Skip to main content
PMC home page
UKPMC Funders Author Manuscripts logoLink to UKPMC Funders Author Manuscripts
. Author manuscript; available in PMC: 2016 Mar 31.
Published in final edited form as: Psychopharmacology (Berl). 2015 Mar 25;232(15):2723–2729. doi: 10.1007/s00213-015-3915-0

Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum

Matthijs G Bossong 1,2, Mitul A Mehta 3, Bart NM van Berckel 1,4, Oliver D Howes 2,5, René S Kahn 1, Paul RA Stokes 5,6
PMCID: PMC4816196  EMSID: EMS66024  PMID: 25801289

Abstract

Rationale

Elevated dopamine function is thought to play a key role in both the rewarding effects of addictive drugs and the pathophysiology of schizophrenia. Accumulating epidemiological evidence indicates that cannabis use is a risk factor for the development of schizophrenia. However, human neurochemical imaging studies that examined the impact of Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, on striatal dopamine release have provided inconsistent results.

Objectives

To assess the effect of a THC challenge on human striatal dopamine release in a large sample of healthy participants.

Methods

We combined human neurochemical imaging data from two previous studies that used [11C]raclopride positron emission tomography (PET) (n=7 and n=13, respectively) to examine the effect of THC on striatal dopamine neurotransmission in humans. PET images were re-analysed to overcome differences in PET data analysis.

Results

THC administration induced a significant reduction in [11C]raclopride binding in the limbic striatum (−3.65%, from 2.39±0.26 to 2.30±0.23, p=0.023). This is consistent with increased dopamine levels in this region. No significant differences between THC and placebo were found in other striatal subdivisions.

Conclusions

In the largest data set of healthy participants so far, we provide evidence for a modest increase in human striatal dopamine transmission after administration of THC compared to other drugs of abuse. This finding suggests limited involvement of the endocannabinoid system in regulating human striatal dopamine release, and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

Keywords: Dopamine, positron emission tomography (PET), Δ9-tetrahydrocannabinol (THC), [11C]raclopride, striatum, cannabis

Introduction

Many abused drugs that can lead to addiction increase synaptic dopamine levels in the human limbic striatum. Most likely, this rapid increase in dopamine release is associated with drug-induced reward, which together with subsequent conditioned responses may lead to changes in incentive motivation and ultimately in drug-seeking behaviour (Volkow et al. 2011; Wise 2009). Indeed, with the use of neuroimaging techniques such as Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) in combination with radioactive tracers that bind to striatal dopamine receptors, increased dopamine concentrations have been demonstrated in the human limbic striatum after the administration of amphetamine (Martinez et al. 2003; Martinez et al. 2007; Oswald et al. 2005; Wand et al. 2007), alcohol (Boileau et al. 2003; Urban et al. 2010) and nicotine (Brody et al. 2009; Takahashi et al. 2008). This was indicated by significant reductions in radiotracer binding in the limbic striatum, which were in the range of 10 - 15% after administration of amphetamine (Martinez et al. 2003; Martinez et al. 2007; Oswald et al. 2005; Wand et al. 2007) and alcohol (Boileau et al. 2003; Urban et al. 2010), and around 10% after nicotine administration (Brody et al. 2009; Takahashi et al. 2008).

Increased striatal dopamine release associated with the use of abused drugs is relevant to psychotic disorders such as schizophrenia as elevated striatal dopamine function is one of the most robust pathophysiological features of the disorder (for review see Howes and Kapur 2014). Accumulating epidemiological evidence indicates that cannabis use during adolescence is a risk factor for the development of schizophrenia (Arseneault et al. 2004; Moore et al. 2007). Therefore, elevated striatal dopamine release after the use of cannabis may explain how cannabis use contributes to the development and pathophysiology of schizophrenia. Indeed, in animals, it has been demonstrated that cannabinoid substances such as Δ9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis and partial agonist of the cannabinoid CB1 receptor, stimulate striatal dopamine signalling (see for reviews El Khoury et al. 2012; Gardner 2005). For example, in vivo single-neuron electrophysiological recordings have shown that cannabinoid agonists are able to enhance neuronal firing of mesolimbic dopamine neurons (French 1997; French et al. 1997; Gessa et al. 1998) and in vivo microdialysis techniques revealed an elevation of striatal dopamine levels following cannabinoid administration (Chen et al. 1990; Fadda et al. 2006; Malone and Taylor 1999; Ng Cheong Ton et al. 1988; Tanda et al. 1997). These effects appear to depend on activation of CB1 receptors as they were blocked by the selective CB1 receptor antagonist SR-141716A (French 1997; French et al. 1997; Gessa et al. 1998; Malone and Taylor 1999; Tanda et al. 1997).

