed nucleus of the stria terminalis, most thalamic nuclei, medial and cortical amygdala, mammillary nuclei, presubiculum, interpeduncular nucleus, median raphe, raphe magnus, parabrachial nucleus, locus coeruleus, nucleus ambiguus, and nucleus of the solitary tract. Differences in μ receptor mRNA and binding distributions are observed in regions such as the neocortex, olfactory bulb, superior colliculus, spinal trigeminal nucleus, and spinal cord, which might be a consequence of receptor transport to presynaptic terminals.” With respect to κ receptor distribution, “a high degree of correlation between κ₁ receptor mRNA expression and binding is observed in regions such as the nucleus accumbens, caudate–putamen, olfactory tubercle, bed nucleus of the stria terminalis, medial preoptic area, paraventricular nucleus, supraoptic nucleus, dorsomedial, and ventromedial hypothalamus, amygdala, midline thalamic nuclei, periaqueductal gray, raphe nuclei, parabrachial nucleus, locus coeruleus, spinal trigeminal nucleus, and the nucleus of the solitary tract. Differences in κ₁ receptor binding and mRNA distribution in the substantia nigra pars compacta, ventral tegmental area, and neural lobe of the pituitary might be due to receptor transport” [Koob and Le Moal (2006), Opioids. In Neurobiology of Addiction pp. 152–153. Academic press, London]. The arrows indicate the increase of activities in the positive and negative reinforcement circuits, and the relative differences in the size of the arrows represent the relative differences in the activities