Reduced Insulin Sensitivity Is Related to Less Endogenous Dopamine at D2/3 Receptors in the Ventral Striatum of Healthy Nonobese Humans (2015)

BACKGROUND:

Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D_2/3 receptor radiotracer [¹¹C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity.

METHODS:

Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [¹¹C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D_2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion.

RESULTS:

Endogenous dopamine at ventral striatum dopamine D_2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D_2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36).

CONCLUSION:

In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D_2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic abnormalities.

© The Author 2015. Published by Oxford University Press on behalf of CINP.

Introduction

The continuous increase in the prevalence of obesity and diabetes in North America, thought to be linked to the overconsumption of high-fat/high-sugar foods, poses a serious public health burden (Mokdad et al., 2001; Seaquist, 2014). The concept of food addiction, where highly palatable foods are seen as rewarding as drugs of abuse (Lenoir et al., 2007), remains a hotly debated topic (Ziauddeen et al., 2012; Volkow et al., 2013a). In vivo brain imaging studies in humans have supported this concept, demonstrating similar brain changes between obese persons and persons with drug addiction (Volkow et al., 2013a, 2013b). More specifically, it has been demonstrated using positron emission tomography (PET) that obese persons and persons with drug addiction have less dopamine D_2/3 receptor (D_2/3R) availability in the striatum (Wang et al., 2001), an addiction-like neural marker also observed in rodents that overconsume palatable foods (Johnson and Kenny, 2010).

Striatal dopamine, particularly in the ventral striatum (VS), is an important modulator of food and drug reward and consumption (Palmiter, 2007). Several lines of evidence suggest that diabetes and reduced insulin sensitivity (IS) may be related to diminished endogenous dopamine in the VS. Reduced brain dopaminergic activity has been observed in diabetic rodents and postmortem human brains, as indicated by reduced dopamine synthesis rates (Crandall and Fernstrom, 1983; Trulson and Himmel, 1983; Saller, 1984; Bitar et al., 1986; Bradberry et al., 1989; Kono and Takada, 1994) and metabolism (Saller, 1984; Kwok et al., 1985; Bitar et al., 1986; Kwok and Juorio, 1986; Lackovic et al., 1990; Chen and Yang, 1991; Lim et al., 1994). Rodents made hypoinsulinemic via streptozotocin demonstrate reduced basal levels of dopamine in the nucleus accumbens (Murzi et al., 1996; O’Dell et al., 2014) as well as blunted dopamine release in response to amphetamine (Murzi et al., 1996; O’Dell et al., 2014). Notably, insulin modulates the cell surface expression (Garcia et al., 2005; Daws et al., 2011) and function (Owens et al., 2005; Sevak et al., 2007; Williams et al., 2007; Schoffelmeer et al., 2011) of the dopamine transporter (DAT). Moreover, insulin receptors are expressed in the nucleus accumbens and in midbrain dopaminergic neurons (Werther et al., 1987; Figlewicz et al., 2003), where they can modulate neuronal firing, energy homeostasis, and behavioral responses to rewarding stimuli like food, cocaine, and amphetamine (Galici et al., 2003; Konner et al., 2011; Schoffelmeer et al., 2011; Mebel et al., 2012; Labouebe et al., 2013). Collectively, these data suggest that decreased IS may be related to lower levels of endogenous dopamine in the VS.

To date, 2 PET studies have investigated the relationship between striatal dopamine D_2/3R availability and levels of fasting neuroendocrine hormones (Dunn et al., 2012; Guo et al., 2014). Using the antagonist radiotracer [¹⁸F]-fallypride, Dunn and colleagues (2012) demonstrated that dopamine D_2/3R availability in the VS was negatively correlated with IS in a sample of obese and nonobese females. Since radiotracer binding is sensitive to endogenous dopamine at baseline (Laruelle et al., 1997; Verhoeff et al., 2001), one possible explanation for this finding is that persons with reduced IS have less endogenous dopamine occupying D_2/3R in the VS and therefore more binding of the radiotracer at baseline. It has also been demonstrated with PET that individuals with cocaine addiction have less endogenous dopamine at D_2/3R in the VS (Martinez et al., 2009). Evidence that individuals with higher insulin resistance also have less endogenous dopamine at D_2/3R in the VS would support the modulatory role of insulin signaling on dopaminergic brain reward circuits (Daws et al., 2011) and food-seeking behaviors (Pal et al., 2002). However, no in vivo studies have examined how direct estimates of endogenous dopamine levels at D_2/3R in the VS relate to estimates of IS in humans.

