Reduced Regional [¹⁴C]2-Deoxyglucose Uptake in Response to Long-Term Clozapine Administration in Rats

Abstract

Clozapine has superior effects in treating negative symptoms of schizophrenia and causes less extrapyramidal side effects than traditional antipsychotics. In this study, we investigated the effects of acute and long-term clozapine administration on [¹⁴C]2-deoxyglucose uptake (2-DG uptake) in rats, as measured using the [¹⁴C]2-deoxy-D-glucose method. The 2-DG uptake was reduced in fewer regions after chronic clozapine (46%) than after acute clozapine (97%). After chronic clozapine treatment, the 2-DG uptake was reduced in the shell, but not the core, of the nucleus accumbens. In addition, long-term clozapine treatment remained affecting 2-DG uptake in several regions of the extrapyramidal system and the thalamus. The pattern of 2-DG uptake changes after long-term clozapine administration may provide information for the regions related to the therapeutic effect of clozapine.

Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement

“…Our patients were studied under a "resting" cognitive condition, but other authors using a standard cognitive activation paradigm also reported lower prefrontal activity following clozapine treatment with respect to fluphenazine-treated (Cohen et al 1997) or placebo-treated (Potkin et al 2003) patients. The metabolic decrease in the PF region agrees with observed effects in animal pre-clinical studies after acute (Tsai et al 2001;Cochran et al 2002) and chronic (Tsai et al 2001) clozapine administration.…”

“…Along the same lines, Tsai et al (2001) have reported a decrease of glucose metabolism in thalamic, limbic, and cortical (including PF) regions in rats following acute and chronic clozapine treatment.…”

“…Second, Pickar et al (1996) reported that negative symptom worsening from standard to low clozapine doses was unrelated to the change in D 2 occupancy. Third, a reduction in basal ganglia metabolism may be primarily caused by clozapine, as demonstrated by studies in animals not previously exposed to classical neuroleptics (Tsai et al 2001;Cochran et al 2002). Fourth, we have reported elsewhere that responders to clozapine (whose negative symptoms improved) showed a significant decrease of basal ganglia perfusion with this drug (Molina Rodriguez et al 1996).…”

Optimizing clozapine for chemogenetic neuromodulation of somatosensory cortex

“…Because CLZ has high uptake in the rat brain, with a brain-to-plasma ratio of 24:1, even low doses of CLZ may induce off-target effects via concurrent action at endogenous CLZ targets 11 . In addition, CLZ is known to influence metabolic activity in multiple areas of the brain 12,13 . Therefore, it is important to find the lowest dose of CLZ that will activate DREADDs while minimizing off-target effects.…”

Atypical antipsychotic drugs and diabetes

“…27 Clozapine has also been observed to reduce glucose uptake into brain regions, especially the extrapyramidal system and thalamus after acute exposure. 28 Although the mechanism is incompletely understood, these results clearly indicate that clozapine can inhibit glucose uptake through GLUT proteins from brain and peripheral tissue. Such research is important in trying to understand the mechanism by which the atypical antipsychotic drugs produce hyperglycaemia in vivo.…”