Results of human neuroimaging studies on the effects of THC on striatal dopamine release have been inconclusive. Using PET and the dopamine D2/D3 receptor tracer [11C]raclopride in seven healthy participants, Bossong et al. (2009) found that inhaled THC (8 mg) induced a relatively modest but significant reduction in [11C]raclopride binding in the limbic striatum and precommissural dorsal putamen (3.4% and 3.9%, respectively), consistent with an increase in dopamine levels in these regions (Bossong et al. 2009). Stokes and colleagues (2009) imaged thirteen healthy participants using the same PET methodology, but did not find significant effects of oral THC administration (10 mg) on [11C]raclopride binding, despite an increase in psychotic-like symptoms (Stokes et al. 2009). Finally, using SPECT and [123I]IBZM, Barkus et al. (2011) found that intravenously administered THC (2.5 mg) had no effect on striatal dopamine release in nine healthy participants, despite inducing transient psychotic symptoms (Barkus et al. 2011).

In the current study, we re-analysed the [11C]raclopride PET images of Bossong et al. (2009) according to the methods described in Stokes et al. (2009) in order to overcome differences in PET data analysis between the two studies. This re-analysis included the assessment of [11C]raclopride binding in regions of interest (ROIs) that were automatically defined using an atlas comprised of three functional subdivisions of the striatum and the cerebellum as a reference region. Subsequently, both data sets were combined to test the hypothesis that THC induces dopamine release in the human striatum in a large sample of healthy participants with previous experience of cannabis use. This approach allows new and better powered analyses to be conducted, such as an interaction test between striatal subdivision and THC effect.

Methods

Both the studies of Bossong et al. (2009) and Stokes et al. (2009) were approved by an independent ethics committee and were conducted in accordance with the Declaration of Helsinki 2008. All participants gave written informed consent before entry into the study. Participant recruitment, study design, drug administration, PET methodology and assessment of THC plasma concentrations are fully described for each study in Bossong et al. (2009) and Stokes et al. (2009), respectively.

Participants

Twenty healthy volunteers (thirteen from the study by Stokes and colleagues and seven from that by Bossong and colleagues) with previous experience of cannabis use without significant adverse effects were recruited to the study through public advertisements. All participants underwent an extensive screening performed by a clinician before they were included in either study. Subjects were in good physical health, and subjects with a current or previous psychiatric disorder including alcohol or drug dependence were excluded from participation. Use of medication at the time of the study and past use of psychiatric medication was not allowed. On study days, volunteers underwent urine drug screen analysis for use of recreational drugs including cannabis, amphetamine, cocaine and opiates. Any volunteer with a positive drug screen was excluded from the study. In addition, participants needed to abstain from alcohol for 24 hours before each study day.

Study design and drug administration

Using a randomised, placebo-controlled, crossover design, volunteers underwent two [11C]raclopride PET scans: one with placebo and one with THC administration. Study days were scheduled at least 2 weeks apart to allow for complete clearance of drugs. Stokes et al. (2009) administered a capsule containing either 10 mg dronabinol (a synthetic form of THC) or placebo 90 minutes before each scan. In the study of Bossong and colleagues (2009), either 8 mg of THC or placebo was inhaled 45 minutes before each scan using a Volcano vaporizer (Storz-Bickel GmbH, Tuttlingen).

Positron Emission Tomography

All PET scans were performed on an ECAT HR+ scanner (Siemens/CTI, Knoxville, TN, USA) with an axial field of 15.5 cm. For each scan, [11C]raclopride was given as a bolus plus constant infusion, providing a state of constant equilibrium (Carson et al. 1997). A 10 minute transmission scan was performed to correct for photon attenuation.

Plasma THC measurements

Venous blood samples were collected 10 minutes into the PET scan, which was 100 minutes (Stokes et al. 2009) and 55 minutes (Bossong et al. 2009) after administration of medication, respectively.

