Expression of Neurotrophins BDNF and NT-3, and Their Receptors in Rat Brain After Administration of Antipsychotic and Psychotrophic Agents

Abstract

We have investigated the potential role of neurotrophic factors in antipsychotic drug action by examining the effects of antipsychotic and psychotropic treatments on the mRNA expression of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and their receptors, trkB and trkC, respectively, in rat brain. Neither acute nor chronic clozapine treatment significantly affected the expression of these mRNAs in any brain area investigated, except for a decrease in trkB expression in the granule cells of the olfactory bulb. We then examined the effects of the psychotropic agent MK-801. MK-801 (5 mg/kg; 4 h) significantly increased BDNF mRNA in the entorhinal cortex, but did not influence NT-3, trkB, or trkC expression in any brain area except for the olfactory bulb. The induction of BDNF mRNA by MK-801 was attenuated by pre-treatment (1 h prior to MK-801 administration) with the antipsychotics, clozapine (25 mg/kg) and haloperidol (2 mg/kg), but not with the antidepressant desipramine (15 mg/kg). Finally, we confirmed that the effects of MK-801 on BDNF mRNA were reflected in the respective changes in BDNF protein levels: MK-801 significantly increased anti-BDNF reactivity in the entorhinal cortex (126 +/- 7% of control) while concomitantly decreasing in the hippocampus (71 +/- 2% of control). These data do not support the hypothesis that neurotrophins play an important role in antipsychotic drug action, but rather suggest that induction of BDNF in the entorhinal cortex may play a significant role in the psychotropic action of MK-801.

Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia

“…7). These findings are consistent with previous studies reporting no effects of chronic exposure to antipsychotic drugs on the levels of BDNF mRNA and protein or the expression of TrkB mRNA in the rodent frontal cortex (Nibuya et al, 1995;Linden et al, 2000;Takahashi et al, 2000;Lipska et al, 2001) (but see Angelucci et al, 2000;Dawson et al, 2001). The results from animal experiments are also complemented by the findings of reduced levels of both BDNF and TrkB mRNAs in the subjects with schizophrenia who were not receiving antipsychotic medications at the time of death.…”

Enhancement of Antidepressant-Like Effects but Not Brain-Derived Neurotrophic Factor mRNA Expression by the Novel N-Methyl-d-aspartate Receptor Antagonist Neramexane in Mice

“…Although Marvanova et al (2001) showed that the structurally related NMDAR-A memantine produced an increase in BDNF mRNA expression in various brain areas, this effect was assessed after acute administration. Similar increases in BDNF expression have been reported for other NMDAR-A, including MK-801 and ifenprodil after acute administration (Linden et al, 2000;Matsuki et al, 2001;Toyomoto et al, 2005).…”

Reductions in neurotrophin receptor mRNAs in the prefrontal cortex of patients with schizophrenia

“…Clozapine, an atypical antipsychotic, when administered either acutely or chronically did not change trkB or trkC mRNA levels in the cingulate cortex of rodents, but did cause a reduction in trkB mRNA in the olfactory bulb. 13 In our study, the correlations between lifetime neuroleptic exposure and trkB TK þ mRNA levels did reach statistical significance. Additionally, significant positive correlations between trkC mRNA in small neurons and neuroleptic exposure estimates were detected; this supports an earlier observation in cerebellum 34 , albeit our observation is in cerebral cortex.…”

“…11 In so far as our classifications may include both pyramidal (large) and nonpyramidal (small) neurons, our observations suggest that both glutamate and GABA-containing neurons in the normal human brain may have the capacity to directly respond to BDNF by activating intracellular tyrosine phosphorylation and associated signaling systems. Indeed trkB mRNA is found in both neuronal types in rodent brain and BDNF can influence the survival, neurite outgrowth and/or synapse formation of both glutamate [12][13][14] and GABA-containing neurons. [15][16][17][18] Since there is evidence for alterations in both excitatory and inhibitory neurons in cortex of subjects with schizophrenia (for reviews, see Blum and Mann 19 ; Goff and Coyle 20 ), we hypothesized that both large and/or small neurons may be compromised by this BDNF reduction and, in turn, may contain abnormal levels of trkB TK þ mRNA in the DLPFC of patients with schizophrenia as compared to controls.…”