- Investigators have shown that 2-AG, an endocannabinoid (i.e., a cannabinoid manufactured within the body, as opposed to plant-derived), augments the cocaine-induced dopamine surge in the brain’s reward system.
- The discovery adds to evidence that inhibiting activity in the endocannabinoid system might reduce cocaine’s rewarding and addictive effects.
Cocaine, like most drugs that produce rewarding and addictive effects, does so by abruptly and massively increasing levels of the neurotransmitter dopamine in the brain’s nucleus accumbens (NAc). Cocaine makes dopamine surge in the NAc primarily by blocking the dopamine transporter, a molecule that removes excess dopamine from circulation. However, recent NIDA research reveals that a second mechanism accounts for a significant portion of cocaine-induced dopamine surfeit in the NAc.
The principal player in the newly discovered mechanism is the endocannabinoid molecule 2-arachidonoylglycerol (2-AG). In the new research, Drs. Huikun Wang and Carl Lupica of NIDA’s Intramural Research Program, with colleagues from NIDA and the University of Maryland, found that:
- Cocaine induced dopaminergic (dopamine-releasing) neurons to step up production of 2-AG.
- Treating rats with a compound (rimonabant) that inhibits 2-AG activity before injecting the animals with cocaine cut cocaine-induced increases in NAc dopamine concentrations by approximately 50 percent.
Dopaminergic neurons release dopamine from axon terminals located in the NAc. How much dopamine they release depends on their firing intensity, which in turn depends on:
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- How much stimulatory input they receive from glutamatergic neurons in another brain region, the ventral tegmental area (VTA) (see Figure 1).
- How much inhibitory input they receive from gamma-aminobutyric (GABA) neurons in the VTA.
Drs. Wang and Lupica demonstrated that cocaine mobilizes the endocannabinoid system to reduce GABA inputs to dopaminergic neurons. In experiments with rats, they showed that cocaine precipitates the release of 2-AG into the VTA synapses between GABAergic neurons and dopaminergic neurons. The 2-AG interacts with cannabinoid receptors on the GABAergic neurons, slowing the neurons' firing and reducing their release of the neurotransmitter.
The researchers elucidated the complete molecular pathway whereby cocaine reduces GABA release in the VTA and increases dopamine release in the NAc (Figure 2):
- Cocaine blocks noradrenergic neurons from clearing the neurotransmitter norepinephrine from circulation in the VTA.
- Norepinephrine levels consequently rise, stimulating α1 receptors on VTA dopaminergic neurons.
- Activation of the α1 receptors triggers reactions within the dopaminergic neurons that culminate in the release of 2-AG.
- 2-AG binds to cannabinoid (CB1) receptors on GABAergic neurons.
- 2-AG’s interaction with the CB1 receptor reduces GABAergic neurons’ release of GABA.
- Less exposure to GABA, an inhibitory neurotransmitter, frees the dopaminergic neurons to fire more intensely and release more dopamine into the NAc.
Figure 2. The Role of 2-AG in Enhancing Cocaine Reward
A. The firing of dopaminergic neurons that are situated in the ventral tegmental area underlies feelings of reward. Dopaminergic-neuron firing is promoted by synaptic glutamate activating glutamate receptors, and inhibited by synaptic gamma-aminobutyric acid (GABA) activating GABAB receptors. A third neurotransmitter, norepinephrine, which can indirectly promote dopaminergic firing by activating α1 receptors, generally is inactive because it is taken back up into its releasing cell via the norepinephrine transporter.
B. Cocaine blocks the norepinephrine transporter from drawing the neurotransmitter back into its releasing cell. Consequently, norepinephrine builds up in the synapse. Higher concentrations of synaptic norepinephrine stimulate G-protein–coupled α1 receptors to:
- increase biochemical processes that release 2-AG, and
- increase dopamine neuron activity, further increasing 2- AG, which;
- enhances activation of cannabinoid-1 (CB1) receptors on GABA neurons, which;
- lowers GABA neurons’ release of GABA into the synapse, which;
- tilts the balance of glutamate stimulation and GABA inhibition of dopaminergic neuron firing in favor of stimulation, which;
- increases the neurons’ release of dopamine into the nucleus accumbens, which;
- enhances feelings of reward.
A Treatment Approach?
2-AG is one of several neurotransmitters in the endocannabinoid system, which serves a wide variety of regulatory functions in the brain and body. The system has previously been implicated in drugs’ rewarding effects: for example, the marijuana ingredient tetrahydrocannabinol (THC) produces its “high” by infiltrating and activating the endocannabinoid system. Some studies with animals have tried using medications that block cannabinoid receptors to alleviate drug-seeking behaviors, with encouraging results.
Drs. Wang and Lupica’s findings further advance this body of research, and provide a more detailed picture of the role of endocannabinoids in cocaine use. The researchers note, however, that the 2-AG pathway does not fully account for cocaine-induced increases in dopaminergic firing intensity: The neurotransmitter serotonin also contributes. When the researchers administered cocaine together with compounds that increase serotonin levels in the VTA, they observed an inhibitory effect on GABA neurons similar to that produced by 2-AG. Moreover, blocking cannabinoid activity did not completely abolish cocaine’s effect on GABA unless serotonin activity was also blocked (see Figure 3).
In summary, Dr. Lupica says, “It appears that the endocannabinoids mediate some of cocaine’s effects within the brain’s reward circuitry. If the rewarding and addictive properties of cocaine require intact endocannabinoid function, then disrupting this function with anti-cannabinoid drugs may help to reduce these properties of cocaine. Through these types of studies, we may be able to develop a useful tool to combat cocaine addiction.”
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This study was supported by NIH grants DA022340 and DA033926, and by the NIH/NIDA Intramural Research Program.
Wang, H.; Treadway, T.; Covey, D.P.; Cheer, J.F.; Lupica, C.R. Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area. Cell Reports 12(12):1997-2008, 2015. Full article
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NIDA (). Endocannabinoid Regulates Cocaine Reward. Retrieved , from https://www.drugabuse.gov/news-events/nida-notes/2017/03/endocannabinoid-regulates-cocaine-reward