Histamine receptors of cones and horizontal cells in Old World monkey retinas.

Retinopetal axons containing histamine were first described in guinea pigs (Airaksinen and Panula, 1988) and later in macaques (Gastinger et al., 1999). These axons emerge from the optic nerve head, run in the optic fiber layer, and descend orthogonally into the inner plexi-form layer (IPL), where they branch extensively. There are no cell bodies containing histamine in the retina, and axons containing histamine are also found among the ganglion cell axons in the optic nerve. A retrograde labeling study indicates that the perikarya that give rise to these axons are located in the tuberomamillary nucleus of the posterior hypothalamus (Labandeira-Garcia et al., 1990), the only area of the macaque brain where cell bodies containing histamine are found (Manning et al., 1996). These hypothalamic neurons containing histamine are not specialized for vision; they project diffusely throughout the central nervous system. They are components of the system that mediates arousal, firing most rapidly while the animal is awake (reviewed by Jones, 2005). In the central nervous system, histamine acts on three types of G-protein coupled receptors: HR1, HR2, and HR3. The primary signaling pathway of HR1 is via activation of Gq/11. HR2 typically activates GS, leading to the stimulation of adenylate cyclase. Both are generally excitatory, but inhibitory effects have also been reported. HR3 activates GO or GI and typically decreases neurotransmitter release by inhibiting voltage gated calcium channels (reviewed by Haas and Panula, 2003). However, in macaque retinas stimulation of HR3 increases the delayed rectifier component of the voltage-dependent potassium conductance in ON bipolar cells, hyperpolarizing the cells by 5 mV, on average (Yu et al., 2009). In dark-adapted baboon retinas, histamine also decreases the rate of maintained firing and the amplitude of the light responses of ON ganglion cells (Akimov et al., 2010). HR3 is the only histamine receptor that has been localized anatomically in the primate retina to date. Puncta containing immunoreactive HR3 are found in the outer plexiform layer (OPL), associated with both rods and cones. The labeled processes have been identified as ON bipolar cell dendrites, both by electron microscopic immunohistochemistry and by light microscopic double labeling with antibody to metabotropic glutamate receptor 6 (mGluR6; Gastinger et al., 2006). HR1 has been characterized in human retinal membrane preparations based on the binding of [3H] mepyramine (Sawai et al., 1988), but the neurons expressing the receptors have not been identified. HR2 has not been localized previously in primate retinas, but histamine elevates cyclic AMP in a cell line derived from human retinoblastoma (Kyritsis et al., 1984). There is indirect evidence for the presence of HR1, HR2, or both in monkey retinas based on the effects of histamine on ganglion cells. When histamine and the HR3 agonist (R)-alpha-methylhistamine are applied to monkey retinas in succession, their effects on ganglion cells are not always the same (Gastinger et al., 2004). These experiments were designed to identify the cells in macaque and baboon retinas that express HR1 and HR2.