Increasing Endocannabinoid Levels in the Ventral Pallidum Restore Aberrant Dopamine Neuron Activity in the Subchronic PCP Rodent Model of Schizophrenia

Overview

Journal Int J Neuropsychopharmacol

Publisher Oxford University Press

Specialty Psychiatry

Date 2014 Dec 25

PMID 25539511

Citations 21

Authors

David D Aguilar

Li Chen

Daniel J Lodge

Affiliations

Soon will be listed here.

Abstract

Background: Schizophrenia is a debilitating disorder that affects 1% of the US population. While the exogenous administration of cannabinoids such as tetrahydrocannabinol is reported to exacerbate psychosis in schizophrenia patients, augmenting the levels of endogenous cannabinoids has gained attention as a possible alternative therapy to schizophrenia due to clinical and preclinical observations. Thus, patients with schizophrenia demonstrate an inverse relationship between psychotic symptoms and levels of the endocannabinoid anandamide. In addition, increasing endocannabinoid levels (by blockade of enzymatic degradation) has been reported to attenuate social withdrawal in a preclinical model of schizophrenia. Here we examine the effects of increasing endogenous cannabinoids on dopamine neuron activity in the sub-chronic phencyclidine (PCP) model. Aberrant dopamine system function is thought to underlie the positive symptoms of schizophrenia.

Methods: Using in vivo extracellular recordings in chloral hydrate-anesthetized rats, we now demonstrate an increase in dopamine neuron population activity in PCP-treated rats.

Results: Interestingly, endocannabinoid upregulation, induced by URB-597, was able to normalize this aberrant dopamine neuron activity. Furthermore, we provide evidence that the ventral pallidum is the site where URB-597 acts to restore ventral tegmental area activity.

Conclusions: Taken together, we provide preclinical evidence that augmenting endogenous cannabinoids may be an effective therapy for schizophrenia, acting in part to restore ventral pallidal activity.

Citing Articles

α5-GABAA Receptor Modulation Reverses Behavioral and Neurophysiological Correlates of Psychosis in Rats with Ventral Hippocampal Alzheimer's Disease-like Pathology.

Eassa N, Perez S, Boley A, Elam H, Sharmin D, Cook J Int J Mol Sci. 2023; 24(14).

PMID: 37511546 PMC: 10380527. DOI: 10.3390/ijms241411788.

Congenital blindness does not protect against a schizophrenia-related phenotype in rodents.

Perez S, Elam H, McCoy A, Boley A, Eassa N, Lodge D Schizophr Res. 2023; 258:1-8.

PMID: 37364392 PMC: 10529675. DOI: 10.1016/j.schres.2023.06.007.

Aberrant Dopamine System Function in the Ferrous Amyloid Buthionine (FAB) Rat Model of Alzheimer's Disease.

Perez S, Boley A, McCoy A, Lodge D Int J Mol Sci. 2023; 24(8).

PMID: 37108357 PMC: 10138591. DOI: 10.3390/ijms24087196.

Crosstalk between the endocannabinoid and mid-brain dopaminergic systems: Implication in dopamine dysregulation.

Kibret B, Canseco-Alba A, Onaivi E, Engidawork E Front Behav Neurosci. 2023; 17:1137957.

PMID: 37009000 PMC: 10061032. DOI: 10.3389/fnbeh.2023.1137957.

Increased Presynaptic Dopamine Synthesis Capacity Is Associated With Aberrant Dopamine Neuron Activity in the Methylazoxymethanol Acetate Rodent Model Used to Study Schizophrenia-Related Pathologies.

Perez S, Elam H, Lodge D Schizophr Bull Open. 2022; 3(1):sgac067.

PMID: 36387971 PMC: 9642313. DOI: 10.1093/schizbullopen/sgac067.

