The dopamine (DA) D3 receptor (D3R) has been associated with impulsivity, pathologic gambling, and drug addiction, making it a potential target for pharmacotherapy development. Positron emission tomography studies using the D3R-preferring radioligand [11C]PHNO ([11C](+)-propyl-hexahydro-naphtho-oxazin) have shown higher binding potentials in drug abusers compared with control subjects. Preclinical studies have examined D3R receptor activation using the DA agonist quinpirole and the unconditioned behavior of yawning. However, the relationship between quinpirole-elicited yawning and D3R receptor availability has not been determined. In Experiment 1, eight drug-naive male rhesus monkeys were scanned with [11C]PHNO, and the ability of quinpirole (0.01–0.3 mg/kg i.m.) to elicit yawning was examined. Significant positive (globus pallidus) and negative (caudate nucleus, putamen, ventral pallidum, and hippocampus) relationships between D3R receptor availability and quinpirole-induced yawns were noted. Experiment 2 replicated earlier findings that a history of cocaine self-administration (n = 11) did not affect quinpirole-induced yawning and extended this to examine monkeys (n = 3) with a history of methamphetamine (MA) self-administration and found that monkeys with experience self-administering MA showed greater potency and significantly higher quinpirole-elicited yawning compared with controls. Finally, quinpirole-elicited yawning was studied in drug-naive female monkeys (n = 6) and compared with drug-naive male monkeys (n = 8). Sex differences were noted, with quinpirole being more potent and eliciting significantly more yawns in males compared with females. Taken together these findings support the use of quinpirole-elicited yawning as a behavioral tool for examining D3R activation in monkeys and that both drug history and sex may influence individual sensitivity to the behavioral effects of D3R compounds.
Psychostimulant drug use is a global problem. In 2011, the United Nations Office on Drugs and Crime estimated 14 to 21 million people worldwide used cocaine at least once in 2009, with 20% of users in the United States meeting the criteria of drug dependence (Degenhardt and Hall, 2012). Despite the array of negative health and societal consequences, a successful pharmacotherapy for psychostimulant addiction has remained elusive (Newman et al., 2005, 2012). There is evidence that dopamine (DA) D3 receptors (D3R), a subtype of the D2-like family of DA receptors, mediate many of the effects of psychostimulants associated with high abuse potential (Heidbreder and Newman, 2010; Heidbreder, 2013), including the role of conditioned stimuli (Neisewander et al., 2004; Achat-Mendes et al., 2009; Orio et al., 2010; Yan et al., 2013), discriminative stimulus effects (Martelle et al., 2007; Achat-Mendes et al., 2009; Collins and Woods, 2009), and cue conditioning (Le Foll et al., 2002). In addition, D3R partial agonists and antagonists have been shown to reduce self-administration of methamphetamine (MA) in a rodent model of compulsive drug intake (Orio et al., 2010). Postmortem studies indicate higher D3R densities in cocaine overdose victims compared with age-matched controls (Staley and Mash, 1996; Segal et al., 1997), supporting a role for this receptor subtype in drug addiction. Finally, recent brain imaging studies in humans using the positron emission tomography (PET) D3R-preferring ligand [11C]PHNO ([11C]-(+)-propyl-hexahydro-naphtho-oxazin) revealed that D3R availability was higher in MA polydrug users (Boileau et al., 2012) and cocaine-dependent individuals (Payer et al., 2014) compared with age-matched controls, an outcome opposite to the decreases in D2-like receptor availability after chronic stimulant exposure (e.g., Volkow et al., 1990, 2001; Nader et al., 2006).
