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The dopamine system and addiction 

The dopamine system and addiction
Chapter:
The dopamine system and addiction
Source:
Addiction (Oxford Psychiatry Library) (2 ed.)
Author(s):

David J. Nutt

and Liam J. Nestor

DOI:
10.1093/med/9780198797746.003.0007

Key points

  • Dopamine release is involved in the reinforcing effects of addictive substances.

  • Dopamine release can be blunted by substance abuse.

  • Dopamine release is involved in drug craving.

  • Dopamine receptors are reduced during substance addiction withdrawal.

  • Medications that boost dopamine functioning may be useful in substance addiction.

  • Reductions in dopamine functioning may predispose people to substance addiction.

It has long been held that the reinforcing effects of substances of abuse involve the release of dopamine from presynaptic neurons of the ventral tegmental are (VTA) onto dopamine receptors (D1/2/3R) in the ventral striatum (VS). There is evidence, however, that not all drugs of abuse (e.g. opiates) increase the release of dopamine in humans. Research using animal models also suggests that dopamine functioning in the brain may predispose some individuals to initiating substance use—particularly the use of stimulants, which induce further deficits within the dopamine system.

In this chapter, we will examine the acute and chronic effects of addictive substances on the dopamine system. The potential efficacy of treatments that specifically target dopamine functioning in substance abuse and addiction will also be discussed.

7.1 The dopamine system

Dopamine is transmitted via three major pathways in the brain (see Figure 7.1). The first pathway extends from the substantia nigra (SN) to the caudate nucleus-putamen (neostriatum) and is concerned with sensory stimuli and movement. The second pathway projects from the ventral tegmental area (VTA) to the mesolimbic forebrain and is thought to be associated with cognitive, reward, and emotional behaviour. The third pathway, known as the tubero-infundibular system, is concerned with neuronal control of the hypothalmic-pituitary endocrine system.

Figure 7.1 Major dopamine pathways in the human brain. Substances of addiction have a particularly strong influence on the pathway projecting from the ventral tegmental area (VTA) to the mesolimbic system containing the nucleus accumbens (NAcc)/ventral striatum (VS).

Figure 7.1 Major dopamine pathways in the human brain. Substances of addiction have a particularly strong influence on the pathway projecting from the ventral tegmental area (VTA) to the mesolimbic system containing the nucleus accumbens (NAcc)/ventral striatum (VS).

Substances of addiction work by triggering transient, exaggerated increases in dopamine at the VS. These surges in dopamine resemble, and can greatly surpass, physiological increases triggered by natural rewards (e.g. food, water). The two main substances of abuse that trigger exaggerated increases in dopamine are cocaine and amphetamines.

Cocaine is a reuptake inhibitor that binds to the presynaptic dopamine transporter (DAT). The DAT is a membrane-spanning protein located in subcortical regions of the brain, particularly in the striatum. It is responsible for sequestering extracellular dopamine back into presynaptic nerve terminals. By binding to the DAT on VTA neurons, for example, cocaine inhibits the reuptake of released dopamine at the VS (see Figure 7.2—cocaine). Amphetamines enter the presynaptic nerve terminal to promote the release of dopamine. This is done by interfering with vesicular storage and promoting carrier-mediated exchange. Amphetamines induce a surge in the release of dopamine from VTA neurons, leading to an increase in synaptic dopamine at the VS (see Figure 7.2—amphetamine). Amphetamines also inhibit the reuptake of dopamine to a lesser degree.

Figure 7.2 Pharmacology of cocaine and amphetamines on dopamine. The effects of cocaine at the presynaptic DAT and amphetamine within the presynaptic neuron—both drug classes block reuptake, and amphetamines additionally stimulate dopamine release from nerve terminals. These increased levels of dopamine stimulate postsynaptic dopamine receptors, which produce the reinforcing effects of these substances (e.g. pleasure).

Figure 7.2 Pharmacology of cocaine and amphetamines on dopamine. The effects of cocaine at the presynaptic DAT and amphetamine within the presynaptic neuron—both drug classes block reuptake, and amphetamines additionally stimulate dopamine release from nerve terminals. These increased levels of dopamine stimulate postsynaptic dopamine receptors, which produce the reinforcing effects of these substances (e.g. pleasure).

