Elsevier

Drug and Alcohol Dependence

Volume 154, 1 September 2015, Pages 167-173
Drug and Alcohol Dependence

A preliminary study of dopamine D2/3 receptor availability and social status in healthy and cocaine dependent humans imaged with [11C](+)PHNO

https://doi.org/10.1016/j.drugalcdep.2015.06.039Get rights and content

Highlights

  • This paper examines social status and D2/3R availability in humans.

  • Healthy and cocaine dependent individuals were studied with the tracer [11C](+)PHNO.

  • Inverse associations between social status and D2/3R availability were observed.

  • These areas included D3R rich brain reward areas in both groups.

  • These findings demonstrate a novel relationship between social status and D2/3R.

Abstract

Background

Previous work in healthy non-human primates and humans has shown that social status correlates positively with dopamine 2/3 receptor (D2/3R) availability imaged with antagonist radioligands and positron emission tomography (PET). Further work in non-human primates suggests that this relationship is disrupted by chronic cocaine administration. This exploratory study examined the relationship between social status and D2/3R availability in healthy (HH) and cocaine dependent (CD) humans using the D3-preferring, agonist radioligand, [11C](+)PHNO.

Methods

Sixteen HH and sixteen CD individuals completed the Barratt Simplified Measure of Social Status (BSMSS) and underwent [11C](+)PHNO scanning to measure regional brain D2/3R binding potentials (BPND). Correlations between BPND and BSMSS scores were then assessed within each group.

Results

Within HH and CD groups, inverse associations between BSMSS score and BPND were observed in the substantia nigra/ventral tegmental area (SN/VTA) and the ventral striatum, and for the CD group alone, the amygdala. After adjusting for body mass index and age, negative correlations remained significant in the SN/VTA for HH and in the amygdala for CD subjects.

Conclusion

These preliminary data utilizing a dopamine agonist tracer demonstrate, for the first time, an inverse association between social status and D2/3R availability in the D3R rich extrastriatal regions of HH and CD humans.

Introduction

Social status is an important factor relating to health and behaviors in mammals, including humans (Adler et al., 1994, Tamashiro et al., 2005). Particularly, dopaminergic function in the brain has been found to relate to social status in different species (Grant et al., 1998, Hall et al., 1998, Morgan et al., 2000). In healthy humans, greater social status as measured by the Barratt Simplified Measure of Social Status (BSMSS; Barratt, 2006), a comprehensive instrument which quantifies social status based on educational and occupational environment, has been associated with higher striatal dopamine subtype 2/3 receptor (D2/3R) availability when imaged with the antagonist positron emission tomography (PET) radioligand, [11C]raclopride (Martinez et al., 2010). This finding is consistent with earlier PET work in nonhuman primates that utilized a social status corollary, social dominance, to show that social dominance was positively associated with striatal D2/3R availability in substance-naïve cynomolgus macaques when measured by [18F]fluoroclebopride (Morgan et al., 2002). Although novel, those previous studies were both done utilizing similar non-selective dopamine D2/3R antagonist tracers either shown to be unreliable outside of the striatum (Graff-Guerrero et al., 2008) or examined the basal ganglia as a whole (Morgan et al., 2002), thus important somatodendritic D2/3R regions within the basal ganglia, such as the substantia nigra/ventral tegmental area (SN/VTA), have not been examined. Additionally, the aforementioned antagonist tracers bind to both “high” affinity (i.e., the D3R and certain active forms of the D2R) and “low” affinity (i.e., the non-active forms of the D2R) dopamine D2/3R receptors (George et al., 1985, Leff, 1995) with equal preference. Consequently, this lack of preference limits the degree to which the relative distribution of dopamine receptor subtype (i.e., D2R vs. D3R) and isoform (i.e., “high” vs. “low” affinity D2R) can be examined in certain regions. However, with an agonist tracer it has been shown that D3R predominates in the SN/VTA (as opposed to the dorsal striatum where D2R is predominant) (Graff-Guerrero et al., 2008, Narendran et al., 2006, Searle et al., 2010, Tziortzi et al., 2011). Thus, to date, no studies have examined social status and D2/3R receptor availability in a non-substance abusing healthy human population with an agonist dopamine tracer, both within and outside the striatum.