A behavioral assay that has been frequently used to characterize D3R agonists is the unconditioned behavior of drug-elicited yawning using the D3/D2 receptor agonist quinpirole in rodents (e.g., Collins et al., 2005, 2007; Baladi and France, 2009) and nonhuman primates (Martelle et al., 2007; Hamilton et al., 2010; Blaylock et al., 2011). The quinpirole-induced yawning dose-response curve is an inverted U-shaped function of dose. Collins et al. (2005, 2007) concluded that the ascending limb of the quinpirole dose-response curve is mediated by D3R, whereas the descending limb is primarily D2 receptor (D2R)–mediated and coincides with an onset of hypothermia. Despite the differences noted in D2-like and D3R availability after cocaine exposure, quinpirole-elicited yawning was not different in cocaine-naive versus cocaine-experienced monkeys (Blaylock et al., 2011). However, although D3R partial agonists do not elicit yawning when administered to cocaine-naive monkeys (Martelle et al., 2007), they do elicit yawning in monkeys with an extensive cocaine history (Blaylock et al., 2011). This finding suggests that drug-elicited yawning may be an effective baseline on which to assess functional consequences of chronic cocaine exposure.
In the present study, we used quinpirole-elicited yawning to examine the relationship between behavioral sensitivity and measures of D3R receptor availability using PET imaging with [11C]PHNO in drug-naive male rhesus monkeys. Second, we extended previous findings that a cocaine history does not influence sensitivity to quinpirole-elicited yawning (Blaylock et al., 2011; Collins et al., 2011) to monkeys with an extensive MA self-administration history. Finally, recent data investigating D2-like receptor availability in cocaine abuse (Nader et al., 2012) suggested possible sex differences in the relationship between DA receptor function and cocaine abuse. Thus, we examined the effects of quinpirole-elicited yawning in a group of drug-naive female rhesus monkeys and compared them to drug-naive male rhesus monkeys.
Materials and Methods
Adult rhesus monkeys (Macaca mulatta; 22 male, 7 female) served as subjects. At the start of the study, 15 monkeys were drug naive (8 males and 7 females), three male monkeys had a lifetime intake of methamphetamine ranging from 143 to 200 mg/kg and 11 male monkeys had varying cocaine histories (minimum of 225 mg/kg). Drug-experienced monkeys were previously implanted with a chronic indwelling catheter and associated vascular access port (Access Technologies, Skokie, IL) as described elsewhere (Czoty et al., 2006) and, excluding days of quinpirole-elicited yawning, underwent experimental sessions involving drug self-administration daily (Monday–Friday). All monkeys were fitted with aluminum collars and trained to sit calmly in a primate restraint chair (Primate Products, Redwood City, CA). Monkeys were individually housed in stainless-steel cages with visual and auditory contact with each other, ad libitum access to water in their home cage, and fed sufficient standard laboratory chow (Purina LabDiet 5045; St. Louis, MO) to maintain healthy body weights (determined by veterinary staff and somewhat less than free-feeding weights). Environmental enrichment was provided as outlined in the Animal Care and Use Committee of Wake Forest University Non-Human Primate Environmental Enrichment Plan. Experimental procedures as well as animal housing and handling were performed in accordance with the 2011 National Research Council Guidelines for the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of Wake Forest University.
Experiment 1: Relationship between D3R Availability and Quinpirole-Elicited Yawning
A magnetic resonance imaging (MRI) scan was acquired in seven of eight experimentally naive male monkeys; monkey #1711 had been previously implanted with a non-MR compatible telemetry device. Monkeys were anesthetized with ketamine (10–15 mg/kg i.m.) approximately 20 minutes prior to scanning, transported to the MRI facility, and T1-weighted images of the entire brain were acquired with a 3.0-T Siemens SKYRA scanner. PET data were coregistered to individual MRIs using PMOD Biomedical Image Quantification Software (version 3.1; PMOD Technologies, Zurich, Switzerland). Spherical regions of interest (ROI) were drawn on individual MR images for the caudate nucleus (Cd; 2.5 mm radii), putamen (Pt; 2.5 mm radii), globus pallidus (GP; 2.5 mm radii), ventral striatum (2.0 mm radii), ventral pallidum (VP; 2.0 mm radii), thalamus (3.0 mm radii), substantia nigra (2.0 mm radii), hippocampus (HIP; 2.4 mm radii), and cerebellum (4.0 mm radii). The GP, VP, thalamus, and substantia nigra were chosen because they are rich in D3R (Tziortzi et al., 2011), the Cd, Pt, and ventral striatum were chosen because of their involvement in addiction (Koob and Volkow, 2010), and the HIP because of its role in yawning (Argiolas and Melis, 1998). For monkey #1711, the PET data were coregistered to the MRI obtained from monkey #1710 based on the similar weight and age of the two subjects.
