Prediction of Reinforcing Responses to Psychostimulants in Humans by Brain Dopamine D2 Receptor Levels
Abstract
OBJECTIVE: This study assessed whether brain dopamine D2 receptor levels, which show significant intersubject variability, predict reinforcing responses to psychostimulants in humans. METHOD: [11C]Raclopride and positron emission tomography were used to measure D2 receptor levels in 23 healthy men (mean age=34 years, SD=7) who had no drug abuse histories in order to assess if there were differences between the subjects who liked and those who disliked the effects of intravenous methylphenidate (0.5 mg/kg). RESULTS: Subjects who liked the effects of methylphenidate had significantly lower D2 receptor levels (mean=2.72 Bmax/Kd, SD=0.3) than subjects who disliked its effects (mean=3.16, SD=0.3). Moreover, the higher the D2 levels found, the more intense were methylphenidate’s unpleasant effects. CONCLUSIONS: These results provide preliminary evidence that D2 receptor levels predict response to psychostimulants in humans and that low D2 receptors may contribute to psychostimulant abuse by favoring pleasant response.
One of the most challenging problems in the neurobiology of drug addiction is understanding why some individuals abuse drugs, whereas others do not. It has been hypothesized that low levels of dopamine D2 receptors predispose subjects to use drugs as a means of compensating for the decrease in activation of reward circuits activated by these receptors (1). However, the data supporting D2 receptor level involvement in predisposition to drug addiction are controversial (2), and the involvement of D2 receptor levels in the reinforcing responses to drugs in humans has not been demonstrated.
In the present study, we used [11C]raclopride and positron emission tomography (PET) to determine if there were differences in striatal D2 receptor levels between subjects who reported the effects of methylphenidate (a psychostimulant drug that, like cocaine, blocks the dopamine transporters [3]) as pleasant and those who reported them as unpleasant and to assess whether D2 receptor levels predict behavioral responses to methylphenidate, which differ markedly among subjects (4, 5). Although raclopride binds to both D2 and D3 receptors, the striatal concentration of D3 receptors is very low (≈1% of D2 receptors) (6), so that the PET measurements mainly reflect binding to D2 receptors.
METHOD
Twenty-three male subjects (mean age=34 years, mean SD=7) without psychiatric, neurological, or medical disease or drug abuse or dependence (except nicotine) were studied. Subjects were scanned by using a CTI 931 tomograph (Siemens, Nashville) after intravenous injection of 4–10 mCi of [11C]raclopride (specific activity=0.5–1.5 Ci/µM) (7). On a different day, subjects were given an intravenous dose of methylphenidate (0.5 mg/kg) after being told they would receive either placebo or methylphenidate. Behavioral effects were measured by using analogue self-rating scales for pleasant (happiness, mood, sexual desire, and desire for methylphenidate) and unpleasant (annoyance, distrust, anxiety, loss of control, and restlessness) drug effects, scored from 0 to 10 minutes before and 27 minutes after methylphenidate treatment (8). At the end of the study, subjects were asked if the effects of methylphenidate were pleasant or unpleasant. Written informed consent was obtained from all subjects after procedures had been fully explained.
Regions in the striatum and cerebellum were outlined on the individual’s summed [11C]raclopride image (between 15 and 54 minutes after injection of the radiotracer) and were then projected into the dynamic images to generate time activity curves (7). These time activity curves, along with the time activity curves for the amount of unchanged tracer in plasma, were used to obtain distribution volumes (equilibrium measurement of the ratio of tissue concentration to plasma concentration) and to compute the Bmax/Kd (ratio of the distribution volume in the striatum to that in the cerebellum minus 1) (9). This method has been shown to yield reliable and accurate estimates of Bmax/Kd(10). Differences in Bmax/Kd between the subjects who liked and those who disliked the effects of methylphenidate were compared by using Student’s t tests (two-tailed); Pearson product-moment correlations were used to compute correlations between D2 receptor levels and methylphenidate-induced behavioral changes (ratings after methylphenidate treatment minus baseline ratings). Significance was set at p<0.01.
RESULTS
Twelve subjects described the effects of methylphenidate as pleasant, nine described them as unpleasant, and two responded neutrally. There were no differences in demographic characteristics, smoking status, or plasma methylphenidate concentrations between individuals who liked and those who disliked the effects of methylphenidate.
Subjects who liked the effects of methylphenidate had significantly lower levels of D2 receptors (mean=2.72 Bmax/Kd, SD=0.32) than did subjects who disliked the effects (mean=3.16, SD=0.26) (t=3.3, df=19, p<0.004) (figure 1 and figure 2). The levels of D2 receptors were correlated negatively with methylphenidate-induced increases in the self-rating scales for happiness (r=–0.58, df=22, p<0.005) and increases in the self-rating scales for mood (r=–0.52, df=12, p=0.01) and positively correlated with the methylphenidate-induced increases in the self-rating scales for annoyance (r=0.53, df=22, p=0.01) and distrust (r=0.66, df=12, p<0.001). Although the results were not significant (p>0.05<0.20), the correlations with D2 receptor levels for the other pleasant drug effects were positive, and those for the other unpleasant effects were negative (figure 3).
