Selective vulnerability in Huntington's disease: Preferential loss of cannabinoid receptors in lateral globus pallidus

Abstract

Selective neuronal vulnerability is a key feature of the neuropathology of Huntington's disease. We used [3H]CP-55,940, a synthetic cannabinoid, to label cannabinoid receptors in tissue sections from individuals dying with Huntington's disease and from normal control subjects. The density of cannabinoid receptors in striatum and pallidum was measured using quantitative autoradiography. There was a greater loss of cannabinoid receptors on striatal nerve terminals in the lateral pallidum compared to the medial pallidum, in Huntington's disease of all neuropathological grades. The disparity in binding density between the lateral and medial pallidum increased with higher grades of disease. There was also a greater loss of receptors in the lateral pallidum than in the putamen. The disproportionate loss of receptors in the lateral pallidum compared to the putamen increased in magnitude with severity of neuropathological grade. These data support the relative preferential loss or dysfunction of striatal neurons projecting to the lateral pallidum compared to neurons projecting to the medial pallidum. Terminals in the lateral pallidum containing cannabinoid receptors may be affected earlier or more severely than terminals in the medial pallidum, and both pallidal segments may be affected before or more severely than cell bodies or dendrites in the striatum. Terminal loss of markers may represent a response to perikaryal injury or dysfunction, or less likely, may indicate the primary site of neuronal damage in Huntington's disease.

Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo

“…Autoradiographic studies in human postmortem brain tissue has documented loss of CB 1 receptor from the substantia nigra (Glass et al, 1993) and lateral globus pallidus (Richfield and Herkenham, 1994) in Huntington's disease. In brains from patients dying of Alzheimer's disease, receptor binding was reduced by up to 50% in hippocampus and in the caudate nucleus, compared with brains from age-matched control subjects (Westlake et al, 1994); lesser reductions were seen in substantia nigra and globus pallidus.…”

A restricted population of CB 1 cannabinoid receptors with neuroprotective activity

“…This devastating disease constitutes so far the best paradigm to study the specific role of CB 1 receptors located on glutamatergic or GABAergic terminals because CB 1 receptors are expressed in the striatum at synapses established by neurons containing GABA (especially MSNs, the cells that primarily degenerate in HD) or glutamate (especially corticostriatal projecting neurons, which critically control MSN function) as transmitters, and play a key role in the control of motor behavior, one of the processes that is most typically affected in HD (11,12). Moreover, a remarkable down-regulation of CB 1 receptors has been documented as one of the earliest and most characteristic neurochemical alterations found in the MSNs of HD animal models (13,14) and patients with HD (15,16). In striking contrast, CB 1 receptors located on glutamatergic terminals are fully preserved in (i) the striatum of symptomatic R6/2 mice (17) (Fig.…”

The cannabinoid receptor agonist WIN 55,212-2 attenuates the effects induced by quinolinic acid in the rat striatum

“…In particular, the finding that in Huntington disease (HD, a devastating and still untreatable neurodegenerative disease) the loss of CB 1 receptor binding in the basal ganglia is one of the earliest neurochemical alterations (Richfield and Herkenham, 1994;Glass et al, 2000), has prompted the investigation of the neuroprotective role of cannabinoids in HD. Interestingly, in transgenic HD mice exposed to an enriched environment, the delayed onset of HD symptoms correlated with a delayed loss of CB 1 receptors (Glass et al, 2004).…”