PET studies were performed on a GE 64 slice PET/CT Discovery VCT scanner (GE Medical Systems, Milwaukee, WI) with an approximate 5- to 6-mm resolution, using the D3R radiotracer [11C]PHNO, synthesized as described in Wilson et al. (2005). On the day of the PET study, monkeys (n = 8) were initially anesthetized with 10–15 mg/kg (i.m.) ketamine HCl and transported to the PET center where they were maintained on inhaled 1.5% isoflurane anesthesia for the duration of the 90-minute PET scan. Arterial and venous catheters were placed by percutaneous stick for blood pressure and tracer injection, respectively. Because of an irregular respiratory rate and hypotension after injection of the radiotracer, two monkeys were put on a ventilator for the remainder of the scan. This effect after tracer doses of PHNO was previously reported (Gallazot et al., 2012). At the start of the PET scan, 4–6 mCi of [11C]PHNO was injected, followed by a 90-minute three-dimensional emission scan consisting of 36 sequential frames: 10 × 6 seconds (0–1 minute), 5 × 1 minutes (1–6 minutes), 7 × 2 minutes (6–20 minutes), 14 × 5 minutes (20–90 minutes). Initiation of each PET scan coincided with intravenous injection of [11C]PHNO. The three-dimensional data were attenuation corrected and reconstructed transaxially using OSEM VUE point (28 subsets; 2 iterations) with a 3-mm FWHM filter resulting in a 128 × 128 matrix. PET studies were obtained prior to examining cumulative quinpirole-elicited yawning dose-response curves.
On the day of testing, monkeys were not fed before the experiment. Prior to the start of the session, monkeys were taken from the home cage, placed in a primate chair, and transferred to a quiet procedure room that contained a camera for video recording. They were allowed to habituate to the room for 5 minutes. The session was divided into five 30-minute components in which saline was administered before the first component followed by ascending doses of quinpirole (cumulative doses of 0.01, 0.03, 0.1, 0.3 mg/kg) injected intramuscularly in the upper quadriceps. Beginning immediately after each injection, the total number of yawns observed during each 30-minute bin was recorded. Yawning was defined as a full extension of the jaws, withdrawal of lips, and exposure of teeth (Code and Tang, 1991). Temperature was taken by rectal thermometer immediately after the monkey habituated to the room and after completion of each 30-minute bin. It was difficult to obtain body temperature measures in some monkeys after the highest dose of quinpirole. Only data from monkeys with temperature obtained from the entire dose response curve were used for hypothermia analyses (n = 4). Videos were scored by two observers blind to the experimental conditions; the interobserver variability was <5%.
Experiment 2: Effects of Sex and Drug History on Quinpirole-Elicited Yawning
Separate groups of monkeys were used in this study and compared with the drug-naive male monkeys used in Experiment 1. First, we replicated an earlier study using 11 male rhesus monkeys with an extensive history of cocaine self-administration and compared quinpirole-elicited yawning with data obtained from the drug-naive male monkeys from Experiment 1. Next, we extended this characterization to three male monkeys with an extensive history of MA self-administration (n = 3) and, finally, to drug-naive female rhesus monkeys (n = 7). For both the cocaine and MA group, 24 hours elapsed between drug self-administration sessions and quinpirole-elicited yawning. Quinpirole-elicited yawning and body temperature (for drug-naive females) measures were obtained as described in Experiment 1. After completion of the quinpirole dose-effect curve for the MA group, the lowest dose of quinpirole (0.01 mg/kg) elicited the most yawns. Therefore, the MA group underwent an additional acute session consisting of a saline injection followed 30 minutes later with 0.003 mg/kg quinpirole; this dose was not included in statistical analyses comparing groups.