Using PET with particular radioligands for D_2/3R, it is possible to achieve direct estimates of endogenous dopamine occupying D_2/3R in humans in vivo. This can be accomplished by comparing the percent change in binding potential (BP_ND) between a baseline PET scan and a scan under acute dopamine depletion (Laruelle et al., 1997; Verhoeff et al., 2001). Based on the occupancy model, since radiotracer binding to D_2/3R is sensitive to dopamine levels at baseline, changes in BP_ND after dopamine depletion reflect how much dopamine was occupying receptors at baseline (Laruelle et al., 1997; Verhoeff et al., 2001). Acute dopamine depletion can be achieved in humans by inhibiting dopamine synthesis via the tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (AMPT). This paradigm has been used to elucidate differences in endogenous dopamine levels occupying D_2/3R in the striatum of individuals with neuropsychiatric diseases (Martinez et al., 2009).

Our group has developed [¹¹C]-(+)-PHNO, the first agonist PET radiotracer for D_2/3R (Wilson et al., 2005; Graff-Guerrero et al., 2008; Caravaggio et al., 2014). The use of an agonist radiotracer, which should more closely mimic the binding of the endogenous ligand, may offer a more sensitive and functionally significant estimate of endogenous dopamine in humans. Further, we have recently validated the use of [¹¹C]-(+)-PHNO to estimate endogenous dopamine levels at D_2/3R using an AMPT challenge (Caravaggio et al., 2014). Collectively, in vivo human data suggest that this tracer is more sensitive to differences in endogenous dopamine levels than antagonist radiotracers such as [¹¹C]-raclopride (Shotbolt et al., 2012; Caravaggio et al., 2014) and thus may be better at elucidating differences in endogenous dopamine levels at D_2/3R in humans. Using [¹¹C]-(+)-PHNO body mass index (BMI) within a nonobese range was found to be positively correlated with BP_ND in the VS but not the dorsal striatum (Caravaggio et al., 2015). One potential explanation for this finding is that persons with greater BMI have less endogenous dopamine occupying D_2/3R in the VS. This previous finding further supports investigating the relationship between IS and endogenous dopamine specifically in the VS as measured with [¹¹C]-(+)-PHNO.

Using [¹¹C]-(+)-PHNO and an acute dopamine depletion paradigm, we sought to examine for the first time whether estimates of endogenous dopamine at D_2/3R in the VS of healthy, nonobese humans are related to IS. We hypothesized that persons with reduced IS would have less endogenous dopamine occupying D_2/3R in the VS at baseline. Healthy participants were evaluated to provide: 1) a proof of concept for the relationship between IS and brain dopamine without the presence of confounding changes that may occur in disease states; and 2) a benchmark for future comparisons in clinical populations. We also sought to determine whether reducing endogenous dopamine with AMPT could lead to changes in IS in healthy individuals. Clarifying the relationship between IS and dopamine levels in the brains of humans in vivo would represent an important first step in understanding the interplay between metabolic health, energy homeostasis, and brain reward circuits in health and disease (Volkow et al., 2013a, 2013b).

Methods and Materials

Results

Eleven healthy, nonobese and nondiabetic individuals (3 female) participated in the PET portion of the study; a subset of these data have been previously reported upon (Table 1) (Caravaggio et al., 2014). Within the full sample of subjects (n=11), examination of correlations between participant metabolic variables revealed that age was positively correlated with waist circumference (r(9)=.76, P=.007), and waist circumference was positively correlated with fasting levels of insulin (r(9)=.80, P=.003) (Table 2).

