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.