7.2 Substance addiction

The increase in dopamine by stimulants (and other substances) induces feelings of pleasure. One of the first studies to confirm these effects in humans showed that the resulting ‘high’ and ‘rush’ that people reported was directly related to dopamine at the D2R (see Figure 7.3).

Figure 7.3 Dopamine release and the subjective effects of amphetamine. (A) [C-11]raclopride displacement from the D2R by methylphenidate-induced dopamine release in the VS. The colour scale (from red to blue) represents the amount of [C-11]raclopride emission decreasing, as it is displaced by increasing levels of dopamine related to the dose of methylphenidate. (B) Correlations between methylphenidate-induced changes in D2R availability in the VS as an effect of dose and methylphenidate-induced changes in self-reports of high (r = 0.78, df22, p <0.0001) and rush (r = 0.75, p <0.0001).

Figure 7.3 Dopamine release and the subjective effects of amphetamine. (A) [C-11]raclopride displacement from the D2R by methylphenidate-induced dopamine release in the VS. The colour scale (from red to blue) represents the amount of [C-11]raclopride emission decreasing, as it is displaced by increasing levels of dopamine related to the dose of methylphenidate. (B) Correlations between methylphenidate-induced changes in D2R availability in the VS as an effect of dose and methylphenidate-induced changes in self-reports of high (r = 0.78, df22, p <0.0001) and rush (r = 0.75, p <0.0001).

Adapted from Journal of Pharmacology and Experimental Therapeutics, 291, 1, Volkow, N. D., Wang, G. J., Fowler, et al., Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors, pp. 409–415. © 1999 American Society for Pharmacology & Experimental Therapeutics.

Due to the surges in dopamine release by substances of abuse, chronic use may result in a pathological shift in the hedonic set point during addiction. This state of dysregulation within evolutionary hard-wired brain reward systems has been demonstrated using a number of different methods. For example, evidence suggests that there are significantly fewer D2/3R numbers in cocaine and alcohol dependence (see Figure 7.4).

Figure 7.4 Reduced D2/3R numbers in substance addiction. The graph shows the results (unpublished) from a meta-analysis of previously published research on D2/3R numbers in alcohol and cocaine addiction.

Figure 7.4 Reduced D2/3R numbers in substance addiction. The graph shows the results (unpublished) from a meta-analysis of previously published research on D2/3R numbers in alcohol and cocaine addiction.

In addition to D2R reductions in substance-dependent populations, there is also evidence for reduced dopamine release in addiction. Using an amphetamine challenge (e.g. methylphenidate administration), it has been shown that cocaine abusers exhibit an attenuated dopamine response in the VS compared to controls (see Figure 7.5). This effect has also been reported in alcohol, heroin, and methamphetamine dependence. The deficit in dopamine release may confer an additional vulnerability to relapse and bingeing in an attempt to overcome this hedonic dysregulation.

Figure 7.5 Reduced dopamine release in substance addiction. Dopamine release induced by methylphenidate (MP) in controls and active cocaine-addicted subjects. (A) Average non-displaceable binding of [11C] raclopride after placebo and after MP (iv). The colour scale (from red to blue) represents the amount of [11C]raclopride emission decreasing, as it is displaced by increasing levels of dopamine related to MP. (B) D2R availability in the caudate, putamen, and VS after placebo (blue) and after MP (red) in controls and cocaine-addicted subjects. Note that cocaine abusers show both decreases in baseline striatal D2R availability (placebo measure) and decreases in dopamine release when given MP (measured as decreases in D2R availability from baseline).

Figure 7.5 Reduced dopamine release in substance addiction. Dopamine release induced by methylphenidate (MP) in controls and active cocaine-addicted subjects. (A) Average non-displaceable binding of [11C] raclopride after placebo and after MP (iv). The colour scale (from red to blue) represents the amount of [11C]raclopride emission decreasing, as it is displaced by increasing levels of dopamine related to MP. (B) D2R availability in the caudate, putamen, and VS after placebo (blue) and after MP (red) in controls and cocaine-addicted subjects. Note that cocaine abusers show both decreases in baseline striatal D2R availability (placebo measure) and decreases in dopamine release when given MP (measured as decreases in D2R availability from baseline).