Nine of the 11 subjects provided both a baseline PET scan as well as a scan under acute AMPT-induced dopamine depletion; this provided estimates of endogenous dopamine occupying D_2/3R in the VS at baseline (ie, the percent change in [¹¹C]-(+)-PHNO BP_ND before and after dopamine depletion). Estimated baseline dopamine occupancy of D_2/3R in the VS was positively correlated with IS (r(7)=.84, P=.005) (Figure 1), a correlation that remained after statistically controlling independently for age (r(6)=.86, P=.007), BMI (r(6)=.72, P=.04), waist circumference (r(6)=.75, P=.03), and plasma levels of AMPT (r(6)=.84, P=.009). Concurrently, estimated baseline dopamine occupancy of D_2/3R in the VS was negatively correlated with fasting insulin levels (r(7)=-.85, P=.004) but was not correlated with fasting levels of glucose (r(7)=-.49, P=.18). Dopamine occupancy in the VS was not correlated with BMI (r(7)=.09, P=.80) or waist circumference (r(7)=-.30, P=.41).

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Figure 1. 

Relationship between estimated insulin sensitivity (IS) and endogenous dopamine at D_2/3 receptors (D_2/3R) in the ventral striatum (VS) of 9 healthy persons.

Notably, the above correlations with estimated baseline dopamine occupancy of D_2/3R were driven primarily by dopamine occupancy in the right VS but not the left VS. Specifically, dopamine occupancy in the left VS was not correlated with IS (r(7)=.41, P=.28), fasting levels of insulin (r(7)=-.46, P=.22), or glucose (r(7)=-.33, P=.39), whereas dopamine occupancy in the right VS was positively correlated with IS (r(7)=.75, P=.01), negatively correlated with fasting levels of insulin (r(7)=-.73, P=.02), and not correlated with levels of glucose (r(7)=-39., P=.31).

Within the full sample of subjects (n=11), baseline [¹¹C]-(+)-PHNO BP_ND in the right VS was negatively correlated with estimated IS (r(9)=-.65, P=.02) (Figure 2). Thus, participants with the lowest levels of endogenous dopamine occupying D_2/3R had the highest BP_ND at baseline, consistent with reduced competition for tracer binding by endogenous dopamine with decreased IS. Concurrently, fasting levels of insulin were positively correlated with [¹¹C]-(+)-PHNO BP_ND in the right VS (r(9)=.77, P=.006), while there was no correlation with fasting glucose levels (r(9)=.27, P=.43). Notably, [¹¹C]-(+)-PHNO BP_ND in the left VS was not correlated with IS (r(9)=-.35, P=.29) or fasting levels of insulin (r(9)=.53, P=.09) and glucose (r(9)=.08, P=.81).

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Figure 2. 

Relationship between baseline dopamine D_2/3 receptor (D_2/3R) availability – [¹¹C]-(+)-PHNO BP_ND – and estimated insulin sensitivity (IS) in 11 healthy persons.

Exploratory analyses revealed that estimated IS was not correlated with estimates of endogenous dopamine at D_2/3R in the caudate (r(7)=.47, P=.20), putamen (r(7)=.52, P=.15), or globus pallidus (r(7)=.33, P=.40). There were also no correlations between estimates of dopamine occupancy in these regions and fasting levels of insulin or glucose, as well as BMI and waist circumference (all P>.05; data not shown).

To examine how reducing endogenous dopamine affects IS, 25 healthy controls (mean age=31±11; 9 female) also provided fasting plasma levels of insulin and glucose before and after AMPT dopamine depletion. AMPT significantly increased plasma levels of fasting insulin (t(24)=-2.62, P=.01) while not significantly altering plasma levels of fasting glucose (t(24)=-0.93, P=.36). Of note, AMPT significantly decreased estimated IS (t(24)=2.82, P=.01) (Figure 3). Removing those subjects who had more than a 2-week interval between collection of blood work did not significantly change the aforementioned results (data not shown).