Regions of Interest

Individual PET frames obtained during steady state (from 40 and 38 minutes post-injection onwards for the study of Bossong et al. and Stokes et al., respectively) were realigned to the first frame obtained at equilibrium to correct for motion, and summed over all frames. Striatal and cerebellar ROIs were automatically defined on each PET scan using an atlas comprised of the three functional subdivisions of the striatum (limbic, associative and sensorimotor striatum) as well as the cerebellum as a reference region. Striatal subdivisions are anatomically analogous to the ventral striatum (limbic striatum), precommissural dorsal putamen, precommissural dorsal caudate and postcommissural dorsal caudate (associative striatum) and postcommissural putamen (sensorimotor striatum) (Martinez et al. 2003). The atlas was coregistered to individual summed PET images in SPM5 (Wellcome Trust Centre for Neuroimaging, London, UK) using an [11C]raclopride template. Activity was assessed for each ROI as the volume weighted average of left and right regions using Analyze software (www.analyzedirect.com). Activity in the overall striatum was calculated as the volume weighted average of all three striatal ROIs.

Outcome Measures

Nondisplaceable binding potential (BPND; Innis et al. 2007) was used as measure of dopamine D2/D3 receptor availability. BPND was defined as the distribution volume ratio (DVR) minus 1 (Lammertsma et al. 1996). As scans were performed during steady state, DVR could be obtained using the average activity concentration in a striatal ROI divided by that of the cerebellum ROI, which was used as reference. Using this method, BPND was calculated for all striatal subdivisions as well as overall striatum for both placebo and THC sessions in twenty participants.

Statistical Analysis

Group differences in BPND between placebo and THC were analysed using repeated measures ANOVA with factors drug (placebo and THC) and striatal subdivision (limbic, associative and sensorimotor striatum). Both post hoc analyses for individual subdivisions and statistical analyses for PET scan parameters were performed using paired t-tests. Correlation between [11C]raclopride binding in the overall striatum and THC plasma concentration was assessed with Pearson’s r. A p value less than 0.05 was considered statistically significant, which was tested two-sided for all outcomes except the correlation analysis. Cohen’s d effect sizes were calculated using pooled standard deviations. All statistical analyses were performed using SPSS 20.0 (SPSS, Chicago, Illinois) and all data are presented as mean±SD.

Results

Results are reported on nineteen subjects as one participant was identified as being a significant outlier according to Chauvenet's criterion (Taylor, 1997) (see Supplementary Results S1). Thirteen male and four female participants were included, with a mean age of 27.9±7.7 years (range 20 - 44).

PET scan parameters

There were no significant differences between placebo and THC sessions for either mean injected dose of [11C[raclopride (539±175 and 559±197 MBq, respectively; p=0.237) or the mean total mass of administered raclopride (3.72±2.38 and 3.46±1.46 μg, respectively; p=0.577).

Dopamine D2/D3 receptor availability

Repeated measures ANOVA revealed a significant interaction effect between drug and striatal subdivision (F(2,36)=6.01, p=0.015), indicating that the effect of THC differs between subdivisions. Post hoc analysis showed that the BPND of [11C]raclopride, reflecting dopamine D2/D3 availability, was significantly reduced in the limbic striatum after THC administration compared to placebo by 3.65% (from 2.39±0.26 to 2.30±0.23; p=0.023). No significant differences between THC and placebo were found in other striatal subdivisions (Fig. 1a and 1b).

Fig 1.

Fig 1

Open in a new tab

Effects of Δ9-tetrahydrocannabinol (THC) on [11C]raclopride Nondisplaceable Binding Potential (BPND), reflecting dopamine D2/D3 receptor availability, in (1a) striatal functional subdivisions and overall striatum (mean±SD), and (1b) limbic striatum of healthy subjects (n=19). (1c) Correlation between percentage change in [11C]raclopride binding in the overall striatum and THC plasma concentration during PET scan (Pearson’s r, one-sided).

* Significant difference between placebo and THC.

Plasma THC levels

Mean THC plasma concentration during the PET scan was 4.41±4.04 ng/ml. THC plasma concentration showed a significant negative correlation with the percentage change in [11C]raclopride binding in the overall striatum (r=−0.50, p=0.015) (Fig. 1c).

