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Brief Summary

According to the NIAAA, Alcohol Use Disorder (AUD) is a “chronic, relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse social, occupational or health consequences.” As of 2015, AUD affected 15.1 million adults and 623,000 adolescents in the US, and data from 2010 estimate an economic burden of $249 billion in the US. Globally, alcohol misuse was the fifth leading risk factor for premature death and disability in 2010.

Neurobiological theories of AUD/alcohol addiction postulate that neuroadaptations occur in brain neurotransmitter systems that contribute to “craving” for alcohol, and relapse to drinking by dependent individuals who have stopped or reduced drinking for a period of time. Lohocla designed Nezavist to target these neuroadaptive changes and reduce relapse drinking. Lohocla is performing pre-clinical studies of Nezavist with the goal of obtaining an Investigational New Drug (IND) approval from the FDA to test Nezavist in humans.

Nezavist in “alternate” binding pocket.
Nezavist in “alternate” binding pocket (Fig. 1).

The research laboratories of the Lohocla leadership have contributed critical information to the understanding of the mechanisms by which alcohol affects behavior and the changes caused in brain by chronic alcohol ingestion that results in alcohol addiction. A discussion of this work can be found in a publication by Tabakoff and Hoffman in the journal Pharmacology, Biochemistry and Behavior, volume 113, pages 20-37, 2013. A succinct summary of the work of Tabakoff and Hoffman and may other researchers would clearly indicate that the actions of alcohol at the biological level are mediated by its actions on the major inhibitory systems of brain, referred to as the GABA transmitter system and the major excitatory system of brain, referred to as the glutamate (NMDA) transmitter system.

Dopaminergic Neurons as Signalers of Reward
Dopaminergic Neurons as Signalers of Reward.
Ethanol increases the release of hypothalamic opiate peptides, further inhibiting the GABAergic interneurons, and leading to enhanced dopamine release through this disinhibition mechanism. At the same time, ethanol can inhibit NMDA receptor function, decreasing excitatory input to the VTA GABAergic interneurons, which further disinhibits VTA dopamine neuron activity.

When you consume alcohol, it acts in the brain to potentiate the actions of the GABA system and inhibit the actions of the glutamate (NMDA) system (Figure 1). The brain is, however, a malleable organ that acts to adapt to the chronic presence of alcohol and, under such conditions, decreases the function of the GABA system and increases the function of the glutamate (NMDA) system to counter the action of ethanol. Such changes may help the individual function while drinking but, when the individual tries to stay sober, the altered brain function produces hyperexcitability, anxiety, depression, and craving to return to drinking.

Lohocla realized that an optimal therapy to help the alcohol dependent individual to maintain sobriety is to create a medication that would promote the normal function of the GABA and glutamate (NMDA) systems of the addicted brains.

Nezavist is such a preparation. We designed Nezavist to potentiate the effects of GABA (the natural neurotransmitter) at the GABA receptor and to simultaneously inhibit the overactivity of glutamate and the NMDA receptor. These actions are accomplished by Nezavist acting directly at the GABA receptor and then being metabolized to the molecule that inhibits the NMDA receptor.

Fig. 1, Human NMDA receptor binding sites
Human GABA receptor with binding sites.