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Figure 3. 

Effect of acute dopamine depletion via alpha-methyl-para-tyrosine (AMPT) on estimated insulin sensitivity (IS), and fasting plasma levels of insulin and glucose, in 25 healthy persons (error bars represent SD). For 8 subjects, their post depletion IS values went against the general trend: 6 increased and 2 remained the same.

Discussion

Using the agonist radiotracer [¹¹C]-(+)-PHNO and an acute dopamine depletion paradigm, we demonstrate for the first time that IS is positively correlated with endogenous dopamine levels at D_2/3R in the VS. In the absence of obesity or overt glucose dysregulation, lower endogenous dopamine levels in the VS are associated with reduced IS. This novel finding is in line with previous in vivo PET studies examining baseline D_2/3R availability in the VS of obese persons (Dunn et al., 2012) and supports previous postmortem human findings (Lackovic et al., 1990) as well as preclinical findings in animals (Murzi et al., 1996; O’Dell et al., 2014). In line with the PET findings, experimentally reducing endogenous dopamine in a sample of healthy persons was associated with reduced IS.

Evidence suggests that brain insulin resistance co-occurs with peripheral insulin resistance, with insulin-resistant individuals demonstrating reduced glucose metabolism in the VS and prefrontal cortex in response to peripheral insulin (Anthony et al., 2006). Interestingly, central D_2/3R agonism in rodents can increase glucose concentrations in the periphery, not just in the brain (Arneric et al., 1984; Saller and Kreamer, 1991). Within this context, it warrants comment that bromocriptine, a nonspecific dopamine receptor agonist, is indicated for the treatment of diabetes (Grunberger, 2013; Kumar et al., 2013). Thus, centrally altering dopamine/insulin receptor functioning in the VS of humans may have clinical implications in the treatment of metabolic disorders. It should be noted that while dopamine in the accumbens is altered by changes in blood glucose in response to hyperinsulinemia, this relationship may be complex, with timing (acute vs chronic) and dose (physiological vs supraphysiological) effects both appearing to be important (Bello and Hajnal, 2006).

Limitations of our current study include not sampling individuals with glucose dysregulation; accordingly, clinical implications specific to overt cardiometabolic pathology are difficult to comment on. It is suggested that future studies examine how different degrees of glucose dysmetabolism (eg, insulin resistance, prediabetes, diabetes) are related to endogenous dopamine levels and dopamine release in the VS of humans. In addition, future studies should examine whether these values alter in the face of treatment for metabolic deficits. Moreover, it is important to examine across a spectrum of glucose dysregulation in humans how dopamine concentrations and functioning in the VS relate to mood, motivation, and reward processing. Finally, our sample in the current study is small. While we did not explicitly control for multiple comparisons, it is important to note that the observed relationship between IS and estimated endogenous dopamine in the VS would survive Bonferroni correction (corrected P value threshold for significance: P=.01 (0.05/4 ROIs). Future AMPT studies examining the relationship between endogenous dopamine in the brain and IS should attempt to employ larger sample sizes. Because of our small sample size, we refrained from exploring relationships between baseline [¹¹C]-(+)-PHNO BP_ND and IS in ROIs other than the VS. In particular, future [¹¹C]-(+)-PHNO studies using larger sample sizes should examine the relationship between IS and baseline BP_ND in the substantia nigra and hypothalamus: regions where 100% of the [¹¹C]-(+)-PHNO BP_ND signal is due to D₃R vs D₂R (Searle et al., 2010; Tziortzi et al., 2011). To our knowledge, studies have not examined if there is a differential relationship between central D₃R vs D₂R expression with peripheral insulin resistance in animals or humans. This warrants investigation, since D₃R may play a role in insulin secretion in the periphery (Ustione and Piston, 2012), and D₃R knockout mice have been characterized as having an obesity-prone phenotype (McQuade et al., 2004).

