The Role of Endocannabinoids in Amphetamine-Driven Actions in Dopamine Neurons: Implications for Understanding and Treating Dysfunction in the Mesolimbic Circuit

Introduction

Amphetamine (AMPH) and AMPH-type psychostimulants (e.g., methamphetamine, MDMA) are the second most widely abused illicit drug worldwide. Prescription psychostimulants like d -AMPH (Adderall) and methylphenidate (Ritalin) remain widely prescribed for disorders such as attention-deficit/hyperactivity disorder (ADHD) and narcolepsy. Because an increase in brain dopamine (DA) levels is the primary action mediating AMPH’s psychostimulant and abuse-related properties, the mechanisms by which AMPH alters brain DA neurotransmission have been studied extensively. Nevertheless, there remains no accepted or effective pharmacotherapy for AMPH abuse or addiction. Recent work demonstrating novel mechanisms by which AMPH alters DA neuron function suggests that the endocannabinoid (eCB) system represents an important target for controlling AMPH effects on DA neurons and a potential target for treating AMPH abuse and addiction.

Mesolimbic Dopamine

Addiction—or the state of engaging in compulsive behaviors despite adverse consequences—is believed to occur as a result of long-lasting changes in neural circuitry associated with rewards that influence cognition, motivation, and learning. Colloquially known as the “reward circuit,” the mesolimbic pathway consists of DA neurons projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc). In the addictive state, these DA neurons exhibit increased activity specifically toward drug-related environmental triggers, with drugs of abuse engaging a variety of cellular processes. Numerous projections throughout the forebrain and midbrain nuclei modulate the activity of VTA DA neurons. Among these inputs, cells releasing glutamate (Glu), γ-aminobutyric acid (GABA), acetylcholine (ACh), and noradrenaline bind to DA neurons to modulate activity and subsequent DA release in the NAc.

Glutamatergic afferents from the prefrontal cortex (PFC), hypothalamus (HY), lateral habenula (LHb), and pedunculopontine (PPT), induce excitatory postsynaptic potentials through ionotropic N -methyl- d -aspartate (NMDA)/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Subsequent depolarization opens voltage-gated Ca ²⁺ channels (VGCC), which triggers a conformational change in calmodulin (a calcium-binding secondary messenger that binds to intracellular proteins), thereby increasing cellular activity. Metabotropic group I Glu receptors (mGluR _1/5 ) activate phospholipase C (PLC), an enzyme that catalyzes phospholipids. In this case, phosphatidylinositol 4,5-bisphosphate (PIP ₂ ) is cleaved into the secondary messengers inositol trisphosphate (IP ₃ ) and 1,2 diacyl glycerol (DAG). IP ₃ initiates transport of Ca ²⁺ from internal stores (e.g., endoplasmic reticulum) into the cytosol, wherein DAG is a precursor for 2-arachidonylglycerol (2-AG), the most prevalent eCB in the brain.