CB1 cannabinoid receptors are involved in neuroleptic-induced enhancement of brain neurotensin

Document Type: Original Article

Authors

1 Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran

2 Research Center for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Targeting the neuropeptide systems has been shown to be useful for the development of more effective antipsychotic drugs. Neurotensin, an endogenous neuropeptide, appears to be involved in the mechanism of action of antipsychotics. However, the available data provide conflicting results and the mechanism(s) by which antipsychotics affect brain neurotensin neurotransmission have not been identified. Therefore, we aimed to investigate the effects of fluphenazine and amisulpride on brain regional contents of neurotensin considering the role of cannabinoid CB1 receptors which interact with neurotensin neurotransmission.
Materials and Methods:Fluphenazine (0.5, 1, and 3 mg/kg) or amisulpride (3, 5, and 10 mg/kg) were administered intraperitoneally to male Wistar rats either for one day or 28 consecutive days.Twenty four hours after the last injection of drug or vehicle, neurotensin contents were determined in the mesocorticolimbic and nigrostriatal dopamine regions by radioimmunoassay. In the case of any significant change, the effect of pre-treatment with CB1 receptor antagonist, AM251 was investigated.
Results:Chronic, but not acute, treatment with the highest dose of fluphenazine or amisulpride resulted in significant enhancement of neurotensin contents in the prefronatal cortex and nucleus accumbens. Fluphenazine also elevated neurotensin levels in the anterior and posterior caudate nuclei and substantia nigra. Neither amisulpride nor fluphenazine affected neurotensin contents in the amygdala or hippocampus. Pre-treatment with AM251 (3 mg/kg) prevented the neuroleptic-induced elevation of neurotensin. AM251 showed no effect by itself.
Conclusion:The brain neurotensin under the regulatory action of CB1 receptors is involved in[T1]  the effects of amisulpride and fluphenazine.

Keywords


1. Saraceno B. Mental health: scarce resources need new paradigms. World Psychiatry 2004; 3:3–5.

2. McGrath J, Saha S, Chant D, Welham J. Schizophrenia: A concise overview of incidence, prevalence, and mortality. Epidemiol Rev 2008, 30:67-76.

3. Joyce JN. The dopamine hypothesis of schizophrenia: limbic interactions with serotonin and norepinephrine. Psychopharmacology 1993; 112:S16-S34.

4. Bachus SE, Kleinman JE. The neuropathology of schizophrenia. J Clin Psychiatry 1996; 57:72–83.

5. Walker MW, Ewald DA, Perney TM, Miller RJ. Neuropeptide Y modulates neurotransmitter release and Ca2+ currents in rat sensory neurons. J Neurosci 1988; 8:2438-2446.

6. Carraway RE, Leeman SE. The isolation of a new hypotensive peptide, neurotensin, from bovine hypothalami. J Biol Chem 1973; 248:6854–6861.

7. Mustain WC, Rychahou PG, Evers BM. The role of neurotensin in physiologic and pathologic processes. Curr Opin Endocrin Diabetes Obes 2011; 18:75–82.

8. Brun P, Mastrotto C, Beggiao E, Stefani A, Barzon L, Sturniolo GC,et al. Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation. Am J Physiol Gastrointest Liver Physiol 2005; 288:G621–G629.

9. Mai JK, Triepel J, Metz J. Neurotensin in the human brain. Neuroscience 1987; 22:499–524.

10. Kitabgi P, De Nadai F, Labbe-Jullie, Dubuc I, Nouel D, Costentin J,et al. Functional and pharmacological aspects of central neuropeptidergic transmission mediated by neurotensin and neuromedin. Clin Neuropharmacol 1992; 15:313A-314A.

11. Lambert PD, Gross R, Nemeroff CB, Kilts CD. Anatomy and mechanisms of neurotensin-dopamine interactions in the central nervous system. Ann N Y Acad Sci 1995; 757:377–389.

12. Kasckow J, Nemeroff CB. The neurobiology of neurotensin: focus on neurotensin-dopamine interactions. Reg Peptides 1991; 36:153–164.

13. Binder EB, Kinkead B, Owens MJ, Nemeroff CB. The role of neurotensin in the pathophysiology of Hassanzadeh and Rostami Neuroleptic-induced neurotensin enhancement schizophrenia and the mechanism of action of antipsychotic drugs. Biol Psychiatry 2001; 50:856-872.

14. Kinkead B, Nemeroff CB. Neurotensin, schizophrenia, and antipsychotic drug action. Int Rev Neurobiol 2004; 59:327-349.

15. Breslin NA, Suddath RL, Bissette G, Nemeroff CB, Lowrimore P, Weinberger DR. CSF concentra-tions of neurotensin in schizophrenia: An investigation of clinical and biochemical correlates. Schizophr Res 1994; 12:35–41.

16. Sharma RP, Janicak PG, Bissette G, Nemeroff CB. CSF neurotensin concentrations and antipsychotic treatment in schizophrenia and schizoaffective disorders. Am J Psychiatry 1997; 154:1019–1021.

17. Wolf SS, Hyde TM, Saunders RC, Herman MM, Weinberger DR, Kleinman JE. Autoradiographic characterization of neurotensin receptors in the entorhinal cortex of schizophrenic patients and control subjects. J Neural Transm 1995; 102:55–65.

