Sex‐dependent alterations of dopamine receptor and glucose transporter density in rat hypothalamus under long‐term clozapine and haloperidol medication

Abstract

Objective Sex‐dependent disturbances of peripheral glucose metabolism are known complications of antipsychotic drug treatment. The influence of long‐term clozapine and haloperidol medication on hypothalamus, maintaining aspects of internal body homeostasis, has not yet been completely clarified. Methods After puberty, male and female Sprague Dawley rats were fed orally with ground pellets containing haloperidol (1 mg/kgBW/day) or clozapine (20 mg/kgBW/day) for 12 weeks. The hypothalamic protein expression of dopamine receptors D2R and D4R, melanocortin receptor MC4R, and glucose transporters Glut1 and Glut3 was examined. Glucose, glycogen, lactate, and pyruvate levels were determined, also malondialdehyde equivalents as markers of oxidative stress. Results D2R expression was increased in the male haloperidol and clozapine group but decreased in females medicated with clozapine. D4R expression was upregulated under clozapine medication. While females showed increased Glut1, Glut3 was elevated in both male and female clozapine‐medicated animals. We found no changes of hypothalamic malondialdehyde, glycogen, and MC4R. Hypothalamic lactate was elevated in the female clozapine group. Conclusion Clozapine sex‐dependently affects the expression of D2R, Glut1, and Glut3. The upregulation of the glucose transporters indicates glucose deprivation in the endothelial cells and consequently in astrocytes and neurons. Increased hypothalamic lactate in females under clozapine points to enhanced glycolysis with a higher glucose demand to produce the required energy. Haloperidol did not change the expression of the glucose transporters and upregulated D2R only in males.

Sex Differences in Dopamine Receptors and Relevance to Neuropsychiatric Disorders

“…It was established that yawning correlated with dopamine D3 receptor densities in various regions, including the globus pallidus, caudate nucleus, putamen, ventral pallidum, and hippocampus [ 90 ]. There is little information that exists on innate sex differences in dopamine D4 receptor expression and function; although, the antagonist clozapine, which has a high affinity for the D4 receptor, was found to increase hypothalamic D4 receptor expression to a greater extent in females compared to males [ 91 ].…”

“…Little is known about sex-specific effects in dopamine function in schizophrenia, despite the presence of sex differences in onset and symptomatology [ 149 ]. Of these studies, the focus is less on the neuropathology of schizophrenia, but rather on sex differences in antipsychotic treatment responses [ 38 , 47 , 91 , 154 ]. A clinical study analyzed findings from four distinct PET imaging studies: three on schizophrenia and one on bipolar disorder [ 154 ].…”

“…Sex differences in dopamine D2 receptor occupancy following administration of the atypical antipsychotic olanzapine was analyzed and it was shown that women required a lower dosage to achieve the same D2 receptor occupancy as men [ 154 ]. Preclinically, chronic administration of the atypical antipsychotic clozapine increased expression of D2 receptors in the hypothalamus of male rats, while it decreased D2 receptor expression in this region in females [ 91 ]. Further, this study showed that chronic administration of the typical antipsychotic haloperidol selectively increased expression of hypothalamic D2 receptors in male rats [ 91 ].…”

“…Preclinically, chronic administration of the atypical antipsychotic clozapine increased expression of D2 receptors in the hypothalamus of male rats, while it decreased D2 receptor expression in this region in females [ 91 ]. Further, this study showed that chronic administration of the typical antipsychotic haloperidol selectively increased expression of hypothalamic D2 receptors in male rats [ 91 ]. Another study that examined acute exposure to haloperidol in rats identified that haloperidol induced dopamine efflux in the striatum of both females and males, although to a much greater extent for the females [ 38 ].…”

The Pharmacodynamics of Antipsychotic Drugs in Women and Men

“…Animal experiments have demonstrated sex effects on receptor uptake of radioactive ligands (8). One pre-clinical study has shown sex effects on the upregulation of D2 receptors after treatment with haloperidol or clozapine (9). In terms of effects in humans, Kaasinen et al (10) found that women had higher D2-like receptor binding potentials than men, especially in the left and right anterior cingulate cortex.…”