Dopamine, opioid and serotonin neurotransmission in behavioral addictions

Behavioral addictions are psychiatric disorders, in which the object of addiction is not a drug but instead behavior itself, such as gambling or eating. Behavioral addictions share clinical features with substance use disorder, including tolerance against behavior, continued behavior despite negative consequences, withdrawal symptoms and craving. However, little is known about the pathophysiology of these disorders. Behavioral addictions may also serve as a model to investigate the brain reward system at its purest form, without confounding chemical properties of misused drugs. The aim of this study was to investigate brain neurotransmitter function in behavioral addictions. Brain dopamine, opioid and serotonin systems were investigated in pathological gambling (PG), in binge eating disorder (BED) and in a control group using positron emission tomography (PET). PET scans were performed using [18F]fluorodopa to target presynaptic dopamine synthesis rate; [11C]carfentanil to label μ-opioid receptors (MORs); and [11C]MADAM to label serotonin transporter. Statistical analyses covered betweengroup comparisons in all three groups, intraregional PET tracer correlations in the PG and the control groups, and correlations between impulsivity and tracer binding in the PG and the control groups. BED patients showed decreased nucleus accumbens dopamine synthesis, wide-spread decreases in MOR binding, and regionally selective increases and decreases in SERT binding, whereas PG patients failed to show any changes in relation to controls. The changes were independent from possible confounding factors. Dopamine synthesis rate correlated positively with MOR binding in the basal ganglia in both PG and control groups. Impulsivity correlated inversely with SERT binding in the prefrontal cortex in controls. This association was lost in PG, and instead, midbrain MOR binding was related both with impulsivity and nucleus accumbens dopamine synthesis rate. The results of this study indicate that phenotypically distinct behavioral addictions differ also by their neurobiology. Importantly, the findings contrast with previously published results in substance addictions, indicating individual neurobiology in distinct addiction disorders. Whether the observed neurotransmitter alterations in BED and altered relationship between receptor densities and impulsivity in PG reflect predisposing pathophysiology or a neural adaptation remains to be established.Aivojen dopamiini-, opioidi- ja serotoniinitoiminta toiminnallisissa riippuvuuksissa Toiminnalliset riippuvuudet ovat psykiatrisia sairauksia, joissa riippuvuuden kohde ei ole kemiallinen aine vaan toiminta tai käytösmalli, kuten esimerkiksi rahapelaaminen tai syöminen. Toiminnallisilla riippuvuuksilla ja päihderiippuvuuksilla on paljon yhteisiä piirteitä, mukaan lukien sietokyvyn nousu, riippuvuuden kohteena olevan toiminnan jatkaminen huolimatta epäedullisista seurauksista, vieroitusoireet ja himo. Kuitenkaan toiminnallisten riippuvuuksien patofysiologiaa ei juurikaan tunneta. Toiminnallisia riippuvuuksia voidaan käyttää myös mallina tutkittaessa aivojen palkkiojärjestelmää puhtaimmillaan ilman päihteiden aiheuttamaa kemiallista sekoittavaa vaikutusta. Tämän tutkimuksen tarkoituksena oli tarkastella aivojen välittäjäaineiden toimintaa toiminnallisissa riippuvuuksissa. Aivojen dopamiini-, opioidi- ja serotoniinijärjestelmiä tutkittiin peliriippuvuudessa, ahmintahäiriössä ja kontrolliryhmässä positroniemissiotomografialla (PET). PET-kuvauksissa [18F]fluorodopa kuvasi presynaptista dopamiinin tuotantokykyä, [11C]karfentaniili sitoutui μ-opioidireseptoriin (MOR) ja [11C]MADAM puolestaan sitoutui serotoniinin takaisinottajaan (SERT). Tilastollisessa analyysissa tarkasteltiin kaikkien ryhmien välisiä eroja merkkiaineiden sitoutumisessa. Lisäksi peliriippuvuudessa ja kontrolliryhmässä tarkasteltiin eri merkkiaineiden sitoutumisen välisiä riippuvuussuhteita ja impulsiivisuuden ja merkkiaineiden sitoutumisen riippuvuussuhteita. Ahmintahäiriössä dopamiinin tuotantokyky oli alentunut accumbens-tumakkeessa, MOR-sitoutuminen oli alentunut laaja-alaisesti aivojen eri osissa ja SERT-sitoutumisessa nähtiin alueellisesti vaihtelevia sitoutumisen nousuja ja laskuja, kun taas peliriippuvuus ei eronnut kontrolleista minkään merkkiaineen osalta. Muutokset eivät johtuneet mahdollisista sekoittavista tekijöistä. Dopamiinin tuotantokyky korreloi tyvitumakkeiden MORsitoutumisen kanssa sekä peliriippuvuudessa että kontrolleilla. Impulsiivisuus korreloi otsalohkon SERT-sitoutumisen kanssa kontrolliryhmässä, mutta tämä riippuvuussuhde ei ilmennyt peliriippuvuudessa, jossa sen sijaan keskiaivojen MOR-sitoutuminen korreloi sekä impulsiivisuuden että accumbens-tumakkeen dopamiinin tuotantokyvyn kanssa. Tämän tutkimuksen tulokset osoittavat, että ilmiasultaan erilaiset toiminnalliset riippuvuudet eroavat myös neurobiologisesti toisistaan. Lisäksi tulokset poikkeavat aiemmin julkaistuista tuloksista päihderiippuvuuksissa, mikä tarkoittaa yksilöllisen neurobiologisen taustan ilmenemistä eri riippuvuussairauksissa. Edelleen jää selvitettäväksi, heijastavatko hermovälittäjäaineiden muutokset ahmintahäiriössä sekä hermovälittäjäaineiden ja impulsiivisuuden riippuvuussuhteiden muutokset peliriippuvuudessa altistavaa patofysiologiaa vai hermostollista mukautumista

