Basic Neurobiology of Addiction


Two major dopamine systems project to the basal ganglia from cell bodies in the ventral part of the midbrain: the mesocorticolimbic dopamine system and the nigrostriatal dopamine system. The nigrostriatal dopamine system projects from the substantia nigra to corpus striatum. Degeneration of this system is the primary basis for many of the motor dysfunctions associated with Parkinson’s disease. The activation of this system is also implicated in the focused repetitive behavior, called stereotyped behavior, that is associated with high doses of psychostimulants, such as cocaine and methamphetamine (Figure 2.11).

The mesocorticolimbic dopamine system projects from the ventral tegmental area to the nucleus accumbens, olfactory tubercle, amygdala, and frontal cortex. This system has been implicated in psychostimulant-induced locomotor activity, drug reward, and non-drug motivational attributes, such as incentive salience, conditioned reinforcement, and conditioned approach (for further reading, see Schultz, 2006).

Thus, dopamine neurons that project to the forebrain are associated with the initiation of behavior, reward, and motivational processes. Pharmacological manipulations that increase or decrease dopaminergic function provided early evidence of the role of the midbrain dopamine systems in reward. Pharmacological activation of dopamine synaptic activity, for example with the dopamine indirect agonist cocaine or amphetamine, produces behavioral activation, facilitated responding for many reinforcers, and decreased reward thresholds (that is, less stimulation is needed for a subject to perceive a stimulus as rewarding). Conversely, blockade of dopamine function decreases responding for both positive and negative reinforcers. Electrophysiological studies that measure the electrical activity of cells have shown that both unpredictable and predictable stimuli activate the firing of midbrain dopamine neurons. Some argue that mainly appetitive or rewarding events (like eating chocolate, having sex, or winning a card game) activated dopamine neurons in the mesocorticolimbic dopamine system. Such hedonic selectivity of the activation of dopamine neurons provides intriguing insights into the conceptualization of what constitutes positive rewards or incentives. Midbrain dopamine neurons may be part of the process by which rewards motivate or guide behavior, referred to as incentive motivation or incentive salience. Positive incentives paired with previously neutral stimuli through activation of the mesocorticolimbic dopamine system facilitate species-specific approach responses or changes in direction toward important incentives via dopamine release. As discussed in the various drug-specific sections in this website, such incentive salience provides a powerful mechanism by which associations are made between previously neutral stimuli and drugs of abuse that pharmacologically facilitate the release of mesocorticolimbic dopamine.

Figure 2.11 Dopamine localization. Schematic illustration of central dopamine pathways. Groups A8 and A9 give rise to nigrostriatal dopamine pathway. Group A10 gives rise to the mesolimbic dopamine pathway. Group A12 gives rise to the tubero-infundibular dopamine neurons. [Modified from Fuxe K, Hokfelt T, Olson L, Ungerstedt U. Central monoaminergic pathways with emphasis on their relation to the so-called "extrapyramidal motor system". Pharmacology and Therapeutics B, 1977, (3), 169-210.]

Five different dopamine receptors, D1 through D5, have been identified. Dopamine acts through these receptors to produce its functional effects. The dopamine receptors fall into two main categories: D1-like (which are coupled to Gs proteins to activate adenylate cyclase; these include D1 and D5 receptors) and D2-like (which are coupled to Gi proteins to inhibit adenylate cyclase; these include D2, D3, and D4). Most pharmacological studies have been performed using agonists and antagonists of D1, D2, and D3 receptors, mainly because agents that are selective for these receptors are available. D1 and D2 receptors are widely distributed throughout the mesocorticolimbic and nigrostriatal dopamine systems. D3 receptors are localized to more specific subregions of the terminals of the mesocorticolimbic dopamine system in the rat, namely the shell subdivision of the nucleus accumbens and the Islands of Calleja.

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