What is the relationship between insulin, changes in dopamine concentrations, and food reward? Changes in insulin appear to modify functioning of the mesolimbic dopamine system, affecting feeding and food reward (Figlewicz et al., 2006; Labouebe et al., 2013). It has been suggested that insulin can inhibit dopamine neurons in the ventral tegmental area (VTA) and thus reduce dopamine release into the accumbens (Palmiter, 2007). Notably, acute insulin injections into the VTA have been shown to inhibit overeating of sweetened high-fat foods in sated rodents without altering hungry feeding (Mebel et al., 2012). Moreover, hypoinsulinemic rodents demonstrate increased feeding related to altered functioning of the nucleus accumbens (Pal et al., 2002). Data in healthy rodents suggest that peripheral insulin injections can increase dopamine release in the nucleus accumbens (Potter et al., 1999), and insulin per se may be rewarding (Jouhaneau and Le Magnen, 1980; Castonguay and Dubuc, 1989). Thus, the exact mechanisms by which acute or chronic insulin receptor activation affects the mesolimbic dopamine system and dopamine levels therein are not entirely clear. In addition, it is unclear how these systems may change in healthy metabolic states vs those that are diseased.

Several studies have examined how insulin affects DAT and reward-related behaviors to drugs of abuse that act on DAT, such as cocaine and amphetamine (Daws et al., 2011). For example, hypoinsulinemic rodents self-administer less amphetamine (Galici et al., 2003), while increasing insulin in the accumbens enhances cocaine-induced impulsivity (Schoffelmeer et al., 2011). However, while the molecular pathways by which insulin can alter DAT function and expression are known, mixed results have been observed across studies employing either acute or chronic insulin manipulations for the striatum (Galici et al., 2003; Owens et al., 2005; Sevak et al., 2007; Williams et al., 2007; Schoffelmeer et al., 2011; Owens et al., 2012; O’Dell et al., 2014) and VTA (Figlewicz et al., 1996, 2003; Mebel et al., 2012). Many of these studies have not differentially examined how insulin affects DAT in the dorsal striatum vs the VS, or the accumbens core vs shell. This may be a potential source of discrepancy, since the expression, regulation, and function of the DAT may be different in different striatal subregions (Nirenberg et al., 1997; Siciliano et al., 2014). To our knowledge, no in vivo human brain imaging study has investigated the relationship between insulin resistance and striatal DAT availability. Findings regarding the relationship between BMI and striatal DAT availability in humans have been mixed (Chen et al., 2008; Thomsen et al., 2013; van de Giessen et al., 2013), although these studies have not examined the VS. Interestingly, amphetamine users report a high incidence of childhood obesity and eating psychopathology (Ricca et al., 2009), further highlighting the important behavioral and neurochemical overlaps between food and drug reward (Volkow et al., 2013b).

The current finding that lower IS is associated with reduced dopamine in the VS could have implications for theories of food and drug addiction. It has been suggested that increased BMI and overeating behavior are related to reduced presynaptic dopamine synthesis capacity in the striatum of healthy humans (Wilcox et al., 2010; Wallace et al., 2014). Data from Wang and colleagues (2014) suggest that obese individuals demonstrate attenuated dopamine release in the VS in response to calorie consumption compared with nonobese persons. Moreover, using SPECT, it has been suggested that obese females demonstrate reduced striatal dopamine release in response to amphetamine (van de Giessen et al., 2014). This may well mirror the blunted VS dopamine release seen in diabetic rodents and in persons with drug addiction in response to psychostimulants (Volkow et al., 2009). It will be important to elucidate whether persons with diabetes also display a blunting of striatal dopamine release in response to food, food cues, and/or psychostimulants. Collectively, in vivo brain imaging studies in humans suggest that obesity and perhaps insulin resistance are associated with reduced dopamine synthesis, release, and endogenous tone in the VS.

