Evidence for the Presence of Histamine Uptake into the Synaptosomes of Rat Brain

Abstract

Histamine has many physiological roles in the brain and periphery. Neuronal histamine is metabolized almost exclusively by histamine N-methyltransferase. Although several neurotransmitter systems such as dopamine and 5-hydroxytryptamine have their specific reuptake system in their neurons and glial cells, a specific histamine reuptake system into the corresponding nerve terminals or glial cells has not yet been clearly elucidated. We characterized the uptake of histamine into the P2 fractions of rat brain homogenized in 0.32 mol/l sucrose using in vitro uptake techniques. [³H]histamine uptake increased with the increment of added protein amount and elapsed time. [³H]histamine uptake was also temperature-dependent. The uptake of [³H]histamine into the P2 fractions occurs by two saturable processes, a high-affinity and a low-affinity, characterized by K_m values of 0.16 and 1.2 µmol/l, respectively. Na⁺, Cl^– and HCO₃^– ions were essential for the uptake of histamine in P2 fractions. [³H]histamine uptake was inhibited in the presence of several tricyclic antidepressants. In accordance with this, the endogenous release of histamine from brain slices evoked by 100 mmol/l K⁺ was augmented in the presence of 20 µmol/l imipramine. These results further support the existence of a specific histamine uptake system in the brain, although the precise molecular entities have not been identified until now.

Kinetic and pharmacological properties of [3H]-histamine transport into cultured type 1 astrocytes from neonatal rats

“…The rate of rat synaptosomal histamine uptake is in the range of fmol/mg of protein/min [23]. These findings also support the idea proposed back in 1987 [37], that astrocytes represent the main inactivation site of histamine in the rat central nervous system when it was documented that histamine had been more readily transported into the astrocyte enriched fraction than into the synaptosomal fraction while the opposite was observed when uptake of histidine was studied.…”

“…The measured K m value was significantly higher than K m obtained by Huszti et al [11] -0.19 µM in astrocytes and 0.30 µM in rat cerebral endothelial cells [33], but similar to the K m value of histamine uptake occurring in the P2 fraction of rat synaptosomes Clearance of histamine into rat type1 astrocytes 99 -1.2 µM [23]. Cultured rat astrocytes express also OCT1, OCT2 and OCT3 [18], of which OCT2 and OCT 3 can also transport histamine, but the K m values for histamine transport by OCTs are significantly different (180-940 µM) [24] than the affinity for histamine uptake obtained in our study, so the observed carrier seems to represent a new entity.…”

“…Some tricyclic antidepressant drugs e.g. trimipramine, doxepin and dothiepin were found to inhibit histamine transport into rat synaptosomes [23]. Out of all tricyclic antidepressant drugs used in our experiments, only amitriptyline and desipramine significantly decreased [ 3 H]-histamine uptake.…”

“…Rat astrocytes might represent the main clearance site for brain histamine since the rate of [ 3 H]-histamine transport into astrocytes [11,12] is significantly greater (Figure 3), than the rate of [ 3 H]-histamine uptake into rat synaptosomes [23]. The rate of rat synaptosomal histamine uptake is in the range of fmol/mg of protein/min [23].…”

“…The K m s for histamine uptake by different OCTs are all in the 10-900 µM range [22] and the authors suggested that the transporter may function on monoamines in the interstitial cleft that have escaped their high affinity uptake systems. Recently, Yanai's group [23] reported a high and low affinity, Na + -, Cl -, and HCO 3 --dependent [ 3 H]histamine transport into rat brain synaptosomes and messages for organic cationic transporters OCT1, OCT2 and OCT3 were expressed in the cultured neonatal Sprague-Dawley rat cortical astrocytes [24].…”