Discussion

In the largest study to date, we have found a significant reduction in [11C]raclopride binding after THC administration in the limbic striatum of healthy participants with previous experience of cannabis use. This result is consistent with a THC-induced increase in limbic striatal dopamine levels, and concords with animal studies which found increased striatal dopamine neurotransmission after administration of cannabinoid agonists (Gardner 2005; El Khoury et al. 2012). Furthermore, although the original Stokes et al. study (2009) found no significant association between THC administration and limbic striatal dopamine release, the addition of further participants from the Bossong et al. (2009) study (analysed using the same protocol as Stokes et al. (2009)) resulted in a significant association of THC administration with limbic striatal dopamine release. One possible explanation for the discrepant findings of the current analysis and the original study of Stokes et al. (2009) is that the original study with thirteen participants may not have been statistically powered to detect small changes in [11C]raclopride binding after oral administration of 10 mg of THC. This idea is further supported by the fact that in the study by Stokes et al. (2009) THC administration was associated with a radiotracer displacement of 1.6% and 3.2% in the right and left limbic striatum, respectively, which is non-significant but in the same direction as that reported in the current analysis.

These findings should be interpreted in the context of results from studies of human striatal dopamine release produced by other recreational drugs. Amphetamine, which pharmacologically directly targets the dopamine system, as well as alcohol have been shown to cause reductions in limbic striatal dopamine D2/D3 receptor availability in the range of 10 - 15% (Boileau et al. 2003; Martinez et al. 2003; Martinez et al. 2007; Oswald et al. 2005; Urban et al. 2010; Wand et al. 2007). Nicotine produces reductions in limbic striatal availability of around 10% (Brody et al. 2009; Takahashi et al. 2008), whereas we found a relatively modest decrease of 3.7% in the limbic striatum after THC administration.

Interestingly, this decrease in [11C]raclopride binding is consistent with animal findings. Assuming a ratio between the increase in dopamine levels and reduction in [11C]raclopride binding of approximately 40 : 1 (Breier et al. 1997; Laruelle et al. 1997), the 25 - 100% increase in striatal dopamine levels measured with microdialysis techniques after THC administration to animals (Chen et al. 1990; Malone and Taylor 1999; Tanda et al. 1997) indicates a reduction in [11C]raclopride binding of 0.6 - 2.5%, which is even lower than the 3.7% decrease demonstrated in this study. Since this modest effect of THC on striatal dopamine release is accompanied by robust behavioural effects (Bossong et al. 2009; Stokes et al. 2009), it seems unlikely that this impact of THC is exclusively mediated by the striatal dopamine system. This view is supported by two studies which found that pre-treatment with the dopamine D2 receptor antagonist haloperidol did not completely reduce the acute psychotic effects of THC (D’Souza et al. 2008; Liem-Molenaar et al. 2010). This implies that the acute behavioural effects of THC may be partially mediated via direct activation of the endocannabinoid system, and thus suggests a principal role for the endocannabinoid system in the association between cannabis use and the increased risk of schizophrenia.

The relatively modest reduction in [11C]raclopride binding after THC administration in the limbic striatum of healthy participants is consistent with findings of PET studies that examined striatal dopamine function in the context of cannabis abuse. Contrary to other substance abusers (e.g. cocaine, methamphetamine, alcohol; see Volkow et al. 2004 for review), no significant differences in dopamine D2/D3 receptor availability nor striatal dopamine release have been demonstrated between chronic cannabis users and controls (Sevy et al. 2008; Stokes et al. 2012; Urban et al. 2012; Volkow et al. 2014). The only study that investigated presynaptic dopamine function found reduced dopamine synthesis capacity in cannabis users, which was not associated with psychotic-like experiences (Bloomfield et al., 2014).

