Deletion of Addiction Gene Keeps Mice off Cocaine

Cocaine can have a devastating effect on people.  It directly stimulates the brain’s reward center, and, more importantly, induces long-term changes to the reward circuitry that are responsible for addictive behaviors.

European researchers have discovered how a gene that has previously been implicated in cancer plays a key role in certain regions of the brain in the control of cocaine addiction in mice. Studies headed by a team at the Université Libre de Bruxelles (ULB) in Belgium showed that animals lacking the melanoma antigen gene (Mage) known as Maged1 were unresponsive to cocaine, and didn’t develop the characteristic behaviors and signs of addiction, such as locomotor sensitization, drug seeking, and drug self-administration, which are evident in control animals after repeated drug administration.

Studies in which the Maged1 gene was deleted in specific regions of the brain indicated that the development of cocaine sensitization required Maged1 expression in the prefrontal cortex (PFC) and amygdala regions of the brain specifically.

“This work identifies Maged1 as a critical molecule in cellular processes and behaviors related to addiction,” write lead scientist Alban de Kerchove d’Exaerde and colleagues in a paper published in EMBO Reports. “Therefore, we hypothesize that the identification of Maged1 molecular partners will shed light on the cellular mechanisms underlying drug addiction.” The ULB researchers and collaborators in Belgium, Italy, France, and Spain describe their findings in a paper titled, “Deletion of Maged1 in mice abolishes locomotor and reinforcing effects of cocaine.”

Exposure to addictive drugs results in increased extracellular dopamine in specific reward-related brain circuits, which can lead to long-lasting circuitry changes, including adaptations in glutamatergic receptors. These changes and adaptations collectively result in an addictive state, the authors explain. Rewarding stimuli that we experience in response to pleasure-giving activities lead to the release of dopamine (DA) from the ventral tegmental area (VTA) of the brain to other connected regions, including the nucleus acccumbens (Nac), which is central to the reward system.

Cocaine directly affects this system by blocking dopamine removal from nerve cell synapses, leading to the extracellular dopamine surge that over-activates the circuitry, and ultimately causes the changes that lead to addiction. “Mechanistically, multiple signaling pathways initiated by the activation of DA and glutamate receptors drive the physiologically changes induced by drugs of abuse,” the authors write.

The Mage family of genes was first identified as tumor suppressors, but some, including Maged1, are active in healthy cells and tissues, including the developing and adult central nervous system. Recent studies have shown that Maged1 is involved in regulating complex behavior functions, including the circadian rhythm, social and sexual behaviors and memory formation, and the gene has also been implicated in depression and eating disorders. Mutations in Maged1 have also been linked with learning problems.

Interestingly, prior studies have suggested that Maged1 may be regulated by cocaine, and these findings prompted the ULB team to investigate whether Maged1 plays a role in cocaine addiction. Their initial studies first confirmed that in control mice, cocaine administration led the animals to exhibit significant increases in locomotor sensitization, cocaine-seeking behaviors – measured through tests including conditioned place preference and self-administration. In contrast, Maged1-deficient mice were completely insensitive to all of the behavioral effects of cocaine, but instead demonstrated reduced motor coordination.

Addictive drugs commonly increase the extracellular concentration of DA in the mesocorticolimbic circuit, such as the NAc, but the Maged1-deficient mice showed what the authors called “a dramatic impairment in cocaine-elicited increase in DA extracellular levels in the NAc ….” The Maged1 mice also demonstrated “severe abnormalities” in glutamate transmission at cortico-accumbal synapses.

The combined results in the Maged1-deficient animals indicated that dysfunction at different levels of the mesocorticolimbic circuit might underlie the animals’ insensitivity to cocaine’s addictive properties. To investigate this further the team carried out a series of electrophysiological tests in brain slices and harnessed gene activation tools to knock out Maged1 in specific populations of neurons in the mesocorticolimbic system.

Their results showed that expression of Maged1 was required in the PFC and amygdala, but not in dopaminergic neurons, nor in striatal or other GABAergic neurons, to mediate cocaine-associated behaviors. Maged1 expression in the PFC was also requisite for cocaine-induced extracellular dopamine release in the NAc.  “…  neither mice with Maged1 deletion in PFC, nor those with deletion in amygdala showed any significant alteration in the ability to self-administer cocaine,” the team writes. Interestingly, a complete lack of Maged1 impaired motor coordination but did not affect motor learning, whereas deletion of Maged1 only in the PFC had no effect on motor coordination, but did result in a severe deficit in motor learning. “ … mice lacking Maged1 in the PFC partially recapitulate the phenotype displayed by mice with constitutive deletion of Maged1, suggesting that expression of Maged1 in PFC is required for motor learning and locomotor sensitization to cocaine, but not for cocaine-induced reward in the CPP paradigm.”

The researchers say their combined results indicate that the function of Maged1 in the mesocorticolimbic circuit most likely results from an interplay between the developmental functions of Maged1, and its combined actions in the various components of the network. The finding of a gene that can be deleted to induce complete lack of addictive responses to cocaine in mice is also “exceptional in the literature” the authors point out. The only other examples that they know of are DAT, which is a direct molecular target of cocaine, and mGluR5, which is a known component of the synapatic transmission machinery.  “Therefore, the phenotypes described in this work identify Maged1 as an essential molecule for behavioral responses to cocaine,” they conclude.