PET imaging of the mGluR5 receptor in addiction: its role in deficient corticostriatal control and glutamatergic modulation of dopaminergic neurotransmission

Addiction is a complex brain disorder, leading  to a compulsive obsession to use a substance  despite serious detrimental consequences. Apart from a dysfunctional reward system, reduced inhibitory corticostriatal control in drug-seeking and drug-taking1 and vulnerability to addiction2 has been emphasized. Genetic, developmental, and environmental factors are major contributors to addiction risk, but the neurobiological processes that underlie vulnerability, craving and relapse are still poorly understood.

Aside from the central role of dopamine in reward (intensively studied through availability of suitable PET radioligands3), pharmacological and animal data indicate that glutamate (GLU) plays a pivotal role in drug addiction4. A central role is proposed for metabotropic glutamate receptors (mGluR), especially mGluR55. Downregulation of mGluR5 is thought to be critical in the transition to dependence and in regulation of reward and drug seeking in the mesocorticolimbic motivational circuitry, where it plays a key role in mediating synaptic plasticity pertinent to addiction and interacts with glutamate and dopamine transmission.

Specific radioligands have been recently developed for in vivo brain imaging of mGluR5, including 18F-FPEB6, that shows best characteristics regarding signal-to-noise and selectivity. To date, only one human study using mGluR5 PET in addiction (nicotine abuse) has been published, showing a global marked decrease in mGluR5 binding in smokers and to a lesser extend in ex-smokers7. These results support the central role of mGluR5 in addiction and encourage future studies to look at similarities with other types of drug abuse, to assess its potential predictive value for relapse and to explore the interaction with DA and glutamate transmissions.

Combined with glutamate magnetic resonance spectroscopy (MRS), dopamine release PET imaging, genetics, temperament and neuropsychological profiling, this project provides a unique window to investigate the determinants of mGluR5 and its modulation of glutamate and dopamine neurotransmission. Apart from pathophysiogical insight into addiction, including craving and relapse, this research may lead to an objective biomarker and tool for proof-of-principle pharmacological treatment.

Research hypotheses

Our central hypothesis is that in addiction, PET mGluR5 availability is decreased and MRS glutamate levels are regionally increased in the reward circuit (prefrontal cortex, striatum) and that this is common to major forms of substance addiction (alcohol, nicotine and cocaine).

Then, we will

- test if regional mGluR5 binding is predictive for addiction development and relapse, in detoxified addicts,

- investigate the direct interaction of glutamatergic and dopaminergic function by relating mGluR5 availability and GLU levels to DA release capacity in the striatum and frontal cortex by acute administration of drugs of abuse, in low-intensity users,

- evaluate if genetics and functional determinants (e.g. executive function and personality traits (especially impulsivity and compulsivity)) are related to these quantitative molecular markers.