CSF concentrations of neurotensin in schizophrenia: an investigation of clinical and biochemical correlates

doi:10.1016/0920-9964(94)90082-5

Schizophrenia Research

Volume 12, Issue 1, April 1994, Pages 35-41

https://doi.org/10.1016/0920-9964(94)90082-5 Get rights and content

Abstract

Neurotensin (NT), a peptide which colocalizes with dopamine in some midbrain and hypothalamic neurons, has been speculated to play a role in schizophrenic illness and in the action of antipsychotic drugs. Previous work suggested a bimodal distribution of NT in patients with schizophrenia, with a subgroup having low drug-free NT concentrations which normalize with neuroleptic treatment. We studied 15 schizophrenic patients with CSF samples collected both off and on neuroleptic medication, 12 with only drug-free (DF) samples, and 10 controls. There was no significant difference in CSF NT concentrations between patients and controls, or between patients off and on medication. However, 7 patients with DFNT CSF concentrations below the patient mean showed an increase with neuroleptic treatment. Moreover, NT was significantly lower for women. Significant correlations with NT concentrations in CSF were found with deficit symptoms in patients, and with the age of the CSF sample for all subjects. There was no correlation between CSF NT concentrations and patient age, duration of illness, or levels of amine metabolites (MHPG, 5HIAA, HVA).

