Interaction of brain histaminergic and dopaminergic systems

Brain neurons containing the neurotransmitter dopamine have two well-characterized functions: they are key regulators of movements, and they mediate reward and motivation induced by natural rewards such as food and sex but also by drugs of abuse including nicotine, alcohol, and illegal drugs [1]. Dopamine neurons from the midbrain and histamine neurons from the posterolateral hypothalamus both send their axons to a brain area called the striatum which is the center for the control of movements, reward, and motivation. The striatum is divided into two subregions: the dorsal striatum which is classically referred to as the motor control region and the ventral striatum, including the nucleus accumbens, which regulates reward and motivation. Recent evidence shows however that the classical division of striatal functions is not that clear and, e.g., dorsal striatal areas have been shown to be involved in the regulation of reward too. The midbrain areas where dopaminergic neuron somas are located, substantia nigra and ventral tegmental area, also receive histaminergic projections [2, 3]. Of importance, the striatum expresses a high density of histamine H1–H3 receptors [4–6] suggesting that histamine can directly affect striatal function and basal ganglia output. The expression of the histamine H3 receptor in the striatum is exceptionally high [5–7]. H3 receptors are G protein-coupled receptors that regulate the release of histamine but also other neurotransmitter release (e.g., GABA, noradrenaline, acetylcholine, and possibly dopamine) [8]. Importantly, majority of the H3 receptors in the striatum are located postsynaptically at GABAergic medium spiny neurons [5, 6, 9], and there is evidence of a direct interaction between H3 and dopamine receptors in co-expressing culture systems [10–12] and in vivo [13].