One-way repeated-measures analyses of variance (ANOVAs) and Bonferroni post hoc analyses were used to analyze quinpirole-induced yawning and hypothermia. For analysis of PET data, a binding potential (BPND) was calculated for each of the eight ROIs (left hemisphere, right hemisphere, and average) by implementing the simplified reference tissue method (Lammertsma and Hume, 1996) in PMOD using the cerebellum as the reference region, resulting in 24 separate measures of BPND. Because of the longitudinal nature of these data, repeated-measures mixed models were conducted to account for within-monkey correlations. For these analyses, the total number of yawns at each of the five 30-minute bins was the dependent variable and average BPND as the independent variable, adjusting for dose of quinpirole. The mixed model analysis has been used in other PHNO studies (Gallezot et al., 2014) and was necessary because of the covariance between structures in the same individuals (Littell et al., 1998). These analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC). Because we could obtain body temperatures from only four monkeys after the highest dose of quinpirole, correlative data of quinpirole-induced hypothermia and BPND could not be obtained.
The effects of sex and drug (cocaine and MA) history on quinpirole-elicited yawning were analyzed with separate two-way repeated-measures ANOVAs using group (drug versus naive and male versus female) and quinpirole dose, followed by post hoc Bonferroni t tests (significance level, P < 0.05). Female rhesus quinpirole-induced yawning and hypothermia were analyzed using one-way repeated-measures ANOVAs.
Experiment 1: Relationship between D3R Availability and Quinpirole-Elicited Yawning.
In experimentally naive male rhesus monkeys, quinpirole-elicited yawning varied as a function of dose [F(4,39) = 3.901, P = 0.012] and was characterized as an inverted U-shaped function of dose, with peak yawns after 0.1 mg/kg (Fig. 1). Post hoc Bonferroni analysis showed that quinpirole elicited significantly more yawns at 0.1 mg/kg (t = 3.59, P < 0.01) and 0.3 mg/kg (t = 2.89, P < 0.05) than saline. Body temperature significantly decreased with increasing doses of quinpirole [F(4,19) = 13.33, P = 0.0002] (Fig. 1). Post hoc Bonferroni analysis revealed temperatures taken after 0.03, 0.1, and 0.3 mg/kg quinpirole were significantly different than temperatures after saline administration (t = 3.05, 4.90, 5.86, respectively; P < 0.05).
Each monkey was also studied with [11C]PHNO (Table 1). There were no significant differences between BPND in left and right regions for any ROI (data not shown), thus average values for each BPND were used for analyses. The highest binding potential was in the putamen, followed by the caudate nucleus and the ventral striatum. In those regions, the between-subject variability was between 5 and 8%. Table 2 summarizes the results of the mixed model analysis for the relationship between quinpirole-elicited yawning and [11C]PHNO BPND. With the mean binding potential for the caudate nucleus as an example, the beta value of −3.95 means that there are approximately four fewer yawns on average for every 1-unit increase in binding potential. There were significant negative relationships between yawns and BPND (Table 2) in the Cd (β = −3.95, P < 0.0001), Pt (β = −2.02, P < 0.0001), VP (β = −2.13, P = 0.0219), and HIP (β = −4.68, P = 0.0289) and a significant positive relationship in the GP (β = 4.63, P = 0.0002).
Experiment 2: Effects of Sex and Drug History on Quinpirole-Elicited Yawning.
There was a significant effect of quinpirole dose on the frequency of yawns [F(4,68) = 4.82, P = 0.002] but no significant group differences or interactions between drug-naive and cocaine-experienced monkeys (Fig. 2, ● versus ○). There was a significant effect of quinpirole dose [F(4,36) = 5.18, P = 0.002] and a significant interaction [F(4,36) = 4.55, P = 0.005] between drug-naive and MA-experienced monkeys (Fig. 2, ● versus ▴). Post hoc Bonferroni comparisons revealed monkeys with a history of MA self-administration yawned significantly more times than drug-naive monkeys (t = 3.25, P < 0.05) at 0.01 mg/kg quinpirole.