This study has several limitations. First, the two data sets were obtained after THC administration with different delivery methods. Whereas Bossong et al. (2009) used pulmonary THC administration with a Volcano vaporizer, Stokes and colleagues administered THC orally. Generally, oral consumption leads to slower absorption and lower bioavailability of THC, and a delay in the onset of acute behavioural effects compared to inhalation (Agurell et al. 1986). It is unlikely, however, that this has affected our [11C]raclopride PET results, as the THC plasma concentration during the PET scan was significantly correlated with the percentage change in overall striatal [11C]raclopride binding (Figure 1C). Second, as in the study of Bossong et al. (2009) the PET scan was performed 45-85 min after inhalation of THC, it could be argued that most of the effect of THC on dopamine release had dissipated at the time of the scan. However, this is highly unlikely, as application of advanced pharmacokinetic/pharmacodynamic (PK/PD) models to these data showed that 84.5-95.9% of the maximum CNS effects were still present during acquisition of the PET scan (Strougo et al. 2008). Moreover, it has been shown that drug-induced effects on striatal dopamine release can be detected for a long time after administration (Breier et al. 1997; Cardenas et al. 2004; Laruelle et al. 1997). Third, although the correlation between THC plasma concentration during the PET scan and the percentage change in overall striatal [11C]raclopride binding is presented as a linear relationship, there is a possibility that in fact THC produces a biphasic dopaminergic response, with lower levels of THC concentrations associated with increased striatal [11C]raclopride binding (Figure 1C). Indeed, biphasic responses have been demonstrated in behavioural animal studies with acute cannabinoid administration (Sulcova et al. 1998). Fourth, information about the participants’ history of recreational drug use is not presented in this paper as this data is lacking for the study of Bossong and colleagues. Although a within-subject design was used in this study, this could be important in the interpretation of our results as long-term changes in the dopamine system can be observed following prolonged abstinence from drug use (Nader et al. 2006). Finally, effects of THC on striatal dopamine release could not be related to acute behavioural effects as these were assessed differently in the studies of Bossong et al. (2009) and Stokes et al. (2009), and, unfortunately, could thus not be pooled.

Conclusion

The present analysis provides further human evidence for a comparatively modest increase in striatal dopamine transmission after administration of THC. This finding suggests limited involvement of the endocannabinoid system in regulating striatal dopamine release, and thereby challenges the hypothesis that an increase in striatal dopamine levels after cannabis use is the primary biological mechanism underlying the associated higher risk of schizophrenia.

Supplementary Material

supplementary data

Acknowledgements

Dr Matthijs Bossong was supported by a Rubicon grant from the Netherlands Organisation for Scientific Research. We would like to thank Dr Ronald Boellaard and Dr Lineke Zuurman for their help with data acquisition and analysis.

Abbreviations

BPND

non-displaceable binding potential

DVR

distribution volume ratio

PET

positron emission tomography

ROI

region of interest

SPECT

single photon emission computed tomography

THC

Δ9-tetrahydrocannabinol

Footnotes

Statement of interest

The authors declare no financial conflict of interest. The authors have full control of all primary data, and they agree to allow the journal to review their data if requested.