18. Jolicoeur FB, Gagne MA, Rivest R, Drumheller A, St-Pierre S. Atypical neuroleptic-like behavioral effects of neurotensin. Brain Res Bull 1993; 32:487-491.

19. Gruber SHM, Nomikos GG, Mathé AA. Effects of haloperidol and risperidone on neurotensin levels in brain regions and neurotensin efflux in the ventral striatum of the rat. Neuropsychopharma- cology 2002; 26:595-604.

20. Kinkead B, Shahid S, Owens MJ, Nemeroff CB. Effects of acute and subchronic administration of typical and atypical antipsychotic drugs on the neurotensin system of the rat brain. J Pharmacol Exp Ther 2000; 295:67–73.

21. Viveros MP, Marco EM, Liorente R, Lopez-Gallardo M. Endocannabinoid system and synaptic plasticity: implication for emotional response. Neural Plast 2007; 2007:52908.

22. Serra G, Fratta W. A possible role for the endocannabinoid system in the neurobiology of depression. Clin Pract Epidemol Ment Health 2007; 3:25.

23. Hassanzadeh P. The endocannabinoid system: critical for the neurotrophic action of psychotropic drugs. Biomed Rev 2010; 21:31-46.

24. Hassanzadeh P, Hassanzadeh A. Involvement of the neurotrophin and cannabinoid systems in the mechanisms of action of neurokinin receptor anta-gonists. Eur Neuropsychopharmacol 2011; 21:905–917.

25. Hassanzadeh P, Rahimpour S. The cannabiner gic system is implicated in the upregulation of central NGF protein by psychotropic drugs. Psychopharmacology 2011; 215:129–141.

26. Hassanzadeh P, Hassanzadeh A. The CB1 receptor-mediated endocannabinoid signaling and NGF: the novel targets of curcumin. Neurochem Res 2012; 37:1112-1120.

27. Hassanzadeh P, Hassanzadeh A. The role of the endocannabinoids in suppression of the hypothalamic-pituitary-adrenal axis activity by doxepin. Iran J Basic Med Sci 2011; 14:414-421.

28.Rodrیguez-Gaztelumendi A, Rojo ML, Pazos A, Dیaz A. Altered CB1 receptor-signaling in prefrontal cortex from an animal model of depression is reversed by chronic fluoxetine. J Neurochem 2009; 108:1423–1433.

29. Mitchell VA, Kawahara H, Vaughan CW. Neurotensin inhibition of GABAergic transmission via mGluR-induced endocannabinoid signalling in rat periaqueductal grey. J Physiol 2009; 587:2511–2520.

30. Vrškovل D. Endocannabinoid brain system involvement in dopamine mechanisms of behavioural sensitization to psychostimulants. Acta Vet Brno 2009; 78:491-496.

31.Hassanzadeh P, Arbabi E. Cannabinoid CB1 receptors mediate the gastroprotective effect of neurotensin. Iran J Basic Med Sci 2012; 15:803-810.

32. Coirini H, Kنllstrِm L, Wiesel FA, Johnson AE. Modulation of basal ganglia neurotransmission by the classical antipsychotic fluphenazine is due in part to the blockade of dopamine D1-receptors. Brain Res Mol Brain Res 1997; 49:197-210.

 33. Papp M, Wieronska J. Antidepressant-like activity of amisulpride in two animal models of depression. J Psychopharmacol 2000; 14:46-52.

 34. Dono LM, Currie PJ. The cannabinoid receptor CB₁ inverse agonist AM251 potentiates the anxiogenic activity of urocortin I in the basolateral amygdala. Neuropharmacology 2012; 62:192-199.

 35. Femenia T, Garcia-Gutierrez MS, Manzanares J. CB1 receptor blockade decreases ethanol intake and associated neurochemical changes in fawn-hooded rats. Alcohol Clin Exp Res 2010; 34:131-141.

 36. Kilts CD, Anderson CM, Bisseite G, Ely TD, Nemeroff CB. Differential effects of antipsychotic drugs on the neurotensin concentration of discrete rat brain nuclei. Biochem Pharmacol 1988; 37:1547-1554.

 37. Guidotti A, Cheney DL, Trabucchi M, Doteuchi M, Wang C. Focused microwave radiations: A technique to minimize post mortem change of cyclic nucleotides, dopa, and choline and to preserve brain morphology. Neuropharmacology 1974; 13:1115-1122.

 38. Palkovits M. Isolated removal of hypothalamic and other brain nuclei of the rat. Brain Res 1973; 59:449-450.

 39. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. San Diego: Academic Press; 1986.

40. Bissette G, Richardson C, Kizer JS, Nemeroff CB. Ontogeny of brain neurotensin in the rat: A radioimmunoassay study. J Neurochem 1984; 43:283–287.

41. Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-254.

42. Adachi DK, Kalivas PW, Schenk JO. Neurotensin binding to dopamine. J Neurochem 1990; 54:1321–1328.

43. Binder EB, Kinkead B, Owens MJ, Kilts CD, Nemeroff CB. Enhanced neurotensin neurotrans-mission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating. J Neurosci 2001; 21:601–608.