Dopamine neurotransmission plays critical roles in regulating complex cognitive and behavioral processes including reward, motivation, reinforcement learning, and movement. Dopamine receptors are classified into five subtypes, widely distributed across the brain, including regions responsible for motor functions and specific areas related to cognitive and emotional functions. Dopamine also acts on astrocytes, which express dopamine receptors as well. The discovery of direct receptor-receptor interactions, leading to the formation of multimeric receptor complexes at the cell membrane and providing the cell decoding apparatus with flexible dynamics in terms of recognition and signal transduction, has expanded the knowledge of the G-protein-coupled receptor-mediated signaling processes. The purpose of this review article is to provide an overview of currently identified receptor complexes containing dopamine receptors and of their modulatory action on dopamine-mediated signaling between neurons and between neurons and astrocytes. Pharmacological possibilities offered by targeting receptor complexes in terms of addressing neuropsychiatric disorders associated with altered dopamine signaling will also be briefly discussed.

Dopamine is known to play a role in the pathogenesis of psychotic symptoms, but the mechanisms driving dopaminergic dysfunction in psychosis remain unclear. Considerable attention has focused on the role of corticostriatothalamic (CST) circuits, given that they regulate and are modulated by the activity of dopaminergic cells in the midbrain. Preclinical studies have proposed multiple models of CST dysfunction in psychosis, each prioritizing different brain regions and pathophysiological mechanisms. A particular challenge is that CST circuits have undergone considerable evolutionary modification across mammals, complicating comparisons across species. Here, we consider preclinical models of CST dysfunction in psychosis and evaluate the degree to which they are supported by evidence from human resting-state functional magnetic resonance imaging studies conducted across the psychosis continuum, ranging from subclinical schizotypy to established schizophrenia. In partial support of some preclinical models, human studies indicate that dorsal CST and hippocampal-striatal functional dysconnectivity are apparent across the psychosis spectrum and may represent a vulnerability marker for psychosis. In contrast, midbrain dysfunction may emerge when symptoms warrant clinical assistance and may thus be a trigger for illness onset. The major difference between clinical and preclinical findings is the strong involvement of the dorsal CST in the former, consistent with an increasing prominence of this circuitry in the primate brain. We close by underscoring the need for high-resolution characterization of phenotypic heterogeneity in psychosis to develop a refined understanding of how the dysfunction of specific circuit elements gives rise to distinct symptom profiles.

Neuropsychiatric disorders, such as schizophrenia, are associated with abnormal brain development. In this review, we discuss how studying dimensional components of these disorders, or endophenotypes, in a wider range of animal models will deepen our understanding of how interactions between biological and environmental factors alter the trajectory of neurodevelopment leading to aberrant behavior. In particular, we discuss some of the advantages of incorporating studies of brain and behavior using a range of teleost fish species into current neuropsychiatric research. From the perspective of comparative neurobiology, teleosts share a fundamental pattern of neurodevelopment and functional brain organization with other vertebrates, including humans. These shared features provide a basis for experimentally probing the mechanisms of disease-associated brain abnormalities. Moreover, incorporating information about how behaviors have been shaped by evolution will allow us to better understand the relevance of behavioral variation to determine their physiological underpinnings. We believe that exploiting the conservation in brain development across vertebrate species, and the rich diversity of fish behavior in lab and natural populations will lead to significant new insights and a holistic understanding of the neurobiological systems implicated in neuropsychiatric disorders.

Prenatal cannabis exposure has been linked to addiction vulnerability, but the neurobiology underlying this risk is unknown.

Striatal dopamine and opioid-related genes were studied in human fetal subjects exposed to cannabis (as well as cigarettes and alcohol). Cannabis-related gene disturbances observed in the human fetus were subsequently characterized with an animal model of prenatal Δ-9-tetrahydrocannabinol (THC) (.15 mg/kg) exposure.

Prenatal cannabis exposure decreased dopamine receptor D2 (DRD2) messenger RNA expression in the human ventral striatum (nucleus accumbens [NAc]), a key brain reward region. No significant alterations were observed for the other genes in cannabis-exposed subjects. Maternal cigarette use was associated with reduced NAc prodynorphin messenger RNA expression, and alcohol exposure induced broad alterations primarily in the dorsal striatum of most genes. To explore the mechanisms underlying the cannabis-associated disturbances, we exposed pregnant rats to THC and examined the epigenetic regulation of the NAc Drd2 gene in their offspring at postnatal day 2, comparable to the human fetal period studied, and in adulthood. Chromatin immunoprecipitation of the adult NAc revealed increased 2meH3K9 repressive mark and decreased 3meH3K4 and RNA polymerase II at the Drd2 gene locus in the THC-exposed offspring. Decreased Drd2 expression was accompanied by reduced dopamine D2 receptor (D(2)R) binding sites and increased sensitivity to opiate reward in adulthood.

These data suggest that maternal cannabis use alters developmental regulation of mesolimbic D(2)R in offspring through epigenetic mechanisms that regulate histone lysine methylation, and the ensuing reduction of D(2)R might contribute to addiction vulnerability later in life.