Addictive and non‐addictive drugs induce distinct and specific patterns of ERK activation in mouse brain

TLDR

Research on addiction seeks to uncover the molecular mechanisms underlying long‑lasting behavioral changes caused by drugs of abuse. The study aims to determine whether striatal ERK activation is specific to cocaine and THC or also occurs with other psychoactive substances. The authors examined phospho‑ERK activation in CD‑1 mouse brains after acute administration of abused drugs (cocaine, morphine, nicotine, THC) and other psychoactive compounds (caffeine, scopolamine, antidepressants, antipsychotics). All abused drugs produced a distinct, dopamine D1‑dependent pattern of ERK activation in nucleus accumbens, bed nucleus of the stria terminalis, amygdala, and prefrontal cortex, whereas non‑addictive drugs induced only modest activation in a few regions, suggesting specific sites where ERK mediates long‑term drug effects.

Abstract

Abstract A major goal of research on addiction is to identify the molecular mechanisms of long‐lasting behavioural alterations induced by drugs of abuse. Cocaine and delta‐9‐tetrahydrocannabinol (THC) activate extracellular signal‐regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho‐ERK immunoreactive neurons in CD−1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor‐dependent mechanism. Although some non‐addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long‐term effects of drugs of abuse, and suggest mapping ERK activation in brain as a way to identify potential sites of action of psychoactive drugs.