There were no significant effects of quinpirole dose on yawning in drug-naive female monkeys (Fig. 3, ●); the increasing trend at 0.3 mg/kg was due to one monkey yawning 36 times, whereas 5 animals did not yawn after this dose. Body temperature (Fig. 3, ▵) decreased as a function of quinpirole dose [F(4,34) = 42.14, P < 0.0001]. Post hoc Bonferroni analysis revealed temperatures taken after 0.01, 0.03, 0.1, and 0.3 mg/kg quinpirole were significantly different than temperatures obtained after saline (t = 2.81, 5.89, 9.19, and 11.3, respectively, P < 0.05). The results of a two-way ANOVA comparing drug-naive males (from Experiment 1) and females found significant effects of dose [F(4,52) = 3.28, P = 0.0181] and sex [F(4,52) = 6.17, P = 0.027] on quinpirole-elicited yawning. For quinpirole-induced hypothermia, there was a significant effect of quinpirole dose [F(4,40) = 37.57, P < 0.0001] but no significant effect of sex or interaction.
The purpose of the present study was 3-fold. The first objective was to ascertain the relationship between D3R binding potentials and the behavioral effects of the D3-preferring agonist quinpirole in monkeys. PET imaging using the D3-preferring radioligand [11C]PHNO revealed a significant correlation between D3R binding potential and quinpirole-induced yawning in several regions of the brain including the caudate nucleus, putamen, globus pallidus, ventral pallidum, and hippocampus. The second objective was to test whether a history of MA self-administration differentially affected sensitivity to the unconditioned behavioral effects of quinpirole. With a cumulative quinpirole dosing procedure, differences between MA-experienced monkeys and drug-naive monkeys were noted, with the MA group showing greater sensitivity to quinpirole. We also replicated an earlier study (Blaylock et al., 2011) showing no differences in quinpirole-elicited yawning between drug-naive and cocaine-experienced monkeys. Lastly, the comparison of drug-naive male and female monkeys revealed sex differences, with quinpirole showing greater efficacy and greater potency in eliciting yawning in males compared with females. These findings suggest that the unconditioned behavior of quinpirole-elicited yawning reflects D3R function in monkeys and that both sex and drug history are determinants of individual sensitivity.
Receptor autoradiography studies have indicated similar D3R receptor distribution in nonhuman primates compared with humans (Levant, 1998; Morissette et al., 1998; Sun et al., 2012). In the present study, the highest uptake and binding potentials were in the caudate nucleus, putamen, and ventral striatum. Previous studies in humans found a similar pattern of distribution of PHNO binding, with highest binding potentials in the putamen, globus pallidus, and substantia nigra (Searle et al., 2010; Boileau et al., 2012; Gallezot et al., 2014). Tziortzi and colleagues (2011) used the D3R antagonist GSK598809 [5-(5-((3-((1S,5R)-1-(2-fluoro-4-(trifluoromethyl)phenyl)-3-azabicyclo[3.1.0]hexan-3-yl)propyl)thio)-4-methyl-4H-1,2,4-triazol-3-yl)-4-methyloxazole] to better determine the contribution of D3R and D2R to the PHNO signal in various brain regions. These investigators found that 100% of PHNO signal in the substantia nigra and hypothalamus and the majority of the signal in the ventral pallidum and globus pallidus were D3R-mediated. In contrast, only 20% of the signal in the ventral striatum was attributed to D3R, whereas 100% of the signal in the caudate nucleus was a result of D2R binding (Tziortzi et al., 2011). Because the ascending limb of the quinpirole-elicited yawning dose-response curve is thought to be D3R-mediated (Collins et al.., 2005, 2007), the results of the mixed model, which showed approximately five greater yawns for every 1-unit increase in binding potential in the globus pallidus, support this conclusion. Furthermore, in the present study, yawning was negatively correlated with binding in the caudate nucleus and putamen, consistent with predominant D2R-mediated signal associated with [11C]PHNO binding potential and pharmacological studies suggesting that the descending limb of the quinpirole-elicited yawning dose-response curve is D2R-mediated (Collins et al., 2005, 2007).