Reproduced from Proceedings of the National Academy of Sciences, 108, 37, Volkow, N. D., Wang, G. J., Fowler, J. S., Tomasi, D., Telang, F., Addiction: beyond dopamine reward circuitry, pp. 15037–15042, 2011 National Academy of Sciences, USA.

Paradoxically, cocaine cues (e.g. objects, people, places associated with the rewarding effects of cocaine) significantly increase dopamine release in the dorsal striatum (DS) in cocaine dependence. The magnitude of this effect is also highly correlated with the subjective experience of craving (see Figure 7.6).

Figure 7.6 Craving-induced dopamine release in substance addiction. Dopamine changes induced by conditioned cues in active cocaine abusers. (A) Average non-displaceable binding potential of [11C]raclopride in cocaine-addicted subjects tested while viewing a neutral video (nature scenes) and while viewing a cocaine video (i.e. people administering cocaine). The colour scale (from red to blue) represents the amount of [11C] raclopride emission decreasing in areas where there is more dopamine binding to the D2R. (B) D2R availability in the DS (i.e. caudate), putamen, and VS for the neutral video (blue) and the cocaine cues video (red). Cocaine cues significantly increased dopamine in the caudate and putamen but not in the VS. (C) Correlation between changes in D2R and cocaine craving induced by the cocaine video.

Figure 7.6 Craving-induced dopamine release in substance addiction. Dopamine changes induced by conditioned cues in active cocaine abusers. (A) Average non-displaceable binding potential of [11C]raclopride in cocaine-addicted subjects tested while viewing a neutral video (nature scenes) and while viewing a cocaine video (i.e. people administering cocaine). The colour scale (from red to blue) represents the amount of [11C] raclopride emission decreasing in areas where there is more dopamine binding to the D2R. (B) D2R availability in the DS (i.e. caudate), putamen, and VS for the neutral video (blue) and the cocaine cues video (red). Cocaine cues significantly increased dopamine in the caudate and putamen but not in the VS. (C) Correlation between changes in D2R and cocaine craving induced by the cocaine video.

Reproduced from Proceedings of the National Academy of Sciences of the United States of America, 108, 37, Volkow, N. D., Wang, G. J., Fowler, J. S. et al, Addiction: beyond dopamine reward circuitry, pp. 15037–15042.Copyright (2011) the Authors. Published by National Academy of Sciences, USA. Source data from Journal of Neuroscience, 26, Volkow, N.D, Wang G.J., Cocaine cues and dopamine in dorsal striatum: Mechanism of craving in cocaine addiction, 2006.

The DS has been implicated in habit learning, as substance abuse progresses. Research also suggests that behavioural changes in addiction are represented by a transition from cortical to subcortical (i.e. striatal) control and, within the striatum, from the VS to the DS (i.e. caudate). Therefore, conditioned cues trigger reflexive, exaggerated surges in dopamine release.

Research also suggests that reduced dopamine transmission, in addiction, might actually predict treatment failure. Patients with low methylphenidate-induced dopamine release respond less favourably to behavioural treatment that uses positive reinforcement to reduce impulsive cocaine use (Martinez et al. 2012).

These findings cannot rule out the possibility of dopamine deficits prior to substance abuse and dependence. Research in animals, for example, suggests a role for the D2R with respect to impulsivity and, consequently, the development of cocaine abuse. High impulsive rats have lower D2R levels in the VS and self-administer cocaine (but not heroin) significantly more than low impulsive rats. Social status in monkeys is also associated with D2R levels and cocaine abuse. Lower social status is associated with fewer D2R and greater cocaine self-administration. If the social status of an animal is reversed, so are D2R levels and cocaine intake.

7.3 Treatment

Research examining potential treatment approaches to substance addiction has involved the use of compounds that modulate dopamine functioning (see Table 7.1). This research has involved the assessment of abstinence and particularly the efficacy of these compounds to reduce the subjective effects and craving that are induced by small, priming doses of a substance (e.g. alcohol, amphetamine, cocaine).

