Striatal dopamine receptor plasticity in neurotensin deficient mice

Abstract

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.

Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity

“…NT is also involved in the mechanism of action of antipsychotic drugs, as the deficits in prepulse inhibition present in NT-deficient mice were restored by clozapine but not haloperidol, olanzapine, or quetiapine (Kinkead et al, 2005), and NT-like peptides were proposed as potential antipsychotics due to its action on the modulation of the serotonin system (Kost et al, 2014). NT in the nucleus accumbens was shown to reverse dopamine supersensitivity evoked by antipsychotic treatment (Servonnet et al, 2017), and therefore confirming its close association with the dopamine system, which includes its dual role in the stimulant and antipsychotic responses (Cáceda et al, 2012;Chastain et al, 2015;Fawaz et al, 2009;Kinkead et al, 2005;Servonnet et al, 2017). In addition, NT can induce a persistent synaptic depression by decreasing dopamine release (Piccart et al, 2015), while conversely, the activity of Ndel1, which has the potential to inactivate NT and BK, seems to be augmented by increased dopamine release (Bradshaw and Hayashi, 2017;Hayashi et al, 2000;Nani et al, 2019a).…”

Angiotensin‐converting enzymes as druggable features of psychiatric and neurodegenerative disorders

“…There are two main pathways by which these compounds could impact upon such disorders. Firstly, ACE is an oligopeptidase that degrades peptides, such as neurotensin and bradykinin, and these peptides are non-classical neurotransmitters that can modulate dopaminergic neurotransmission (Chastain et al, 2015;Rodríguez et al, 2020).…”

Opioid Analgesia and Opioid-Induced Adverse Effects: A Review

“…However, the effects were absent in D1 and D2 receptor knockout mice [202]. Acute morphine administration induces phosphorylation of dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), which activates the D1 receptor on dopaminergic neurons of NAc, substantia nigra and dorsal striatum and stimulates locomotor activity [202][203][204][205]. The D1, D2 and D3 receptors are responsible for the control of locomotion, learning and memory-related functions [206].…”

“…Studies suggested that the morphine-induced behavioural effects are probably derived from its binding to the KOP receptor but not to the MOP receptor [217,218]. The likely multiple mechanisms that link chronic morphine treatment to its behavioural effects are not completely understood but may be controlled by a combination of dopaminergic, GABAergic, opioidergic and additional unknown neuronal signals [107,[202][203][204][212][213][214]. The combination of multiple independent behavioural measurements is generally regarded as the most reliable approach to assess the total motor effects induced by opioids [193,194,[219][220][221].…”