Dopamine Depletion of the Prefrontal Cortex Induces Dendritic Spine Loss: Reversal by Atypical Antipsychotic Drug Treatment

Abstract

Dystrophic changes in dendrites of cortical neurons are present in several neuro-psychiatric disorders, including schizophrenia. The mechanisms that account for dendritic changes in the prefrontal cortex (PFC) in schizophrenia are unclear. Cognitive deficits in schizophrenia have been linked to compromised cortical dopamine function, and the density of the PFC dopamine innervation is decreased in schizophrenia. We determined if 6-hydroxydopamine lesions of the ventral tegmental area that disrupt the PFC dopamine innervation cause dystrophic changes in cortical neurons. Three weeks post-operatively we observed a marked decrease in basal dendritic length and spine density of layer V pyramidal cells in the prelimbic cortex; no change was seen in neurons of the motor cortex. We then examined rats in which the PFC dopamine innervation was lesioned and 3 weeks later were started on chronic treatment with an atypical (olanzapine) or typical (haloperidol) antipsychotic drug. Olanzapine but not haloperidol reversed lesion-induced changes in PFC pyramidal cell dendrites. These data suggest that dopamine regulates dendritic structure in PFC neurons. Moreover, the findings are consistent with a decrease in cortical dopaminergic tone contributing to the pathological changes in the cortex of schizophrenia, and suggest that the progressive cortical loss in schizophrenia may be slowed or reversed by treatment with atypical antipsychotic drugs.

Phencyclidine-induced Loss of Asymmetric Spine Synapses in Rodent Prefrontal Cortex is Reversed by Acute and Chronic Treatment with Olanzapine

“…The cognitive deficits resulting from a lesion-induced dopaminergic dysfunction in PFC is known to be severe (Brozoski et al, 1979), supporting the potential link between DA neurotransmission and cognitive function. The morphological consequences of a disruption to DA transmission in PFC has been demonstrated by a recent study, which showed that selective damage to the dopaminergic innervation of PFC causes a loss of dendritic spines on pyramidal cells in the rat, whereas the restoration of dopaminergic tone with olanzapine reversed this effect (Wang and Deutch, 2008). Our data builds on the data of Wang and Deutch (2008) by demonstrating that that olanzapine treatment counteracts the asymmetric synapse loss in the PFC induced in the PCP model.…”

“…The morphological consequences of a disruption to DA transmission in PFC has been demonstrated by a recent study, which showed that selective damage to the dopaminergic innervation of PFC causes a loss of dendritic spines on pyramidal cells in the rat, whereas the restoration of dopaminergic tone with olanzapine reversed this effect (Wang and Deutch, 2008). Our data builds on the data of Wang and Deutch (2008) by demonstrating that that olanzapine treatment counteracts the asymmetric synapse loss in the PFC induced in the PCP model. Furthermore, the ability of olanzapine to restore asymmetric synapse number when given acutely is consistent with a dopaminergic mechanism, as a rapid elevation of DA levels in the PFC is induced by olanzapine, which lasts at least 120 min after i.p.…”

“…In fact, alterations in BDNF levels have been reported in PFC and CSF of schizophrenic patients, even in antipsychotic-naive firstepisode subjects (Durany et al, 2001;Hashimoto et al, 2005;Issa et al, 2010;Weickert et al, 2003). Thus, olanzapineinduced increases in DA turnover and BDNF levels may function individually or in concert to contribute to the effectiveness of olanzapine in reversing the enduring dystrophic changes in dendrites and asymmetric spine synapses seen following mesocortical lesions (Wang and Deutch, 2008) or chronic PCP treatment.…”

“…This agent, similar to clozapine, has been shown to have some benefit in treatment of cognitive deficits associated with schizophrenia (Keefe et al, 2007;Woodward et al, 2005). Olanzapine was chosen for this study as chronic administration of this atypical antipsychotic drug was shown to reverse the dystrophic changes in dendrites of PFC pyramidal neurons induced by DA denervation of the PFC (Wang and Deutch, 2008). In the current study, olanzapine was given chronically and acutely to determine whether the loss of PFC asymmetric spine synapses elicited by PCP treatment is influenced by treatment with this atypical antipsychotic drug.…”

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

“…Chronic PCP treatment decreases parvalbumin mRNA expression and chronic administration of clozapine, but not haloperidol, reversed the PCP-induced decreases in parvalbumin mRNA expression in prefrontal cortical GABAergic interneurons (Cochran et al, 2003). Chronic treatment with olanzapine, but not haloperidol, has been reported to slow volume loss in the prefrontal cortex in a prefrontal cortical dopamine denervation model of schizophrenia (Wang and Deutch, 2008). Some clinical reports also suggest some atypical APDs may have a neuroprotective effect.…”