References

  1. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, Hollister L. Pharmacokinetics and metabolism of delta1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38:21–43. [PubMed] [Google Scholar]
  2. Arseneault L, Cannon M, Witton J, Murray RM. Causal association between cannabis and psychosis: examination of the evidence. Br J Psychiatry. 2004;184:110–117. doi: 10.1192/bjp.184.2.110. [DOI] [PubMed] [Google Scholar]
  3. Barkus E, Morrison PD, Vuletic D, Dickson J, Ell PJ, Pilowsky LS, Brenneisen R, Holt DW, Powell J, Kapur S, Murray RM. Does intravenous delta9-tetrahydrocannabinol increase dopamine release? A SPET study. J Psychopharmacol. 2011;25:1462–1468. doi: 10.1177/0269881110382465. [DOI] [PubMed] [Google Scholar]
  4. Bloomfield MA, Morgan CJ, Egerton A, Kapur S, Curran HV, Howes OD. Dopaminergic function in cannabis users and its relationship to cannabis-induced psychotic symptoms. Biol Psychiatry. 2014;75:470–478. doi: 10.1016/j.biopsych.2013.05.027. [DOI] [PubMed] [Google Scholar]
  5. Boileau I, Assaad JM, Pihl RO, Benkelfat C, Leyton M, Diksic M, Tremblay RE, Dagher A. Alcohol promotes dopamine release in the human nucleus accumbens. Synapse. 2003;49:226–231. doi: 10.1002/syn.10226. [DOI] [PubMed] [Google Scholar]
  6. Bossong MG, van Berckel BN, Boellaard R, Zuurman L, Schuit RC, Windhorst AD, van Gerven JMA, Ramsey NF, Lammertsma AA, Kahn RS. Delta 9-tetrahydrocannabinol induces dopamine release in the human striatum. Neuropsychopharmacology. 2009;34:759–766. doi: 10.1038/npp.2008.138. [DOI] [PubMed] [Google Scholar]
  7. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, De Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A. 1997;94:2569–2574. doi: 10.1073/pnas.94.6.2569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Brody AL, Mandelkern MA, Olmstead RE, Allen-Martinez Z, Scheibal D, Abrams AL, Costello MR, Farahi J, Saxena S, Monterosso J, London ED. Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette. Neuropsychopharmacology. 2009;34:282–289. doi: 10.1038/npp.2008.87. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cardenas L, Houle S, Kapur S, Busto UE. Oral D-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET. Synapse. 2004;51:27–31. doi: 10.1002/syn.10282. [DOI] [PubMed] [Google Scholar]
  10. Carson RE, Breier A, de Bartolomeis A, Saunders RC, Su TP, Schmall B, Der MG, Pickar D, Eckelman WC. Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion. J Cereb Blood Flow Metab. 1997;17:437–447. doi: 10.1097/00004647-199704000-00009. [DOI] [PubMed] [Google Scholar]
  11. Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL. Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology (Berl) 1990;102:156–162. doi: 10.1007/BF02245916. [DOI] [PubMed] [Google Scholar]
  12. D'Souza DC, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B, Ranganathan M, Bhakta S, Zimolo Z, Cooper T, Perry E. Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Delta-9-tetrahydrocannabinol in humans. Psychopharmacology (Berl) 2008;198:587–603. doi: 10.1007/s00213-007-1042-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. El Khoury MA, Gorgievski V, Moutsimilli L, Giros B, Tzavara ET. Interactions between the cannabinoid and dopaminergic systems: evidence from animal studies. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:36–50. doi: 10.1016/j.pnpbp.2011.12.005. [DOI] [PubMed] [Google Scholar]
  14. Fadda P, Scherma M, Spano MS, Salis P, Melis V, Fattore L, Fratta W. Cannabinoid self-administration increases dopamine release in the nucleus accumbens. Neuroreport. 2006;17:1629–1632. doi: 10.1097/01.wnr.0000236853.40221.8e. [DOI] [PubMed] [Google Scholar]
  15. French ED. Delta9-tetrahydrocannabinol excites rat VTA dopamine neurons through activation of cannabinoid CB1 but not opioid receptors. Neurosci Lett. 1997;226:159–162. doi: 10.1016/s0304-3940(97)00278-4. [DOI] [PubMed] [Google Scholar]
  16. French ED, Dillon K, Wu X. Cannabinoids excite dopamine neurons in the ventral tegmentum and substantia nigra. Neuroreport. 1997;8:649–652. doi: 10.1097/00001756-199702100-00014. [DOI] [PubMed] [Google Scholar]
