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Stimulant addiction treatment should target dopaminergic pathways

Results from a meta-analysis indicated decreases in both presynaptic and postsynaptic measures of the dopamine system in the striatum among stimulant users, suggesting their utility as a target for addiction treatment.

“Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) enable us to measure dopaminergic function in vivo in humans,” Abhishekh H. Ashok, MBBS, of Medical Research Council London Institute of Medical Sciences Centre, and colleagues wrote. “Using these imaging tools, human studies have found that stimulant drugs increase synaptic dopamine levels in the whole striatum (including ventral striatum, which encompasses the nucleus accumbens) and that increases are associated with the subjective perception of drug reward in controls who are not abusing drugs.”

To review in vivo imaging evidence for dopaminergic alterations in stimulant abuse or dependence, researchers conducted a systematic review and meta-analysis of case-control studies that used PET or SPECT imaging to compare dopaminergic measures between stimulant users and healthy controls. Analysis included 31 studies among 519 stimulant users and 512 healthy controls. Abstinence duration ranged from 5 days to 3 weeks.

Striatal dopamine release significantly decreased among stimulant users for stimulants combined (effect size = –0.84; 95% CI, –1.08 to –0.6) and cocaine only (effect size = –0.87; 95% CI, –1.15 to –0.6), compared with healthy controls.

Dopamine transporter availability also significantly decreased, with effect sizes of –0.91 (95% CI, – 1.5 to –0.32) for stimulants combined and –1.47 (95% CI, –1.83 to –1.1) for amphetamine and methamphetamine.

D2/D3 receptor availability significantly decreased among stimulant users, for stimulants combined (effect size = 0.76; 95% CI, 0.92 to 0.6), for cocaine (effect size = 0.73; 95% CI, 0.94 to 0.53), and for amphetamine and methamphetamine (effect size = 0.81; 95% CI, 1.12 to 0.49), compared with healthy controls.

Researchers did not find consistent changes in vesicular monoamine transporter, dopamine synthesis or D1 receptor studies.

“Our data identify several clear targets for treatment interventions. Given our finding of a large effect size reduction, D2/D3 receptors stand out. That they stand out as a target for treatment intervention is further supported by studies in cocaine users and methamphetamine users...Our data support the development of drugs that target the presynaptic dopaminergic system to restore tonic striatal dopamine release, which is necessary for the function of the striatocortical indirect pathway, a key system disrupted in addiction,” the researchers wrote. “Our findings may also explain why strategies to block dopamine neurotransmission (eg, using dopamine receptor antagonists) have largely been disappointing to date, because dopamine receptor levels are already low, and the results suggest that methods to increase dopamine receptor levels or sensitivity could have potential.” – by Amanda Oldt

Disclosure: Ashok reports conducting research funded by the Medical Research Council and King’s College London. Please see the study for a full list of relevant financial disclosures.