Table 7.1 Dopamine-modulating compounds that have been tested as potential treatments for substance addiction

Medication

Mechanism of action

Addiction type

Efficacy

Amantadine

Dopamine releaser

Cocaine

Not effective and its discontinuation may increase in cocaine use

Does not reduce preference for cocaine

May reduce the desire to use cocaine when combined with the GABAB agonist baclofen

May be effective in patients with severe cocaine withdrawal symptoms

Aripiprazole

Partial D2R agonist

Alcohol

May reduce drinking in those with lower self-control

Less efficacious than naltrexone for craving

Attenuates ventral striatal activation in response to alcohol cues

Amphetamine

Reduces subjective effects of amphetamine challenge

Cocaine

Increases cocaine self-administration

Methamphetamine

Increases rewarding effects of acute methamphetamine

Bupropion

DAT inhibitor

Cocaine

Does not alter the acute subjective effects of cocaine

May enhance the positive subjective effects of cocaine

Methamphetamine

Reduces the positive subjective effects of methamphetamine

Reduces cue-induced craving

Disulfiram

Dopamine β‎-hydroxylase inhibitor

Alcohol

Deters alcohol consumption

Cocaine

Reduces the positive subjective effects of cocaine

Weight-based medication doses negatively predict the preference for cocaine

Levodopa

Dopamine precursor

Cocaine

No effect on cocaine use, craving, or mood

Methamphetamine

Dopamine releaser

Cocaine

Methamphetamine SR reduces cocaine use and craving

Methylphenidate

Dopamine releaser

Cocaine

Enhances anterior cingulate activation and reduces impulsive responding

Oral slow release decreases the reinforcing effects of cocaine in those with ADHD

Provides no advantage over placebo in reducing cocaine use

Methamphetamine

No different to placebo in reducing methamphetamine use

Modafinil

DAT inhibitor

Alcohol

May improve state impulsivity in those with poor response inhibition

Cocaine

In combination with individual behavioural therapy may reduce cocaine use

Methamphetamine

Does not reduce methamphetamine use

May reduce the acute reinforcing effects of methamphetamine

Selegiline

Monoamine oxidase B Inhibitor

Cocaine

No significant effect over placebo in reducing cocaine use

Methamphetamine

May increase negative subjective effects of acute methamphetamine

The partial D2R agonist aripiprazole may possess some efficacy in reducing alcohol intake and increasing abstinence from alcohol (Voronin et al. 2008). Aripiprazole blocks the effects of dopamine when they are high but augments dopamine when it is low. This may, therefore, be beneficial in both reducing dopamine tone (e.g. during craving in response to cues) and increasing dopamine tone (e.g. during low mood and anhedonia). Aripiprazole also attenuates activation in the VS of alcoholics in response to alcohol cues and reduces the reinforcing subjective effects (e.g. good effect, like, willing to take again) of amphetamine in stimulant abusers (Lile et al. 2005).

Bupropion inhibits the reuptake of dopamine and enhances residual dopamine neurotransmission. Research has shown that it attenuates the reinforcing effects of methamphetamine and reduces methamphetamine craving (Newton et al. 2006). This effect appears to be due to bupropion’s inhibition of methamphetamine uptake—limiting the ability of methamphetamine to displace vesicular dopamine. The inhibition of dopamine uptake at the DAT may ameliorate the methamphetamine abstinence syndrome. Bupropion has not demonstrated any efficacy for cocaine dependence, however.

Disulfiram inhibits aldehyde dehydrogenase, resulting in acetaldehyde accumulation. This produces symptoms of hypotension, diaphoresis, flushing, nausea, and vomiting in response to alcohol consumption during drinking. This reaction is aimed at making alcohol use negatively reinforcing. There are currently no medications approved for the treatment of cocaine dependence. Disulfiram is also a dopamine β‎-hydroxylase inhibitor—it prevents the conversion of dopamine to norepinephrine in presynaptic nerve terminals, thus increasing vesicular dopamine stores. Research suggests that disulfiram may possess some clinical efficacy during cocaine relapse, as it significantly attenuates the reinforcing effects (e.g. reported high, rush) of cocaine compared to placebo (Baker et al. 2007).