The neural substrates of risky rewards and losses in healthy volunteers and patient groups: a PET imaging study.

BACKGROUND: Risk is an essential trait of most daily decisions. Our behaviour when faced with risks involves evaluation of many factors including the outcome probabilities, the valence (gains or losses) and past experiences. Several psychiatric disorders belonging to distinct diagnostic categories, including pathological gambling and addiction, show pathological risk-taking and implicate abnormal dopaminergic, opioidergic and serotonergic neurotransmission. In this study, we adopted a transdiagnostic approach to delineate the neurochemical substrates of decision making under risk. METHODS: We recruited 39 participants, including 17 healthy controls, 15 patients with pathological gambling and seven binge eating disorder patients, who completed an anticipatory risk-taking task. Separately, participants underwent positron emission tomography (PET) imaging with three ligands, [18F]fluorodopa (FDOPA), [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine synthesis capacity and serotonin transporter and mu-opioid receptor binding respectively. RESULTS: Risk-taking behaviour when faced with gains positively correlated with dorsal cingulate [11C]carfentanil binding and risk-taking to losses positively correlated with [11C]MADAM binding in the caudate and putamen across all subjects. CONCLUSIONS: We show distinct neurochemical substrates underlying risk-taking with the dorsal cingulate cortex mu-opioid receptor binding associated with rewards and dorsal striatal serotonin transporter binding associated with losses. Risk-taking and goal-directed control appear to dissociate between dorsal and ventral fronto-striatal systems. Our findings thus highlight the potential role of pharmacological agents or neuromodulation on modifying valence-specific risk-taking biases

Dopamine synthesis capacity correlates with µ-opioid receptor availability in the human basal ganglia: A triple-tracer PET study

Animal studies have suggested that dopamine and opioid neurotransmitter systems interact in brain regions that are relevant for reward functions, but data in humans are very limited. The interaction is potentially important in disorders affecting these neurotransmitter systems, such as addiction. Here, we investigated whether subcortical μ-opioid receptor (MOR) availability and presynaptic dopamine synthesis capacity are correlated in the healthy human brain or in pathological gamblers (PGs) using positron emission tomography with 6-[18F]fluoro-l-dopa and [11C]carfentanil. The specificity of the findings was further investigated by including a serotonin transporter ligand, [11C]MADAM, as a negative control. Thirteen PG patients and 15 age-, sex- and weight-matched controls underwent the scans. In both groups, presynaptic dopamine synthesis capacity was associated with MOR availability in the putamen, caudate nucleus and globus pallidus. No similar associations were observed between dopamine synthesis capacity and [11C]MADAM binding, supporting a specific interplay between presynaptic dopamine neurotransmission and opioid receptor function in the basal ganglia. Correlations were similar between the groups, suggesting that the dopamine-opioid link is general and unaffected by behavioral addiction. The results provide in vivo human evidence of a connection between endogenous opioid and dopamine signaling in the brain.</p