Recent PET studies of chronic cocaine (Payer et al., 2014) and polydrug MA (Boileau et al., 2012) users reported that both drugs were associated with elevated levels of D3R availability in the substantia nigra. Furthermore, the use of cocaine and MA has previously been shown to be associated with decreased D2-like receptor availability (Volkow et al., 1990, 2001; Nader et al., 2006; Payer et al., 2014). In the present study, quinpirole-elicited yawning was used to assess group differences in D3R activity in monkeys with a cocaine or MA history and drug-naive male monkeys. In drug-naive monkeys, the quinpirole dose-response curve was an inverted U-shaped function of dose, as has been reported previously in monkeys (Martelle et al., 2007; Hamilton et al., 2010; Blaylock et al., 2011). Similarly, quinpirole-elicited yawning was not different between drug-naive and cocaine-exposed monkeys (Blaylock et al., 2011), although there was substantial individual-subject variability in the quinpirole dose-response curves. The reasons for these individual differences are not yet determined but may be due to differences in cocaine intake. Consistent with the present findings, a recent study found substantial individual subject differences in the reinforcing effects of D3R agonists, quinpirole, pramipexole, and ropinirole (Koffarnus et al., 2012), which may be due to differences in cocaine self-administration histories. Additional studies are needed to better understand how different cocaine exposures affect D3R compounds.
In contrast to the lack of differences between drug-naive and cocaine-exposed monkeys, MA-exposed monkeys were more sensitive to the behavioral effects of quinpirole compared with control monkeys. Changes in sensitivity on the ascending limb of the quinpirole dose-response curve have been hypothesized to be due to upregulation of D3R and/or downregulation of D2R (Collins et al., 2011); PET and receptor autoradiography studies support this mechanism after long-term MA exposure (Kuczenski et al., 2009; Boileau et al., 2012). It also remains possible that changes in DA transporter (DAT) and subsequent changes in extracellular DA may interact with quinpirole’s effects at D3R and D2R. Consistent with this hypothesis is that MA exposure has been shown to decrease DAT (Chu et al., 2008; Groman et al., 2013), whereas chronic cocaine exposure has been reported to increase DAT density (Letchworth et al., 2001). Irrespective of the mechanisms, the present findings suggest that despite both stimulants resulting in increases in [11C]PHNO binding (Boileau et al., 2012; Payer et al., 2014), the behavioral effects of D3R compounds may be different in subjects with a MA history compared with a cocaine history.
There is accumulating evidence of sex differences in cocaine abuse (O’Brien and Anthony, 2005), including greater vulnerability in initiating drug use, progressing to dependence faster, and more adverse physical, mental, and social consequences of abuse in women compared with men (Zilberman et al., 2003; Greenfield et al., 2010). Several animal models using female subjects have supported these observations (e.g., Lynch et al., 2002; Mello et al., 2007; Mello, 2010; Nader et al., 2012). As it relates to D3R function, sex differences have not been reported. In the present study, we found significant differences between male and female monkeys at lower quinpirole doses, with females being less sensitive to the behavioral effects of quinpirole. It is possible that the entire quinpirole dose-response curve for females is shifted to the right of males and that if higher doses of quinpirole were tested, even greater sex differences would have been observed. However, it is important to note that quinpirole-induced hypothermia was not different in drug-naive females and males, suggesting that baseline D2R availability is not different. PET data using D2-like radiotracers in monkeys have confirmed no significant differences between male and female monkeys (Hamilton et al., 2010). Although D2-like receptor availability may not be different at baseline, our data suggest sex differences in the behavioral effects of DA agonists. Consistent with this hypothesis, an investigation of healthy human subjects reported that drug-elicited DA release in the ventral striatum, caudate nucleus, and putamen was greater in male subjects compared with females (Munro et al., 2012). Additionally, a recent study showed that female smokers have significantly higher D2-like receptor availability than male smokers (Brown et al., 2012), further supporting the growing evidence of sex differences in dopaminergic system dynamics (Becker, 1999; Dreher et al., 2007; Festa et al., 2010; Hedges et al., 2010). On the other hand, the quinpirole-elicited yawning dose-response curve has been shown to be malleable to changes in food content and body weight (Baladi and France, 2009). Although males and females in this study ate the same high-protein diet, the heaviest female weighed less than the lightest male. Whether changes in diet would similarly affect the quinpirole dose-response curve in males and females remains to be investigated.