DISCUSSION
The differences in response to methylphenidate between subjects with high and low D2 receptor levels can be explained by the hypothesis that there is an optimal range in which D2 receptor stimulation can be perceived as reinforcing; too little may not be sufficient, but too much may be aversive (11). Thus, it is possible that in subjects with high D2 receptor levels, a small dose of methylphenidate may be perceived as pleasant. If D2 receptor levels modulate sensitivity to physiological reinforcers (12), then one could postulate that low D2 receptor levels would predispose a subject to use drugs as a means of compensating for decreased activation of reward circuits (1). Alternatively, low D2 receptor levels could predispose individuals to psychostimulant abuse by favoring initial pleasant drug responses, which have been shown to predict future drug use (13), and/or high D2 receptor levels may protect against drug abuse by favoring unpleasant drug responses.
Subjects who reported the effects of methylphenidate as pleasant, as most cocaine abusers do (13), had D2 receptor levels similar to those previously reported in cocaine abusers (Bmax/Kd=2.6, SD=0.3) (14). Thus, these results bring to light the possibility that low D2 receptor levels in cocaine abusers may have antedated their cocaine use and may have contributed to their cocaine abuse. However, even if this possibility were to be corroborated, the fact that the subjects who liked methylphenidate had D2 receptor levels similar to those found in cocaine addicts but were not drug abusers suggests that additional variables are involved in the vulnerability to drug abuse.
These results are highly suggestive of an involvement of D2 receptor levels in the perception of the reinforcing effects of psychostimulants. These results agree with those from studies in laboratory animals indicating that D2 receptor levels mediate reinforcing responses to drugs of abuse. This is evidenced by the decrease in the reinforcing effects of alcohol and morphine in mice who lack D2 receptors (D2 receptor knockout) (15, 16) and by the decrease in the reinforcing effects of cocaine in animals given drugs that block D2 receptors (17, 18). While the studies on the effects of D2 receptor antagonists in the reinforcing effects of psychostimulants in humans have not been as conclusive as those in laboratory animals, they have shown a decrease in the subjective ratings of pleasant sensations and of the craving induced by cocaine (19, 20). The lower efficacy of D2 receptor antagonists reported in human studies may reflect the fact that the doses used were lower than those used in laboratory animals.
Although analogue scales for self-reports of drug effects have been shown to be reliable and consistent across studies and to predict administration of drugs in human subjects (21), this study would have benefited had these measures been corroborated by other behavioral instruments—e.g., the Profile of Mood States.
This is the first evidence in humans showing an association between D2 receptor levels in brain and the reinforcing responses to psychostimulants. Further studies are required to determine the involvement of D2 receptors in the predisposition to drug abuse.
Received Nov. 16, 1998; revision received Feb. 12, 1999; accepted Feb. 23, 1999. From the Medical and Chemistry Departments, Brookhaven National Laboratory, Upton, N.Y.; and the Department of Psychiatry, State University of New York at Stony Brook. Address reprint requests to Dr. Volkow, Medical Department, Bldg. 490, Upton, NY 11973; [email protected] (e-mail). Supported in part by U.S. Department of Energy contract ACO2-76CH00016 and National Institute on Drug Abuse grant DA-06891. The authors thank David Alexoff, Robert Carciello, Paula Cervany, Richard Ferrieri, Payton King, Alex Levy, Robert MacGregor, Noelwah Netusil, Carol Redvanly, David Schlyer, Colleen Shea, Donald Warner, and Cristopher Wong for their help.
FIGURE 1. Distribution Volume Images of [11C]Raclopride at the Levels of the Striatum (left) and Cerebellum (right) in a Healthy Male Subject Who Reported the Effects of Methylphenidate as Pleasant and in a Healthy Male Subject Who Reported Them as Unpleasanta
The images have been normalized to the cerebellar activity of each subject because this reflects nonspecific binding. Notice the lower activity in the striatum of the subject who reported the effects of methylphenidate as pleasant than in the striatum of the subject who reported them as unpleasant. 100% = 25 ml/mg; 10% = 0.4 ml/mg.
FIGURE 2. D2 Receptor Levels (Bmax/K d) in 23 Healthy Male Subjects Who Reported the Effects of Methylphenidate as Pleasant, Unpleasant, or Neutrala
aBmax/Kd values were lower in subjects who reported the effects of methylphenidate as pleasant than in those who reported them as unpleasant. The horizontal lines represent the means for the Bmax/Kd estimates for the different groups.
FIGURE 3. Regression Slopes and Correlations Between the Behavioral Effects of Methylphenidatea and the Measures of Dopamine D2 Receptor Levels (B max/K d) in 23 Healthy Male Subjects
Ratings after methylphenidate treatment minus baseline ratings.
