Effects of antipsychotic D2 antagonists on long-term potentiation in animals and implications for human studies

Abstract

In people with schizophrenia, cognitive abilities - including memory - are strongly associated with functional outcome. Long-term potentiation (LTP) is a form of neuroplasticity that is believed to be the physiological basis for memory. It has been postulated that antipsychotic medication can impair long-term potentiation and cognition by altering dopaminergic transmission. Thus, a systematic review was performed in order to assess the relationship between antipsychotics and D2 antagonists on long-term potentiation. The majority of studies on LTP and antipsychotics have found that acute administration of antipsychotics was associated with impairments in LTP in wild type animals. In contrast, chronic administration and acute antipsychotics in animal models of schizophrenia were not. Typical and atypical antipsychotics and other D2 antagonists behaved similarly, with the exception of clozapine and olanzapine. Clozapine caused potentiation independent of tetanization, while olanzapine facilitated tetanus-induced potentiation. These studies are limited in their ability to model the effects of antipsychotics in patients with schizophrenia as they were largely performed in wild type animals as opposed to humans with schizophrenia, and assessed after acute rather than chronic treatment. Further studies using patients with schizophrenia receiving chronic antipsychotic treatment are needed to better understand the effects of these medications in this population.

Uncoupling DISC1 × D2R Protein-Protein Interactions Facilitates Latent Inhibition in Disc1-L100P Animal Model of Schizophrenia and Enhances Synaptic Plasticity via D2 Receptors

“…First, we did not find any significant facilitation of LTP by TAT-D2pep in control C57BL/6N mice. This finding could be viewed as added bonus of TAT-D2pep since acute administration of APDs impaired LTP in WT animals in the majority of studies (reviewed in Price et al, 2014 ). LTP is generally regarded as the cellular basis of neuroplasticity which underlies learning and long-term memory (Malenka and Bear, 2004 ).…”

Inefficient neural system stabilization: a theory of spontaneous resolutions and recurrent relapses in psychosis

“…They also facilitate the intrinsic functional homeostatic plasticity that counteracts the Hebbian potentiation, reducing the time taken for symptom resolution. 194,195 In particular, typical neuroleptics result in the inhibition of long-term potentiation and spike-timing dependent plasticity. 194 This effect rapidly reduces the runaway facilitation that occurs at the synaptic level during a psychotic episode, facilitating the resolution of the psychosis (early responders) and restoring the efficient sparse connectivity.…”

“…194,195 In particular, typical neuroleptics result in the inhibition of long-term potentiation and spike-timing dependent plasticity. 194 This effect rapidly reduces the runaway facilitation that occurs at the synaptic level during a psychotic episode, facilitating the resolution of the psychosis (early responders) and restoring the efficient sparse connectivity. 196 Nevertheless, in patients with defective intrinsic homeostasis such rapid response may not occur; in addition, when response occurs eventually, discontinuation or dose reduction may carry a higher risk of relapse.…”

Inefficient Neural Self-Stabilization: A theory of spontaneous resolutions and recurrent relapses in psychosis

“…They also facilitate the intrinsic functional homeostatic plasticity that counteracts the Hebbian potentiation, thus reducing the time taken for symptom resolution 183,184 . In particular, typical neuroleptics result in inhibition of long-term potentiation and spike-timing dependent plasticity 183 .…”

“…They also facilitate the intrinsic functional homeostatic plasticity that counteracts the Hebbian potentiation, thus reducing the time taken for symptom resolution 183,184 . In particular, typical neuroleptics result in inhibition of long-term potentiation and spike-timing dependent plasticity 183 . This effect will rapidly reduce the runaway facilitation occurring at the synaptic level during a psychotic episode, thus facilitating resolution of psychosis (early responders) and restoring the efficient sparseconnectivity 185 189 demonstrated a 59% increase in primary dendritic spine density in rat hippocampal neurons upon clozapine administration, while haloperidol had an opposing effect (also see 190 ).…”