While we did not find any relationship between IS and levels of endogenous dopamine in the dorsal striatum, it is important to highlight that several animal studies have reported alterations in dorsal striatal dopamine and functioning of neurons in the substantia nigra in relation to insulin resistance (Morris et al., 2011). Notably, in humans dopamine release in response to food in the dorsal striatum has been found to be correlated with ratings of meal pleasantness (Small et al., 2003). Perhaps, reduced IS affects VS dopamine functioning first, with changes in dorsal striatal dopamine functioning only evident with greater insulin resistance. It is possible that the present study was underpowered and/or did not sample a wide enough range of IS to detect an effect in the dorsal striatum.

These data have important implications for those neuropsychiatric disorders in which insulin resistance may be co-morbid or concurrent. For example, several lines of evidence suggest links between insulin resistance and the development of Parkinson’s disease (Santiago and Potashkin), Alzheimer’s disease (Willette et al., 2014), and depression (Pan et al., 2010). Consistent with the hypothesis that insulin resistance may be associated with decreased striatal dopamine, it is tempting to speculate that lower IS could confer protective effects on psychosis in persons with schizophrenia. For example, in Chinese first-episode, never-medicated persons with schizophrenia, greater insulin resistance was correlated with reduced severity of positive symptoms (Chen et al., 2013). It is well established that persons with schizophrenia, as well as their unaffected relatives (Fernandez-Egea et al., 2008), are more likely to have metabolic abnormalities; this has been found prior to antipsychotic use and after controlling for lifestyle habits (Kirkpatrick et al., 2012). Moreover, differences in glucose tolerance may differentiate subgroups of persons with schizophrenia characterized by different courses of symptom severity (Kirkpatrick et al., 2009). In the context of these findings, combined with the historical observation that insulin-induced comas can ameliorate psychotic symptoms (West et al., 1955), it is appealing to speculate that central insulin signaling on dopamine neurons may play a role in the pathology and treatment of schizophrenia (Lovestone et al., 2007). Future PET studies exploring the interaction between psychopathology and insulin resistance on central dopamine levels certainly appear warranted.

In conclusion, using PET and an acute dopamine depletion challenge, we have demonstrated for the first time that estimates of IS are related to levels of endogenous dopamine at D_2/3R in the VS of healthy humans. Furthermore, acutely reducing endogenous dopamine in healthy persons can alter estimated IS. Taken together, these findings represent an important preliminary step in elucidating how metabolic status may interface with major mental illnesses such as schizophrenia.

Statement of Interest

Dr. Nakajima reports having received grants from Japan Society for the Promotion of Science and Inokashira Hospital Research Fund and speaker’s honoraria from GlaxoSmith Kline, Janssen Pharmaceutical, Pfizer, and Yoshitomiyakuhin within the past 3 years. Dr. Graff-Guerrerro currently receives research support from the following external funding agencies: Canadian Institutes of Health Research, the U.S. National Institute of Health, and the Mexico Instituto de Ciencia y Tecnologıa para la Capital del Conocimiento en el Distrito Federal (ICyTDF). He has also received professional services compensation from Abbott Laboratories, Gedeon-Richter Plc, and Lundbeck; grant support from Janssen; and speaker compensation from Eli Lilly. Dr. Remington has received research support, consulting fees, or speaker’s fees from the Canadian Diabetes Association, the Canadian Institutes of Health Research, Hoffman-La Roche, Laboratorios Farmacéuticos Rovi, Medicure, Neurocrine Biosciences, Novartis Canada, Research Hospital Fund–Canada Foundation for Innovation, and the Schizophrenia Society of Ontario. The other authors have no competing interests to disclose.

Acknowledgments

This study was funded by Canadian Institutes of Health Research (MOP-114989) and U.S. National Institute of Health (RO1MH084886-01A2). The authors thank the PET Centre staff at the Centre for Addiction and Mental Health for technical assistance in data collection. They also sincerely thank Yukiko Mihash, Wanna Mar, Thushanthi Balakumar, and Danielle Uy for their assistance.

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