Binge eating disorder and morbid obesity are associated with lowered mu-opioid receptor availability in the brain

Both morbid obesity and binge eating disorder (BED) have previously been linked with aberrant brain opioid function. Behaviorally these two conditions are however different suggesting also differences in neurotransmitter function. Here we directly compared mu-opioid receptor (MOR) availability between morbidly obese and BED subjects. Seven BED and nineteen morbidly obese (non-BED) patients, and thirty matched control subjects underwent positron emission tomography (PET) with MOR-specific ligand [C-11]carfentanil. Both subjects with morbid obesity and BED had widespread reduction in [C-11]carfentanil binding compared to control subjects. However, there was no significant difference in brain MOR binding between subjects with morbid obesity and BED. Thus, our results indicate that there is common brain opioid abnormally in behaviorally different eating disorders involving obesity

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Abstract: Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [18F]FDOPA, [11C]MADAM and [11C]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [11C]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

The neurochemical substrates of habitual and goal-directed control

Our daily decisions are governed by the arbitration between goal-directed and habitual strategies. However, the neurochemical basis of this arbitration is unclear. We assessed the contribution of dopaminergic, serotonergic, and opioidergic systems to this balance across reward and loss domains. Thirty-nine participants (17 healthy controls, 15 patients with pathological gambling, and 7 with binge eating disorder) underwent positron emission tomography (PET) imaging with [F-18]FDOPA, [C-11]MADAM and [C-11]carfentanil to assess presynaptic dopamine, and serotonin transporter and mu-opioid receptor binding potential. Separately, participants completed a modified two-step task, which quantifies the degree to which decision-making is influenced by goal-directed or habitual strategies. All participants completed a version with reward outcomes; healthy controls additionally completed a version with loss outcomes. In the context of rewarding outcomes, we found that greater serotonin transporter binding potential in prefrontal regions was associated with habitual control, while greater serotonin transporter binding potential in the putamen was marginally associated with goal-directed control; however, the findings were no longer significant when controlling for the opposing valence (loss). In blocks with loss outcomes, we found that the opioidergic system, specifically greater [C-11]carfentanil binding potential, was positively associated with goal-directed control and negatively associated with habit-directed control. Our findings illuminate the complex neurochemical basis of goal-directed and habitual behavior, implicating differential roles for prefrontal and subcortical serotonin in decision-making across healthy and pathological populations

Dopamine and Opioid Neurotransmission in Behavioral Addictions: A Comparative PET Study in Pathological Gambling and Binge Eating

Although behavioral addictions share many clinical features with drug addictions, they show strikingly large variation in their behavioral phenotypes (such as in uncontrollable gambling or eating). Neurotransmitter function in behavioral addictions is poorly understood, but has important implications in understanding its relationship with substance use disorders and underlying mechanisms of therapeutic efficacy. Here, we compare opioid and dopamine function between two behavioral addiction phenotypes: pathological gambling (PG) and binge eating disorder (BED). Thirty-nine participants (15 PG, 7 BED, and 17 controls) were scanned with [11C]carfentanil and [18F]fluorodopa positron emission tomography using a high-resolution scanner. Binding potentials relative to non-displaceable binding (BPND) for [11C]carfentanil and influx rate constant (Ki) values for [18F]fluorodopa were analyzed with region-of-interest and whole-brain voxel-by-voxel analyses. BED subjects showed widespread reductions in [11C]carfentanil BPND in multiple subcortical and cortical brain regions and in striatal [18F]fluorodopa Ki compared with controls. In PG patients, [11C]carfentanil BPND was reduced in the anterior cingulate with no differences in [18F]fluorodopa Ki compared with controls. In the nucleus accumbens, a key region involved in reward processing, [11C]Carfentanil BPND was 30–34% lower and [18F]fluorodopa Ki was 20% lower in BED compared with PG and controls (p</p