Subchronic haloperidol increases CB₁ receptor binding and G protein coupling in discrete regions of the basal ganglia

Abstract

The present study was designed to test whether chronic neuroleptic treatment, which is known to alter both expression and density of dopamine D(2) receptors in striatal regions, has effects upon function and binding level of the cannabinoid CB(1) receptor in the basal ganglia by using receptor autoradiography. As predicted, subchronic haloperidol treatment resulted in increased binding of (3)H-raclopride and quinpirole-induced guanosine 5'-O-(gamma-[(35)S]thio)triphosphate ([(35)S]GTPgammaS) in the striatum when compared to that measured in control animals. This increased D(2) receptor binding and function after 3 days washout was normalized after a 2-week washout period. Effect of haloperidol treatment was studied for CB(1) receptor binding and CP55,940-stimulated [(35)S]GTPgammaS in the striatum, globus pallidus, and substantia nigra. (3)[H]CP55,940 binding levels were found in rank order from highest to lowest in substantia nigra > globus pallidus > striatum. Furthermore, subchronic haloperidol treatment resulted in elevated binding levels of (3)[H]CP55,940 in the striatum and the substantia nigra and CB(1) receptor-stimulated [(35)S]GTPgammaS bindings in the substantia nigra after 3 days washout. These increased binding levels were normalized at 1-4 weeks after termination of haloperidol treatment. Haloperidol treatment had no significant effect on CB(1) receptor or [(35)S]GTPgammaS binding levels in globus pallidus. The results help to elucidate the underlying biochemical mechanism of CB(1) receptor supersensitivity after haloperidol treatment.

Reduced Brain Cannabinoid Receptor Availability in Schizophrenia

“…While the preclinical literature on the effects of antipsychotics on CB1R availability are mixed (24–26), our results are consistent with data demonstrating regional increase in CB1R binding associated with treatment with haloperidol (27) and risperidone (28). …”

“…In a second cohort that also included unmedicated SCZs (n=6), Eggan et al suggested that antipsychotic treatment might blunt the decrease in CB1R immunoreactivity levels observed in SCZ (17). Others have shown in animals that treatment with haloperidol (27), risperidone (28) and clozapine (29) resulted in altered CB1R density in various brain regions.…”

Risperidone Treatment Increases CB₁ Receptor Binding in Rat Brain

“…Therefore, the possibility that direct binding of risperidone to CB 1 receptors was the cause of the observed CB 1 receptor alterations appears to be unlikely. Risperidone may modulate the endocannabinoid system indirectly through other neurotransmitters, such as dopamine [70]. Risperidone has the highest antagonistic affinity for 5-HT 2A and D 2 receptors [71].…”

Upregulation of Cannabinoid Type 1 Receptors in Dopamine D2 Receptor Knockout Mice Is Reversed by Chronic Forced Ethanol Consumption

“…These receptors influence each other’s expression: (i) stimulation of either receptor increases the neurotransmitter levels of the other (Giuffrida et al, 1999; Tanda et al, 1997), (ii) the life-long absence of CB1R leads to DRD2 over-expression in the striatum (Houchi et al, 2005), and (iii) rodents and primates treated with antipsychotics (DRD2 antagonists), 6-OHDA or MPTP, as well as Parkinson’s disease patients, show increased CB1 mRNA and receptor levels (Andersson et al, 2005; Lastres-Becker et al, 2001; Mailleux and Vanderhaeghen, 1993). …”