Given the role of dopamine in mediating cocaine effects, investigators have sought to understand potential relationships between social status, cocaine, and brain dopamine function. Morgan et al. (2002) found that the vulnerability to self-administer cocaine was associated with lower social status in cynomolgus macaques. Follow-up work from the same group showed that after an extended period (between 5 and 45 months) of cocaine self-administration the positive association between social dominance and striatal D2/3R availability in socially housed nonhuman primates was lost (Czoty et al., 2004; for a complete review of social status and cocaine administration paradigms in nonhuman primates see Nader and Banks, 2014). Thus, current nonhuman primate evidence suggests a potentially complex relationship between the vulnerability to abuse cocaine, social status, and striatal dopamine function – a relationship that has yet to be examined in brain regions of clinical populations.

In light of these prior works (Czoty et al., 2004, Martinez et al., 2010, Morgan et al., 2002), this preliminary study looks, for first time, to utilize the D3-preferring agonist tracer [11C](+)PHNO to examine the association between social status and (1) striatal and extrastriatal (e.g., SN/VTA) D2/3R availability in non-substance abusing healthy humans (HH) humans and (2) investigate these same relationships in cocaine dependent (CD) humans for the first time with a radioligand.

Section snippets

Participants

Sixteen HH participants without a clinical history of illicit substance use and sixteen medically healthy, non-treatment-seeking CD participants were studied. Subject eligibility was confirmed by comprehensive medical and psychiatric histories, physical examination, neurological and mental status exam, routine laboratory studies, electrocardiogram, and semi-structured (Sheehan et al., 1998) or structured clinical interview (American Psychiatric Association Task Force on DSM-IV, 2000).

CD

Results

Means and standard deviations of demographic, clinical characteristic, and injection parameter data for both HH and CD participants are shown in Table 1, Table 2. There were no significant associations between daily cigarette intake or weekly alcohol consumption and regional measures of BPND in either group.

Mean BSMSS scores for HH (44.8 ± 10.1, range 30–62) and CD participants (30.2 ± 7.1, range 15–44) differed significantly (p < 0.001). Years of education were not statistically correlated with

Discussion

To our knowledge, the current study is the first to examine the relationship between social status and extrastriatal D2/3R availability in humans using the D3-preferring agonist radioligand, [11C](+)PHNO. This work found two major findings. The first was an inverse association between social status and D2/3R availability in the SN/VTA of HH participants. This relationship retained significance after adjusting for the known effects of age (Correa et al., 2014, Ishibashi et al., 2009, Kim et al.,

Role of funding source

Dr. Potenza has received financial support or compensation for the following: Dr. Potenza has consulted for and advised Boehringer Ingelheim, Lundbeck, Ironwood, Shire and INSYS; has consulted for and has financial interests in Somaxon; has received research support from the National Institutes of Health, Veteran's Administration, Mohegan Sun Casino, the National Center for Responsible Gaming and its affiliated Institute for Research on Gambling Disorders, and Forest Laboratories, Ortho-McNeil,

Contributors

All authors have read and approve of submission of this manuscript to Drug and Alcohol Dependence. We would like to thank the staff of the Clinical Neuroscience Research Unit (CNRU) at Connecticut Mental Health Center (CMHC), the Hospital Research Unit (HRU) of the Yale Center for Clinical Investigation (YCCI) at Yale-New Haven Hospital (YNHH), the Yale PET Center, the Yale Magnetic Resonance Research Center (MRRC), and especially Julie Holub, Nina Levine, Jane Wanyiri, and Lauren Kantrovitz.

Conflicts of interest

No conflict declared.

Acknowledgements

This work was supported by a NARSAD Young Investigator Award Grant (M132018; DM), the National Institute on Drug Abuse (NIDA) (K24 DA017899; 1R03DA027456-01; RTM; K12DA00167; JH; P20 DA027844; RTM, MNP), the National Institute of Mental Health (NIMH; T32 MH019961; DM/RTM), Yale PET Center, and YCCI Pilot Projects Utilizing Core Technologies and the Department of Mental Health and Addiction Services (DMHAS) of the State of Connecticut. This work was also made possible by CTSA Grant Number UL1

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