Brain Structures and Functions Relevant to the Three Stages of the Addiction Cycle

Binge/Intoxication Stage - Basal Ganglia

The binge/intoxication stage heavily involves the basal ganglia. The basal ganglia are considered a key part of the extrapyramidal motor system and are historically associated with a number of key functions, including voluntary motor control, procedural learning related to routine behaviors or habits, and action selection. The basal ganglia include the following structures: striatum, globus pallidus, substantia nigra, and subthalamic nucleus (Figure 2.18). The striatum can be further divided into the ventral striatum and dorsal striatum. The ventral striatum includes the nucleus accumbens, olfactory tubercle, and ventral pallidum. This is a subarea of the basal ganglia that has gained recognition for its involvement in motivation and reward function. The ventral striatum is now considered a major integrative center for converting motivation to action. In the domain of addiction, it mediates the rewarding effects of drugs of abuse. The basal ganglia receive neurochemical inputs (or afferents) from the prefrontal cortex and midbrain dopamine system. They then send neurochemical signals (or efferents) from the globus pallidus to the thalamus, which then relays motor and sensory signals to the cerebral cortex. The functions of the basal ganglia involve a series of cortical-striatal-pallidal-thalamic-cortical loops that encode habits related to compulsive behavior (Figure 2.19).

Positive reinforcement with drugs of abuse occurs when presentation of a drug increases the probability of a response to obtain the drug and usually refers to producing a positive hedonic state. Animal models of the positive reinforcing or rewarding effects of drugs in the absence of withdrawal or deprivation are extensive and well validated. These models include intravenous drug self-administration, conditioned place preference, and decreased brain stimulation reward thresholds (see Animal Models).

The acute reinforcing effects of drugs of abuse are mediated by brain structures connected by the medial forebrain bundle reward system, with a focus on the ventral tegmental area, nucleus accumbens, and amygdala. Much evidence supports the hypothesis that the mesocorticolimbic dopamine system, projecting from the ventral tegmental area to the nucleus accumbens, is dramatically activated by psychostimulant drugs during limited-access self-administration. This system is critical for mediating the rewarding effects of cocaine, amphetamines, and nicotine. However, although acute administration of other drugs of abuse activates the dopamine systems, opioids and alcohol have both dopamine-dependent and -independent rewarding effects (Figure 2.20). μ opioid receptors in both the nucleus accumbens and ventral tegmental area mediate the reinforcing effects of opioid drugs. Opioid peptides in the ventral striatum and amygdala mediate the acute reinforcing effects of alcohol, largely observed experimentally through the effects of opioid antagonists and in knockout mice. γ-Aminobutyric acid (GABA) systems are activated pre- and postsynaptically in the extended amygdala by alcohol at intoxicating doses, and GABA receptor antagonists block alcohol self-administration. A specific nicotinic receptor, the α4β2 subtype, either in the ventral tegmental area or nucleus accumbens, mediates the reinforcing effects of nicotine via actions on the mesocorticolimbic dopamine system. The cannabinoid CB1 receptor, involving the activation of dopamine and opioid peptides in the ventral tegmental area and nucleus accumbens, mediates the reinforcing actions of marijuana.

Figure 2.18 Brain regions recruited during the binge/intoxication stage of the addiction cycle. [Modified with permission from Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology Reviews, 2010, (35), 217-238 (erratum: 35: 1051).]

Drugs of abuse have a profound effect on the response to previously neutral stimuli to which the drugs become paired; a phenomenon called conditional reinforcement and now linked with the concept of "incentive salience." Psychostimulants caused rats to show compulsive-like lever pressing in response to a cue that was previously paired with a water reward (for further reading of this seminal finding, see Robbins, 1976).

In a subsequent series of studies that recorded the electrical activity of ventral tegmental area dopamine neurons in primates during repeated presentation of rewards and presentation of stimuli associated with reward, dopamine cells fired at the first exposure to the novel reward, but repeated exposure caused the neurons to stop firing during reward consumption and instead fire when they were exposed to stimuli that were predictive of the reward (for further reading, see Schultz et al., 1997). Through the process of conditioning, previously neutral stimuli are linked to either a natural or drug reinforcer and acquire the ability to increase dopamine levels in the nucleus accumbens in anticipation of the reward, thus engendering strong motivation to seek the drug, termed incentive salience.

Figure 2.19 Functional topography of cortico-basal ganglia-thalamocortical circuits. Each color represents a different function. Each functional region of the cortex projects to a specific region of the striatum, represented by the same color. The striatum projects to a specific region of the globus pallidus/substantia nigra pars reticulata, also represented by the same color. The globus pallidus/substantia nigra pars reticulata projects to a specific thalamic region and back to the cortical region of origin. [Taken with permission from Haber S, McFarland NR. The place of the thalamus in frontal cortical-basal ganglia circuits. Neuroscientist, 2001, (7), 315-324.]

As noted previously, all drugs of abuse can initially elicit increased physiological dopamine release in the nucleus accumbens. This drug-induced dopamine signaling can eventually trigger neuroadaptations in other basal ganglia brain circuits that are related to habit formation. Key synaptic changes involve glutamate-modulated N-methyl-D-aspartate (NMDA) receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in glutamatergic projections from the prefrontal cortex and amygdala to the ventral tegmental area and nucleus accumbens (for further reading, see Kalivas, 2009; Lüscher and Malenka, 2011; Wolf and Ferrario, 2010). The power of initial dopamine release (and activation of opioid peptide systems) upon initial drug taking begins the neuroadaptations that lead to tolerance and withdrawal and triggers the ability of drug-associated cues to increase dopamine levels in the dorsal striatum, a region that is involved in habit formation (for further reading, see Belin et al., 2009) and the strengthening of those habits as addiction progresses. The recruitment of these circuits is significant for the progression through the addiction cycle because such conditioned responses help explain the intense desire for the drug (craving) and its compulsive use when subjects with addiction are exposed to drug cues. Conditioned responses within the incentive salience process can drive dopamine signaling to maintain the motivation to take the drug even when the direct pharmacological effects of the drug lessen.

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