1. Blum K, Cull JC, Braverman ER, Comings DE: Reward deficiency syndrome. Am Sci 1996; 84:132–145Google Scholar
2. Goldman D, Urbanek M, Guenther D, Robin R, Long JC: A functionally deficient DRD2 variant [Ser311Cys] is not linked to alcoholism and substance abuse. Alcohol 1998; 16:47–52Crossref, Medline, Google Scholar
3. Ritz MC, Lamb RJ, Goldberg SR, Kuhar MJ: Cocaine receptors on dopamine transporters are related to self-administration of cocaine. Science 1987; 237:1219–1223Google Scholar
4. Joyce PR, Donald RA, Nicholls MG, Lievesey JH, Abbott RM: Endocrine and behavioral responses to methylphenidate in normal subjects. Biol Psychiatry 1986; 21:1015–1023Google Scholar
5. Chait LD: Reinforcing and subjective effects of methylphenidate in humans. Behav Pharmacol 1994; 5:281–288Crossref, Medline, Google Scholar
6. Sokoloff P, Schwartz JC: Novel dopamine receptors half a decade later. Trends Pharmacol Sci 1995; 16:270–275Crossref, Medline, Google Scholar
7. Volkow ND, Fowler JS, Wang GJ, Dewey SL, Schlyer D, MacGregor R, Logan J, Alexoff D, Shea C, Hitzemann R, Angrist B, Wolf AP: Reproducibility of repeated measures of 11C raclopride binding in the human brain. J Nucl Med 1993; 34:609–613Medline, Google Scholar
8. Wang G-J, Volkow ND, Hitzemann RJ, Wong C, Angrist B, Burr G, Pascani K, Pappas N, Lu A, Cooper T, Lieberman JA: Behavioral and cardiovascular effects of intravenous methylphenidate in normal subjects and cocaine abusers. Eur Addict Res 1997; 3:49–54Crossref, Google Scholar
9. Logan J, Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, MacGregor RR, Hitzemann R, Bendriem B, Gatley SJ, Christman DR: Graphical analysis of reversible radioligand binding from time-activity measurements applied to [N-11C-methyl]cocaine PET studies in human subjects. J Cereb Blood Flow Metab 1990; 10:740–747Crossref, Medline, Google Scholar
10. Endres CJ, Carson RE: Assessment of dynamic neurotransmitter changes with bolus or infusion delivery of neuroreceptor ligands. J Cereb Blood Flow Metab 1998; 18:1196–1210Google Scholar
11. Glick SD, Raucci J, Wang S, Keller RW Jr, Carlson JN: Neurochemical predisposition to self-administer cocaine in rats: individual differences in dopamine and its metabolites. Brain Res 1994; 653:148–154Crossref, Medline, Google Scholar
12. Chausmer AL, Ettenberg A: A role for D2, but not D1, dopamine receptors in the response-reinstating effects of food reinforcement. Pharmacol Biochem Behav 1997; 57:681–685Crossref, Medline, Google Scholar
13. Davidson ES, Finch JF, Schenk S: Variability in subjective responses to cocaine: initial experiences of college students. Addict Behav 1993; 18:445–453Crossref, Medline, Google Scholar
14. Volkow ND, Wang GJ, Fowler JS, Logan J, Gatley SJ, Hitzemann R, Chen AD, Dewey SL, Pappas N: Decreased striatal dopaminergic responsivity in detoxified cocaine abusers. Nature 1997; 386:830–833Crossref, Medline, Google Scholar
15. Phillips TJ, Brown KJ, Burkhart-Kasch S, Wenger CD, Kelly MA, Rubinstein M, Grandy DK, Low MJ: Alcohol preference and sensitivity are markedly reduced in mice lacking D2 receptors. Nat Neurosci 1998; 1:610–615Crossref, Medline, Google Scholar
16. Maldonado R, Saiardi A, Valverde O, Samad TA, Roques BP, Borrelli E: Absence of opiate rewarding effects in mice lacking dopamine D2 receptors. Nature 1997; 388:586–589Crossref, Medline, Google Scholar
17. De Wit H, Wise RA: Blockade of cocaine reinforcement in rats with the dopamine receptor blocker pimozide, but not with the noradrenergic blockers phentolamine or phenoxybenzamine. Can J Psychol 1977; 31:195–203Crossref, Medline, Google Scholar
18. Spealman RD: Antagonism of behavioral effects of cocaine by selective dopamine receptor blockers. Psychopharmacology (Berl) 1990; 101:142–145Crossref, Medline, Google Scholar
19. Berger SP, Hall S, Mickalian JD, Reid MS, Crawford CA, Delucchi K, Carr K, Hall S: Haloperidol antagonism of cue-elicited cocaine craving. Lancet 1996; 347:504–508Crossref, Medline, Google Scholar
20. Sherer MA, Kumor KM, Jaffe JH: Effects of intravenous cocaine are partially attenuated by haloperidol. Psychiatry Res 1989; 27:117–125Crossref, Medline, Google Scholar
21. Fischman MW, Foltin RW: Utility of subjective-effects measurements in assessing abuse liability of drugs in humans. Br J Addict 1991; 86:1563–1570Google Scholar