References

Hall W, Degenhardt L . Cannabis use and the risk of developing a psychotic disorder. World Psychiatry. 2008; 7(2):68-71. PMC: 2424288. DOI: 10.1002/j.2051-5545.2008.tb00158.x. View

DSouza D, Abi-Saab W, Madonick S, Forselius-Bielen K, Doersch A, Braley G . Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction. Biol Psychiatry. 2005; 57(6):594-608. DOI: 10.1016/j.biopsych.2004.12.006. View

Moore T, Zammit S, Lingford-Hughes A, Barnes T, Jones P, Burke M . Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007; 370(9584):319-28. DOI: 10.1016/S0140-6736(07)61162-3. View

Tanda G, Pontieri F, Di Chiara G . Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997; 276(5321):2048-50. DOI: 10.1126/science.276.5321.2048. View

Yang C, MOGENSON G . An electrophysiological study of the neural projections from the hippocampus to the ventral pallidum and the subpallidal areas by way of the nucleus accumbens. Neuroscience. 1985; 15(4):1015-24. DOI: 10.1016/0306-4522(85)90250-7. View

Morgan C, Curran H . Effects of cannabidiol on schizophrenia-like symptoms in people who use cannabis. Br J Psychiatry. 2008; 192(4):306-7. DOI: 10.1192/bjp.bp.107.046649. View

Egertova M, Cravatt B, Elphick M . Comparative analysis of fatty acid amide hydrolase and cb(1) cannabinoid receptor expression in the mouse brain: evidence of a widespread role for fatty acid amide hydrolase in regulation of endocannabinoid signaling. Neuroscience. 2003; 119(2):481-96. DOI: 10.1016/s0306-4522(03)00145-3. View

Glenthoj B, Mackeprang T, Svarer C, Rasmussen H, Pinborg L, Friberg L . Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry. 2006; 60(6):621-9. DOI: 10.1016/j.biopsych.2006.01.010. View

Leweke F, Giuffrida A, Wurster U, Emrich H, Piomelli D . Elevated endogenous cannabinoids in schizophrenia. Neuroreport. 1999; 10(8):1665-9. DOI: 10.1097/00001756-199906030-00008. View

10.

Grace A, Bunney B . Intracellular and extracellular electrophysiology of nigral dopaminergic neurons--1. Identification and characterization. Neuroscience. 1983; 10(2):301-15. DOI: 10.1016/0306-4522(83)90135-5. View

11.

Friston K, Liddle P, Frith C, Hirsch S, Frackowiak R . The left medial temporal region and schizophrenia. A PET study. Brain. 1992; 115 ( Pt 2):367-82. DOI: 10.1093/brain/115.2.367. View

12.

Kathuria S, Gaetani S, Fegley D, Valino F, Duranti A, Tontini A . Modulation of anxiety through blockade of anandamide hydrolysis. Nat Med. 2002; 9(1):76-81. DOI: 10.1038/nm803. View

13.

Miller A, Walker J . Electrophysiological effects of a cannabinoid on neural activity in the globus pallidus. Eur J Pharmacol. 1996; 304(1-3):29-35. DOI: 10.1016/0014-2999(96)00111-2. View

14.

Epstein J, Stern E, Silbersweig D . Mesolimbic activity associated with psychosis in schizophrenia. Symptom-specific PET studies. Ann N Y Acad Sci. 1999; 877:562-74. DOI: 10.1111/j.1749-6632.1999.tb09289.x. View

15.

Mouri A, Noda Y, Enomoto T, Nabeshima T . Phencyclidine animal models of schizophrenia: approaches from abnormality of glutamatergic neurotransmission and neurodevelopment. Neurochem Int. 2007; 51(2-4):173-84. DOI: 10.1016/j.neuint.2007.06.019. View

16.

Giuffrida A, Leweke F, Gerth C, Schreiber D, Koethe D, Faulhaber J . Cerebrospinal anandamide levels are elevated in acute schizophrenia and are inversely correlated with psychotic symptoms. Neuropsychopharmacology. 2004; 29(11):2108-14. DOI: 10.1038/sj.npp.1300558. View

17.

Leweke F, Piomelli D, Pahlisch F, Muhl D, Gerth C, Hoyer C . Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012; 2:e94. PMC: 3316151. DOI: 10.1038/tp.2012.15. View

18.

Ames F . A clinical and metabolic study of acute intoxication with Cannabis sativa and its role in the model psychoses. J Ment Sci. 1958; 104(437):972-99. DOI: 10.1192/bjp.104.437.972. View

19.

Chen L, Perez S, Lodge D . An augmented dopamine system function is present prior to puberty in the methylazoxymethanol acetate rodent model of schizophrenia. Dev Neurobiol. 2014; 74(9):907-17. PMC: 4106988. DOI: 10.1002/dneu.22172. View

20.

Meltzer H, Arvanitis L, Bauer D, Rein W . Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am J Psychiatry. 2004; 161(6):975-84. DOI: 10.1176/appi.ajp.161.6.975. View