Increased desensitization of dopamine D ₂ receptor-mediated response in the ventral tegmental area in the absence of adenosine A _2A receptors

G-protein coupled receptors interact to provide additional regulatory mechanisms for neurotransmitter signaling. Adenosine A _2A receptors are expressed at a high density in striatal neurons, where they closely interact with dopamine D ₂ receptors and modulate effects of dopamine and responses to psychostimulants. A _2A receptors are expressed at much lower densities in other forebrain neurons but play a more prominent yet opposing role to striatal receptors in response to psychostimulants in mice. It is, therefore, possible that A _2A receptors expressed at low levels elsewhere in the brain may also regulate neurotransmitter systems and modulate neuronal functions. Dopamine D ₂ receptors play an important role in autoinhibition of neuronal firing in dopamine neurons of the ventral tegmental area (VTA) and dopamine release in other brain areas. Here, we examined the effect of A _2A receptor deletion on D ₂ receptor-mediated inhibition of neuronal firing in dopamine neurons in the VTA. Spontaneous activity of dopamine neurons was recorded in midbrain slices, and concentration-dependent effects of the dopamine D ₂ receptor agonist, quinpirole, was compared between wild-type and A _2A knockout mice. The potency of quinpirole applied in single concentrations and the expression of D ₂ receptors were not altered in the VTA of the knockout mice. However, quinpirole applied in stepwise escalating concentrations caused significantly reduced maximal inhibition in A _2A knockout mice, indicating an enhanced agonist-induced desensitization of D ₂ receptors in the absence of A _2A receptors. The A _2A receptor agonist, CGS21680, did not exert any effect on dopamine neuron firing or response to quinpirole, revealing a novel non-pharmacological interaction between adenosine A _2A receptors and dopaminergic neurotransmission in midbrain dopamine neurons. Altered D ₂ receptor desensitization may result in changes in dopamine neuron firing rate and pattern and dopamine release in other brain areas in response to persistent dopamine release and administration of psychostimulants.