  17. Gardner EL. Endocannabinoid signaling system and brain reward: emphasis on dopamine. Pharmacol Biochem Behav. 2005;81:263–284. doi: 10.1016/j.pbb.2005.01.032. [DOI] [PubMed] [Google Scholar]
  18. Gessa GL, Melis M, Muntoni AL, Diana M. Cannabinoids activate mesolimbic dopamine neurons by an action on cannabinoid CB1 receptors. Eur J Pharmacol. 1998;341:39–44. doi: 10.1016/s0014-2999(97)01442-8. [DOI] [PubMed] [Google Scholar]
  19. Howes OD, Kapur S. A neurobiological hypothesis for the classification of schizophrenia: type A (hyperdopaminergic) and type B (normodopaminergic) Br J Psychiatry. 2014;205:1–3. doi: 10.1192/bjp.bp.113.138578. [DOI] [PubMed] [Google Scholar]
  20. Innis RB, Cunningham VJ, Delforge J, Fujita M, Gjedde A, Gunn RN, Holden J, Houle S, Huang SC, Ichise M, Iida H, Ito H, Kimura Y, Koeppe RA, Knudsen GM, Knuuti J, Lammertsma AA, Laruelle M, Logan J, Maguire RP, Mintun MA, Morris ED, Parsey R, Price JC, Slifstein M, Sossi V, Suhara T, Votaw JR, Wong DF, Carson RE. Consensus nomenclature for in vivo imaging of reversibly binding radioligands. J Cereb Blood Flow Metab. 2007;27:1533–1539. doi: 10.1038/sj.jcbfm.9600493. [DOI] [PubMed] [Google Scholar]
  21. Lammertsma AA, Bench CJ, Hume SP, Osman S, Gunn K, Brooks DJ, Frackowiak RS. Comparison of methods for analysis of clinical [11C]raclopride studies. J Cereb Blood Flow Metab. 1996;16:42–52. doi: 10.1097/00004647-199601000-00005. [DOI] [PubMed] [Google Scholar]
  22. Laruelle M, Iyer RN, Al-Tikriti MS, Zea-Ponce Y, Malison R, Zoghbi SS, Baldwin RM, Kung HF, Charney DS, Hoffer PB, Innis RB, Bradberry CW. Microdialysis and SPECT measurements of amphetamine-induced dopamine release in nonhuman primates. Synapse. 1997;25:1–14. doi: 10.1002/(SICI)1098-2396(199701)25:1<1::AID-SYN1>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  23. Liem-Moolenaar M, te Beek ET, de Kam ML, Franson KL, Kahn RS, Hijman R, Touw D, van Gerven JMA. Central nervous system effects of haloperidol on THC in healthy male volunteers. J Psychopharmacol. 2010;24:1697–1708. doi: 10.1177/0269881109358200. [DOI] [PubMed] [Google Scholar]
  24. Malone DT, Taylor DA. Modulation by fluoxetine of striatal dopamine release following Delta9-tetrahydrocannabinol: a microdialysis study in conscious rats. Br J Pharmacol. 1999;128:21–26. doi: 10.1038/sj.bjp.0702753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Martinez D, Slifstein M, Broft A, Mawlawi O, Hwang DR, Huang Y, Cooper T, Kegeles L, Zarahn E, Abi-Dargham A, Haber SN, Laruelle M. Imaging human mesolimbic dopamine transmission with positron emission tomography. Part II: amphetamine-induced dopamine release in the functional subdivisions of the striatum. J Cereb Blood Flow Metab. 2003;23:285–300. doi: 10.1097/01.WCB.0000048520.34839.1A. [DOI] [PubMed] [Google Scholar]
  26. Martinez D, Narendran R, Foltin RW, Slifstein M, Hwang DR, Broft A, Huang Y, Cooper TB, Fischman MW, Kleber HD, Laruelle M. Amphetamine-induced dopamine release: markedly blunted in cocaine dependence and predictive of the choice to self-administer cocaine. Am J Psychiatry. 2007;164:622–629. doi: 10.1176/ajp.2007.164.4.622. [DOI] [PubMed] [Google Scholar]
  27. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, Lewis G. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370:319–328. doi: 10.1016/S0140-6736(07)61162-3. [DOI] [PubMed] [Google Scholar]
  28. Nader MA, Morgan D, Gage HD, Nader SH, Calhoun TL, Buchheimer N, Ehrenkaufer R, Mach RH. PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nat Neuroscience. 2006;9:1050–1056. doi: 10.1038/nn1737. [DOI] [PubMed] [Google Scholar]
  29. Ng Cheong Ton JM, Gerhardt GA, Friedemann M, Etgen AM, Rose GM, Sharpless NS, Gardner EL. The effects of delta 9-tetrahydrocannabinol on potassium-evoked release of dopamine in the rat caudate nucleus: an in vivo electrochemical and in vivo microdialysis study. Brain Res. 1988;451:59–68. doi: 10.1016/0006-8993(88)90749-4. [DOI] [PubMed] [Google Scholar]
  30. Oswald LM, Wong DF, McCaul M, Zhou Y, Kuwabara H, Choi L, Brasic J, Wand GS. Relationships among ventral striatal dopamine release, cortisol secretion, and subjective responses to amphetamine. Neuropsychopharmacology. 2005;30:821–832. doi: 10.1038/sj.npp.1300667. [DOI] [PubMed] [Google Scholar]
