The novel neurotensin analog NT69L blocks phencyclidine (PCP)-induced increases in locomotor activity and PCP-induced increases in monoamine and amino acids levels in the medial prefrontal cortex

Abstract

Schizophrenia is a life-long, severe, and disabling brain disorder that requires chronic pharmacotherapy. Because current antipsychotic drugs do not provide optimal therapy, we have been developing novel treatments that focus on receptors for the neuropeptide neurotensin (NT). NT69L, an analog of neurotensin(8-13), acts like an atypical antipsychotic drug in several dopamine-based animal models used to study schizophrenia. Another current animal model utilizes non-competitive antagonists of the NMDA/glutamate receptor, such as the psychotomimetic phencyclidine (PCP). In the present study, we investigated the effects of NT69L on PCP-induced behavioral and biochemical changes in the rat. The top of an activity chamber was modified to allow us to perform microdialysis in rat brain, while simultaneously recording the locomotor activity of a rat. PCP injection significantly increased activity as well as the extracellular concentration of norepinephrine (NE), 5-HT, dopamine (DA), and glutamate in the medial prefrontal cortex (mPFC). Pretreating with NT69L blocked the PCP-induced hyperactivity as well as the increase of DA, 5-HT, NE, and glutamate in mPFC. Interestingly and unexpectedly, NT69L markedly increased glycine levels, while PCP was without effect on glycine levels. Thus, NT69L showed antipsychotic-like effects in this glutamate-based animal model for studying schizophrenia. Previous work from our group suggests that NT69L also has antipsychotic-like effects in dopaminergic and serotonergic rodent models. Taken together, these data suggest that NT69L in particular and NT receptor agonists in general, will be useful as broad-spectrum antipsychotic drugs.

Figure 1

Coronal sections showing microdialysis probe placement within mPFC for all animals. Panel A: A picture of real brain coronal section. Black arrow points out probe location. Panel B-C, Brain coronal section figures. Solid lines indicate the active dialysis regions. Numbers below the figure represent the position of the slice relative to Bregma. The figure was adapted from Paxinos and Watson (2005).

Figure 2

NT69L blocked PCP-induced hyperactivity. The data are shown as the mean of total travel distance measured every 20 min (±S.E.M.). (N=5 for Saline/PCP group, Saline/Saline group and NT69L/Saline group, N=6 for NT69L/PCP group). *, P<0.05 NT69L treated groups versus Saline treated groups. #, P<0.05 versus Saline/Saline, NT69L/Saline and NT69L/PCP groups. Gray arrow indicates when rats received either saline or NT69L injection. Black arrow indicates when rats received either saline or PCP injection.

Figure 3

In panels A, NT69L blocked the PCP-induced increase of NE levels in mPFC. In panels B, NT69L blocked the PCP-induced increase of 5-HT levels in mPFC. In panels C, NT69L blocked PCP-induced increases of DA levels in mPFC. In panels D, NT69L increased DOPAC levels in mPFC. All data are shown as the % baseline of monoamines measured every 20 min (±S.E.M.). (N=5 for Saline/PCP group, Saline/Saline group and NT69L/Saline group, N=6 for NT69L/PCP group). %, P<0.05 versus NT69L/Saline and NT69L/PCP groups. *, P<0.05 NT69L treated groups versus Saline treated groups. &, P<0.05 versus NT69L/Saline and Saline/Saline groups. #, P<0.05 versus Saline/Saline, NT69L/Saline and NT69L/PCP groups. @, P<0.05 versus Saline/Saline and NT69L/PCP groups. **, P<0.05 versus Saline/Saline group. +, P<0.05 versus NT69L/PCP group. Gray arrow indicates when rats received either saline or NT69L injection. Black arrow indicates when rats received either saline or PCP injection.

Figure 4

In panels A, NT69L blocked the PCP-induced increase of glutamate levels in mPFC. In panels B, NT69L significantly increased glycine levels in mPFC in both NT69L/Saline group and NT69L/PCP group. All data are shown as % baseline of amino acids measured every 20 min (±S.E.M.). (N=5 for PCP group, Saline/Saline group and NT69L/Saline group, N=6 for NT69L pretreated group). *, P<0.05 NT69L treated groups versus Saline treated groups. @, P<0.05 versus Saline/Saline and NT69L/PCP groups. $, P<0.05 versus Saline/Saline, and Saline/PCP groups. Gray arrow indicates when rats received either saline or NT69L injection. Black arrow indicates when rats received either saline or PCP injection.