There is evidence supporting the use of D3R antagonists and partial agonists for the treatment of cocaine and MA abuse as well as accompanying symptoms such as cognitive dysfunction (Newman et al., 2012; Mugnaini et al., 2013; Nakajima et al., 2013). Considering female rhesus monkeys in the current study were less sensitive to the behavioral effects of quinpirole, it is likely that drug potency will be a critical variable in future studies investigating D3R compounds as a treatment option. As there are known sex differences in drug pharmacokinetics and pharmacodynamics (see Gandhi et al., 2004, for review) and also that the fields of neuroscience and pharmacology publish predominately male subject-based studies (Beery and Zucker, 2011), the present findings support the consideration of sex differences as a critical variable in the development of treatment strategies for drug abuse (Zilberman et al., 2003; see Becker and Hu, 2008). Finally, this and other studies (Boileau et al., 2012; Payer et al., 2014) have associated D3R availability and a history of psychostimulant abuse but have yet to establish the nature of this relationship. Future studies will need to focus on whether high or low D3R availability is a risk factor in psychostimulant abuse or a result of exposure to the drug.
There are some limitations to the present study. The relationship between [11C]PHNO binding potential and quinpirole-elicited yawning is not consistent with D3R and D2R signal in every brain region examined. For example, monkeys experienced fewer yawns with increasing D3R binding potential in the ventral pallidum. This relationship is not consistent with the high D3R signal reported in that brain region (Tziortzi et al., 2011), suggesting a possible alternative mechanism. Past studies have implicated specific brain areas in dopamine agonist-elicited yawning, including the nigrostriatal pathway, hypothalamus, and the paraventricular nucleus (Dourish and Hutson, 1985; Melis et al., 1987); thus, it is expected that yawning does not necessarily have to correlate with D3R and D2R signal in every brain region. Furthermore, yawning is not limited to dopaminergic modulation and several other neurotransmitters and neurohormones are involved (Argiolas and Melis, 1998), creating a complex neural circuit (Sanna et al., 2012) that requires additional testing.
The authors thank H. Donald Gage for PMOD assistance.
Participated in research design: Martelle, S. H. Nader, Czoty, John, Duke, P. K. Garg, Newman, M. A. Nader.
Conducted experiments: Martelle, S. H. Nader, John, S. Garg, Newman.
Performed data analysis: Martelle, S. H. Nader, Duke.
Wrote or contributed to the writing of the manuscript: Martelle, S. H. Nader, Czoty, John, Duke, P. K. Garg, S. Garg, Newman, M. A. Nader.
- Received March 20, 2014.
- Accepted May 28, 2014.
The research described in this manuscript was supported by grants from the National Institutes of Health National Institute on Drug Abuse [Grants DA012460 and DA021658]; the National Institutes of Health National Institute on Alcohol Abuse and Alcoholism [Grant AA021099]; and the Intramural Research Program of the National Institutes of Health [National Institute on Drug Abuse].
- analysis of variance
- binding potential
- caudate nucleus
- dopamine transporter
- dopamine D2 receptor
- dopamine D3 receptor
- globus pallidus
- magnetic resonance imaging
- positron emission tomography
- regions of interest
- ventral pallidum
- U.S. Government work not protected by U.S. copyright