Six Decades of Dopamine Hypothesis: Is Aryl Hydrocarbon Receptor the New D2?

Abstract

In 1957, Arvid Carlsson discovered that dopamine, at the time believed to be nothing more than a norepinephrine precursor, was a brain neurotransmitter in and of itself. By 1963, postsynaptic dopamine blockade had become the cornerstone of psychiatric treatment as it appeared to have deciphered the “chlorpromazine enigma”, a 1950s term, denoting the action mechanism of antipsychotic drugs. The same year, Carlsson and Lindqvist launched the dopamine hypothesis of schizophrenia, ushering in the era of psychopharmacology. At present, six decades later, although watered down by three consecutive revisions, the dopamine model remains in vogue. The latest emendation of this paradigm proposes that “environmental and genetic factors” converge on the dopaminergic pathways, upregulating postsynaptic transmission. Aryl hydrocarbon receptors, expressed by the gut and blood–brain barrier, respond to a variety of endogenous and exogenous ligands, including dopamine, probably participating in interoceptive awareness, a feed-back loop, conveying intestinal barrier status to the insular cortex. The conceptualization of aryl hydrocarbon receptor as a bridge, connecting vagal terminals with the microbiome, may elucidate the aspects of schizophrenia seemingly incongruous with the dopamine hypothesis, such as increased prevalence in urban areas, distance from the equator, autoantibodies, or comorbidity with inflammatory bowel disease and human immunodeficiency 1 virus. In this review article, after a short discussion of schizophrenia outcome studies and insight, we take a closer look at the action mechanism of antipsychotic drugs, attempting to answer the question: do these agents exert their beneficial effects via both dopaminergic and nondopaminergic mechanisms? Finally, we discuss potential new therapies, including transcutaneous vagal stimulation, aryl hydrocarbon receptor ligands, and restoring the homeostasis of the gut barrier.

The Future of Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

“…In our previous work, we have hypothesized that SCZ and SLDs may be initiated by aberrant AhR hyperactivation by endogenous or exogenous ligands, including intestinal or environmental toxins, such as LPS or plasticizers respectively [215].…”

Novel Insights into Psychosis and Antipsychotic Interventions: From Managing Symptoms to Improving Outcomes

“…IL-22 has been successfully used to restore the integrity of the gut barrier in various conditions, including IBD, HIV, and nonalcoholic fatty liver disease [ 225 , 226 ]. We construe that recombinant IL-22 would be effective for SCZ by limiting the translocation of bacteria and/or their molecules.…”

Receptor-Independent Therapies for Forensic Detainees with Schizophrenia–Dementia Comorbidity

“…Although neuroscience has made significant inroads into the courtroom, due to the complexity of criminal behavior, a crime cannot, without speculation, be directly corelated to a specific central nervous system (CNS) region or pathology [51][52][53][54]. For example, the suicide of the renowned actor Robin Williams cannot be attributed to the Lewy body disease (LBD), with which he had been diagnosed, because most patients with LBD do not take their lives [55]. Another example, Charles Whitman, an individual who committed mass murder in 1966 and had a brain tumor involving his amygdala, this pathology could not be reliably linked to the crime as individuals with similar conditions may not engage in violent acts [56].…”