Histamine and the striatum

Abstract

The neuromodulator histamine is released throughout the brain during periods of wakefulness. Combined with an abundant expression of histamine receptors, this suggests potential widespread histaminergic control of neural circuit activity. However, the effect of histamine on many of these circuits is unknown. In this review we will discuss recent evidence for histaminergic modulation of the basal ganglia circuitry, and specifically its main input nucleus; the striatum. Furthermore, we will discuss recent findings of histaminergic dysfunction in several basal ganglia disorders, including in Parkinson's disease and most prominently, in Tourette's syndrome, which has led to a resurgence of interest in this neuromodulator. Combined, these recent observations not only suggest a central role for histamine in modulating basal ganglia activity and behaviour, but also as a possible target in treating basal ganglia disorders. This article is part of the Special Issue entitled 'Histamine Receptors'.

Keywords: Basal ganglia; Histamine; Parkinson's disease; Striatum; Tourette's syndrome.

Fig. 1

(A) A simplified, schematic diagram of the basal ganglia (within the pale blue box) and their associated structures. Glutamatergic connections are in red, GABAergic connections are in dark blue, dopaminergic connections are in yellow and histaminergic projections are in purple. The major excitatory afferents to the basal ganglia are from the cortex and thalamus and are directed to both the striatum and the subthalamic nucleus (STN). The striatum influences the basal ganglia output nuclei substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi) directly, or indirectly via connections with the network between the STN and external globus pallidus (GPe). The dopaminergic substantia nigra pars compacta (SNc) influences the operation of the basal ganglia via connections with each nucleus. Similarly, the histaminergic tuberomamillary nucleus (TMN) influences the basal ganglia as well as the input structures to the basal ganglia. The major targets of the basal ganglia output nuclei are the thalamus and the midbrain and brainstem premotor regions, which influence movement via direct or indirect connections with motor nuclei. (B) Histaminergic neurons located in the tuberomamillary nucleus project to nearly all regions of the brain. Emphasized here are the histaminergic projections to basal ganglia, in particular the striatum (blue), and the input structures to the basal ganglia, namely the cortex and thalamus. The histaminergic neurons fire at high frequency during wakefulness and are virtually silent during sleep.