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For instance, NT-deficient mice have deficits in prepulse inhibition (PPI) and NT was shown to differentially affect the effects of APDs, which differ each in their dependence on an intact NT system (Kinkead et al., 2005). Lower levels of NT in cerebrospinal fluid (CSF) were also correlated with higher functional impairment (Garver et al., 1991), and neuroleptic treatment was shown to restore the levels of NT in CSF (Breslin et al., 1994). Lastly, long-term exposure to APDs like haloperidol can also increase the sensitivity to dopamine agonist stimulation, which contributes to treatment failure and increases relapse to psychosis, besides elevating the NT levels in the nucleus accumbens, where NT modulates dopamine function.
Schizophrenia (SCZ) is a complex psychiatric disorder with severe impact on patient’s livelihood. In the last years, the importance of neuropeptides in SCZ and other CNS disorders has been recognized, mainly due to their ability to modulate the signaling of classical monoaminergic neurotransmitters as dopamine. In addition, a class of enzymes coined as oligopeptidases are able to cleave several of these neuropeptides, and their potential implication in SCZ was also demonstrated. Interestingly, these enzymes are able to play roles as modulators of neuropeptidergic systems, and they were also implicated in neurogenesis, neurite outgrowth, neuron migration, and therefore, in neurodevelopment and brain formation. Altered activity of oligopeptidases in SCZ was described only more recently, suggesting their possible utility as biomarkers for mental disorders diagnosis or treatment response. We provide here an updated and comprehensive review on neuropeptides and oligopeptidases involved in mental disorders, aiming to attract the attention of physicians to the potential of targeting this system for improving the therapy and for understanding the neurobiology underlying mental disorders as SCZ.
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The results from the present study show for the first time that constitutive NT deficiency is sufficient to increase D2 binding in the striata in mice, a schizophrenia-like phenotype. As noted above, decreased CSF NT concentrations have been reported in schizophrenic patients [9,10,12]. These results suggest a decrease in the synaptic availability of NT in some patients with schizophrenia, which may contribute to the observed increases in striatal D2 expression and in the development of psychosis.
Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT^−/−), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT^−/− mice compared to wildtype (NT^+/+) mice. NT^−/− mice did not differ from NT^+/+ mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT^−/− mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT^+/+ controls. NT^−/− mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT^+/+ mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT^−/− mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia.
Repeated effects of the neurotensin receptor agonist PD149163 in three animal tests of antipsychotic activity: Assessing for tolerance and cross-tolerance to clozapine
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Neurotensin is an endogenous neuropeptide closely associated with the mesolimbic dopaminergic system and shown to possess antipsychotic-like effects. In particular, acute neurotensin receptor activation can inhibit conditioned avoidance response (CAR), attenuate phencyclidine (PCP)-induced prepulse inhibition (PPI) disruptions, and reverse PCP-induced hyperlocomotion. However, few studies have examined the long term effects of repeated neurotensin receptor activation and results are inconsistent. Since clinical administration of antipsychotic therapy often requires a prolonged treatment schedule, here we assessed the effects of repeated activation of neurotensin receptors using an NTS1 receptor selective agonist, PD149163, in 3 behavioral tests of antipsychotic activity. We also investigated whether reactivity to the atypical antipsychotic clozapine was altered following prior PD149163 treatment. Using both normal and prenatally immune activated rats generated through maternal immune activation with polyinosinic:polycytidylic acid, we tested PD149163 in CAR, PCP (1.5 mg/kg)-induced PPI disruption, and PCP (3.2 mg/kg)-induced hyperlocomotion. For each paradigm, rats were first repeatedly tested with vehicle or PD149163 (1.0, 4.0, 8.0 mg/kg, sc) along with vehicle or PCP for PPI and hyperlocomotion tests, then challenged with PD149163 after 2 drug-free days. All rats were then challenged with clozapine (5.0 mg/kg, sc). During the repeated test period, PD149163 exhibited antipsychotic-like effects in all three models. On the PD149163 challenge day, prior drug treatment only caused a tolerance effect in CAR. This tolerance in CAR was transferrable to clozapine, as it enhanced clozapine tolerance in the same group of animals. Although no tolerance effect was seen in the PD149163 challenge for the PCP-induced hyperlocomotion test, the clozapine challenge showed increased sensitivity in groups previously exposed to repeated PD149163 treatment. Our findings suggest that repeated exposure to NTS1 receptor agonists can induce a dose-dependent tolerance and cross-tolerance to clozapine to some of its behavioral effects but not others.
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Alternatively, mast cells may release additional mediators that have not been identified so far. It has been repeatedly demonstrated that subgroups of drug-free schizophrenic patients have low NTS in cerebrospinal fluid (CSF) concentrations compared with non-schizophrenic controls.30–35 One of the most robust findings in these reports is that NTS concentrations in schizophrenic patients with decreased CSF; NTS increase to control values following antipsychotic drug treatment and clinical improvement.30–33
Neuroinflammation may play a role in the pathogenesis of autism in some patients. The aim of this study was to measure serum levels of neurotensin (NTS) in relation to the degree of the severity of autism.
Serum NTS was measured in autistic children (n = 38; mean age 7.02 ± 2.03 years) and healthy, unrelated sex matched controls (n = 39); mean age 7.25 ± 1.64 years). The severity of autism symptoms was assessed using Childhood Autism Rating Scale (CARS) scores.
The serum level of NTS was significantly (P < 0.001) lower in autistic children (mean ± S.D. = 54.71 ± 12.4 pg/ml) than control group (mean ± S.D. = 77.58 ± 10.29 pg/ml). Children with severe autism had significantly lower serum NTS levels than patients with mild to moderate autism (P < 0.002). There was significant negative correlation between serum levels of NTS and CARS SCORES (r² = 0.79, P = 0.001).
Serum NTS levels were elevated in some autistic children and they were significantly correlated with the severity of autism. However, this is an initial report that warrants further research to determine the pathogenic role of NTS and its possible link to neuroinflammation in autism.
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Neuropeptides play a crucial role in the normal function of the central nervous system and peptide receptors hold great promise as therapeutic targets for the treatment of several CNS disorders. In general, the development of peptide therapeutics has been limited by the lack of drug-like properties of peptides and this has made it very difficult to transform them into marketable therapeutic molecules. Some of these challenges include poor in vivo stability, poor solubility, incompatibility with oral administration, shelf stability, cost of manufacture. Recent technical advances have overcome many of these limitations and have led to rapid growth in the development of peptides for a wide range of therapeutic indications such as diabetes, cancer and pain. This review examines the therapeutic potential of peptide agonists for the treatment of major CNS disorders such as schizophrenia, anxiety, depression and autism. Both clinical and preclinical data has been accumulated supporting the potential utility of agonists at central neurotensin, cholecystokinin, neuropeptide Y and oxytocin receptors. Some of the successful approaches that have been developed to increase the stability and longevity of peptides in vivo and improve their delivery are also described and potential strategies for overcoming the major challenge that is unique to CNS therapeutics, penetration of the blood–brain barrier, are discussed.

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CSF concentrations of neurotensin in schizophrenia: an investigation of clinical and biochemical correlates

Abstract

Biochem. Pharmacol.

Prog. Neuro-Psychopharmacol. Biol. Psychiatry

Eur. J. Pharmacol.

Schizophr. Res.

Schizophr. Res.

Psychoneuroendocrinology

Diagnostic and Statistical Manual of Mental Disorders

Dopamine and neurotensin storage in colocalized and noncolocalized neuronal populations

J. Pharmacol. Exp. Ther.

The Psychiatric Symptom Assessment Scale (PSAS)

Psychopharmacol. Bull.

The Prefrontal Cortex

Relation of CSF neurotensin concentrations to symptoms and drug response of psychotic patients

Am. J. Psychiatry