DREADD to the Core. Commentary on Purohit et al. (2018): Pharmacogenetic Manipulation of the Nucleus Accumbens Alters Binge‐Like Alcohol Drinking in Mice

Abstract

A LCOHOL USE DISORDERS (AUDs) are a devastating class of addictive disorders that incur a tremendous societal and economic burden. AUDs cost an estimated annual $235 billion in the United States (Rehm et al., 2009) and are very common with a 12-month prevalence of 13.9% and lifetime prevalence of 29.1% (Grant et al., 2015). Current treatment options are limited to psychosocial intervention, 3 FDA-approved medications (disulfiram, acamprosate, and naltrexone), and a handful of other drugs approved for other indications, all with relatively small effect sizes. In addition, most of the knowledge we have on the neurobiology of alcohol drinking in animals comes from male subjects. There is a clear need for a deeper understanding of the neurobiological mechanisms underlying AUDs.The nucleus accumbens (NAc) is a key component of brain reward circuitry important for motivated behaviors related to AUDs and other addictive disorders. The NAc drives motivation with dopamine supplied by the ventral tegmental area and medium spiny neuron (MSN) populations expressing dopamine D1 (G s -coupled) or D2 (G i/o -coupled) receptors, among other neurological markers (e.g., dynorphin, enkephalin, substance P). Extensive work shows that these populations exert opposing actions, such that D1 MSNs drive while D2 MSNs suppress motivated behavior (Bock et al., 2013). Dopamine modulates physiologic responses of MSNs to glutamate released from many cortical and limbic regions. Thus, dopamine likely exerts its drive over motivation through enhancing D1 MSN responses to glutamate while dampening these responses in D2 MSNs (Surmeier et al., 2007). In line with a role in addiction, alcohol self-administration increases extracellular dopamine in the NAc (Weiss et al., 1993) and the reinforcing effects of alcohol are blocked by dopamine antagonists when delivered into the NAc, for example, Rassnick and colleagues (1992). Moreover, alterations in NAc circuit function are thought to underlie certain features of AUDs. Physiologic data demonstrate that alcohol exposure leads to a potentiation of excitatory transmission in D1 MSNs and weakened or unchanged excitatory transmission in D2 MSNs (Beckley et al., 2016;Ji et al., 2017;Renteria et al., 2017Renteria et al., , 2018. These data support a role for D1 MSNs in driving and D2 MSNs in inhibiting motivated behavior and suggest that synaptic modifications within NAc subcircuits might underlie escalated drinking behavior after alcohol exposure. Thus, the NAc plays an essential role in AUDs and may serve as a candidate brain region for therapeutic intervention.A recent study reported reduced binge drinking following inhibition of NAc neurons with genetic tools (Designer Receptors Exclusively Activated by Designer Drugs [DREADDs]) in male mice (Cassataro et al., 2014). These data are consistent with the physiologic results described above, which were collected from male NAc brain slices. Thus, DREADD inhibition of the male NAc most likely reduced alcohol consumption by attenuating enhanced D1 MSN drive ove...

Morphopathological approaches in alcoholism

“…Since the neurons specific to this formation are specialized in formulating reward behavioral responses, it seems that stopping their stimulation may become essential in treating EtOH addiction. This inhibition of the motivation to seek the fulfillment of the pleasure created by the addiction is achieved by the opposite action of the dopaminergic population like medium spiny neurons (MSN) through D2 receptors, as opposed to D1 [10].…”