  31. Sevy S, Smith GS, Ma Y, Dhawan V, Chaly T, Kingsley PB, Kumra S, Abdelmessih S, Eidelberg D. Cerebral glucose metabolism and D2/D3 receptor availability in young adults with cannabis dependence measured with positron emission tomography. Psychopharmacology (Berl) 2008;197:549–56. doi: 10.1007/s00213-008-1075-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Stokes PR, Mehta MA, Curran HV, Breen G, Grasby PM. Can recreational doses of THC produce significant dopamine release in the human striatum? Neuroimage. 2009;48:186–190. doi: 10.1016/j.neuroimage.2009.06.029. [DOI] [PubMed] [Google Scholar]
  33. Stokes PR, Egerton A, Watson B, Reid A, Lappin J, Howes OD, Nutt DJ, Lingford-Hughes AR. History of cannabis use is not associated with alterations in striatal dopamine D2/D3 receptor availability. J Psychopharmacol. 2012;26:144–149. doi: 10.1177/0269881111414090. [DOI] [PubMed] [Google Scholar]
  34. Strougo A, Zuurman L, Roy C, Pinquier JL, van Gerven JM, Cohen AF, Schoemaker RC. Modelling of the concentration-effect relationship of THC on central nervous system parameters and heart rate - insight into its mechanisms of action and a tool for clinical research and development of cannabinoids. J Psychopharmacol. 2008;22:717–726. doi: 10.1177/0269881108089870. [DOI] [PubMed] [Google Scholar]
  35. Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav. 1998;59:347–352. doi: 10.1016/s0091-3057(97)00422-x. [DOI] [PubMed] [Google Scholar]
  36. Takahashi H, Fujimura Y, Hayashi M, Takano H, Kato M, Okubo Y, Kanno I, Ito H, Suhara T. Enhanced dopamine release by nicotine in cigarette smokers: a double-blind, randomized, placebo-controlled pilot study. Int J Neuropsychopharmacol. 2008;11:413–417. doi: 10.1017/S1461145707008103. [DOI] [PubMed] [Google Scholar]
  37. Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997;276:2048–2050. doi: 10.1126/science.276.5321.2048. [DOI] [PubMed] [Google Scholar]
  38. Taylor JR. An Introduction to error analysis. University Science Books; Sausalito, California: 1997. pp. 166–168. second edition. [Google Scholar]
  39. Urban NB, Kegeles LS, Slifstein M, Xu X, Martinez D, Sakr E, Castillo F, Moadel T, O'Malley SS, Krystal JH, Abi-Dargham A. Sex differences in striatal dopamine release in young adults after oral alcohol challenge: apositron emission tomography imaging study with [11C]raclopride. Biol Psychiatry. 2010;68:689–696. doi: 10.1016/j.biopsych.2010.06.005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Urban NB, Slifstein M, Thompson JL, Xu X, Girgis RR, Raheja S, Haney M, Abi-Dargham A. Dopamine release in chronic cannabis users: a [11C]raclopride positron emission tomography study. Biol Psychiatry. 2012;71:677–683. doi: 10.1016/j.biopsych.2011.12.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Volkow ND, Fowler JS, Wang GJ, Swanson JM. Dopamine in drug abuse and addiction: results from imaging studies and treatment implications. Mol Psychiatry. 2004;9:557–569. doi: 10.1038/sj.mp.4001507. [DOI] [PubMed] [Google Scholar]
  42. Volkow ND, Wang GJ, Fowler JS, Tomasi D, Telang F. Addiction: beyond dopamine reward circuitry. Proc Natl Acad Sci U S A. 2011;108:15037–15042. doi: 10.1073/pnas.1010654108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Volkow ND, Wang GJ, Telang F, Fowler JS, Alexoff D, Logan J, Jayne M, Wong C, Tomasi D. Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity. Proc Natl Acad Sci U S A. 2014;111:E3149–E3156. doi: 10.1073/pnas.1411228111. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Wand GS, Oswald LM, McCaul ME, Wong DF, Johnson E, Zhou Y, Kuwabara H, Kumar A. Association of amphetamine-induced striatal dopamine release and cortisol responses to psychological stress. Neuropsychopharmacology. 2005;32:2310–2320. doi: 10.1038/sj.npp.1301373. [DOI] [PubMed] [Google Scholar]
  45. Wise RA. Roles for nigrostriatal - not just mesocorticolimbic - dopamine in reward and addiction. Trends Neurosci. 2009;32:517–524. doi: 10.1016/j.tins.2009.06.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplementary data
NIHMS66024-supplement-supplementary_data.docx (114.3KB, docx)

RESOURCES