Substance addiction is associated with dysregulated dopaminergic transmission. This dysregulation of the dopamine system may also result in functional impairments in regions heavily innervated by dopamine, such as the prefrontal cortex (PFC). The PFC is essential to higher-order cognitive processing, such as impulse control. Therefore, medications that enhance dopamine functioning in the PFC may confer increased cognitive control over impulsive and risk-taking behaviours, such as substance use.

Methylphenidate has been shown to improve inhibitory control and decrease abnormal risk-taking in adolescents with attention deficit hyperactive disorder (ADHD). Compared to placebo, it has also been shown to significantly reduce impulsivity while, at the same time, enhance activation in the anterior cingulate gyrus (ACG) in cocaine abusers (Goldstein et al. 2010). Interestingly, this effect was found in the dorsal-cognitive division of the ACG, suggesting that methylphenidate may augment the neural cognitive control over impulsivity. While methylphenidate may be efficacious in those with ADHD and cocaine dependence, its efficacy in other non-ADHD populations with addictions remains to be fully tested.

7.4 Conclusion

Reward is a central component for driving incentive-based learnings. Substances of abuse are rewarding because they induce the release of dopamine in evolutionary hard-wired neural circuitry that is critical for survival-based behaviours. Chronic substance use, however, can induce a pathological shift in the responsiveness of this circuitry in response to both natural and substance reinforcers. Medications that augment dopamine functioning may be helpful in the treatment of substance addiction—particularly in reducing impulsivity and the acute reinforcing effects of substances upon relapse. There may be deficits in dopamine reward functioning, however, that predate substance abuse and addiction.

Further Reading

Baker JR, Jatlow P, and McCance-Katz EF (2007). Disulfiram effects on responses to intravenous cocaine administration. Drug and Alcohol Dependence, 87, 202–9.Find this resource:

Dackis CA, Kampman KM, Lynch KG, et al.# (2005). A double-blind, placebo-controlled trial of modafinil for cocaine dependence. Neuropsychopharmacology, 30, 205–11.Find this resource:

Goldstein RZ and Volkow ND (2002). Drug addiction and its underlying neurobiological basis: neuroimaging evidence for the involvement of the frontal cortex. American Journal of Psychiatry, 159, 1642–52.Find this resource:

Goldstein RZ, Woicik PA, Maloney T, et al. (2010). Oral methylphenidate normalizes cingulate activity in cocaine addiction during a salient cognitive task. Proceedings of the National Academy of Science of the United States of America, 107, 16667–72.Find this resource:

Heal DJ, Smith SL, Gosden J, et al. (2013). Amphetamine, past and present—a pharmacological and clinical perspective. Journal of Psychopharmacology, 27(6), 479–96.Find this resource:

Lile JA, Stoops WW, Vansickel AR, et al. (2005). Aripiprazole attenuates the discriminative-stimulus and subject-rated effects of D-amphetamine in humans. Neuropsychopharmacology, 30, 2103–14.Find this resource:

Martinez D, Carpenter KM, Liu F, et al. (2012). Imaging dopamine transmission in cocaine dependence: link between neurochemistry and response to treatment. American Journal of Psychiatry, 168, 634–41.Find this resource:

Newton TF, Roache JD, De La Garza R, 2nd, et al. (2006). Bupropion reduces methamphetamine-induced subjective effects and cue-induced craving. Neuropsychopharmacology, 31, 1537–44.Find this resource:

Volkow ND, Wang GJ, Fowler JS, et al. (1999). Reinforcing effects of psychostimulants in humans are associated with increases in brain dopamine and occupancy of D(2) receptors. Journal of Pharmacology and Experimental Therapeutics, 291, 409–15.Find this resource:

Volkow ND, Wang GJ, Telang F, et al. (2007). Profound decreases in dopamine release in striatum in detoxified alcoholics: possible orbitofrontal involvement. Journal of Neuroscience, 27, 12700–6.Find this resource:

Volkow ND, Wang GJ, Fowler JS, et al. (2011). Addiction: beyond dopamine reward circuitry. Proceedings of the National Academy of Sciences of the United States of America, 108, 15037–42.Find this resource:

Voronin K, Randall P, Myrick H, et al. (2008). Aripiprazole effects on alcohol consumption and subjective reports in a clinical laboratory paradigm—possible influence of self-control. Alcoholism: Clinical and Experimental Research, 32, 1954–61.Find this resource:

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