Dopamine supersensitivity occurs in schizophrenia and other psychoses, and after hippocampal lesions, antipsychotics, ethanol, amphetamine, phencyclidine, gene knockouts ofDbh(dopamine β-hydroxylase),Drd4receptors,Gprk6(G protein-coupled receptor kinase 6),Comt(catechol-O-methyltransferase), orTh^-/-,Dbh^Th/+(tyrosine hydroxylase), and in rats born by Cesarean-section. The functional state of D2, or the high-affinity state for dopamine (D2^High), was measured in these supersensitive animal brain striata. Increased levels and higher proportions (40-900%) for D2^Highwere found in all these tissues. If many types of brain impairment cause dopamine behavioral supersensitivity and a common increase in D2^Highstates, it suggests that there are many pathways to psychosis, any one of which can be disrupted.

Although the perturbation of either the dopaminergic system or brain-derived neurotrophic factor (BDNF) levels has been linked to important neurological and neuropsychiatric disorders, there is no known signaling pathway linking these two major players. We found that the exclusive stimulation of the dopamine D1–D2 receptor heteromer, which we identified in striatal neurons and adult rat brain by using confocal FRET, led to the activation of a signaling cascade that links dopamine signaling to BDNF production and neuronal growth through a cascade of four steps: (i) mobilization of intracellular calcium through Gq, phospholipase C, and inositol trisphosphate, (ii) rapid activation of cytosolic and nuclear calcium/calmodulin-dependent kinase IIα, (iii) increased BDNF expression, and (iv) accelerated morphological maturation and differentiation of striatal neurons, marked by increased microtubule-associated protein 2 production. These effects, although robust in striatal neurons from D5^−/−mice, were absent in neurons from D1^−/−mice. We also demonstrated that this signaling cascade was activated in adult rat brain, although with regional specificity, being largely limited to the nucleus accumbens. This dopaminergic pathway regulating neuronal growth and maturation through BDNF may have considerable significance in disorders such as drug addiction, schizophrenia, and depression.

The distribution and function of neurons coexpressing the dopamine D1 and D2 receptors in the basal ganglia and mesolimbic system are unknown. We found a subset of medium spiny neurons coexpressing D1 and D2 receptors in varying densities throughout the basal ganglia, with the highest incidence in nucleus accumbens and globus pallidus and the lowest incidence in caudate putamen. These receptors formed D1-D2 receptor heteromers that were localized to cell bodies and presynaptic terminals. In rats, selective activation of D1-D2 heteromers increased grooming behavior and attenuated AMPA receptor GluR1 phosphorylation by calcium/calmodulin kinase IIα in nucleus accumbens, implying a role in reward pathways. D1-D2 heteromer sensitivity and functional activity was up-regulated in rat striatum by chronic amphetamine treatment and in globus pallidus from schizophrenia patients, indicating that the dopamine D1-D2 heteromer may contribute to psychopathologies of drug abuse, schizophrenia, or other disorders involving elevated dopamine transmission.

Dopaminergic signaling within the basal ganglia has classically been thought to occur within two distinct neuronal pathways; the direct striatonigral pathway which contains the dopamine D1 receptor and the neuropeptides dynorphin and substance P, and the indirect striatopallidal pathway which expresses the dopamine D2 receptor and enkephalin. A number of studies have also shown, however, that D1 and D2 receptors can co-exist within the same medium spiny neuron and emerging evidence indicates that these D1/D2-coexpressing neurons, which also express dynorphin and enkephalin, may comprise a third neuronal pathway, with representation in both the striatonigral and striatopallidal projections of the basal ganglia. Furthermore, within these coexpressing neurons it has been shown that the dopamine D1 and D2 receptor can form a novel and pharmacologically distinct receptor complex, the dopamine D1-D2 receptor heteromer, with unique signaling properties. This is indicative of a functionally unique role for these neurons in brain. The aim of this review is to discuss the evidence in support of a novel third pathway coexpressing the D1 and D2 receptor, to discuss the potential relevance of this pathway to basal ganglia signaling, and to address its potential value, and that of the dopamine D1-D2 receptor heteromer, in the search for new therapeutic strategies for disorders involving dopamine neurotransmission.