Vol. 53, Issue 4, 453-486, December 2001

Neurotensin and Dopamine Interactions

Elisabeth B. Binder, Becky Kinkead, Michael J. Owens and Charles B. Nemeroff¹

Laboratory of Neuropsychopharmacology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia

I. Introduction
    A. Neurotensin Background
    B. Dopamine Background
II. Neurotensin/Dopamine Anatomy
    A. Anatomy of the Dopamine System
    B. Neurotensin and Dopamine in the Midbrain
    C. Neurotensin and Dopamine in the Striatum
        1. The Nucleus Accumbens.
        2. Caudate/Putamen.
    D. Neurotensin and Dopamine in Cortical Areas and the Hippocampus
    E. Neurotensin and Dopamine in the Amygdala, Bed Nucleus of the Stria Terminalis, and Lateral Septum
    F. Neurotensin and Dopamine in the Diencephalon
    G. Differences between Interactions of Neurotensin and Dopamine in the Mesolimbic and Nigrostriatal Systems and Interactions with Other Neurotransmitter Systems
III. Functional Interactions between the Neurotensin and Dopamine Systems
    A. The Neurochemical and Electrophysiologic Effects of Neurotensin on the Dopamine System
        1. Mechanism of Action of Neurotensin.
            a. Internalization of the Neurotensin-Neurotensin Receptor Complex and Regulation of Gene Expression.
            b. Neurotensin-Induced Changes in Dopamine Receptor Affinity.
            c. Activation of Neurotensin Receptors.
        2. The Neurochemical and Electrophysiologic Effects of Centrally Administered Neurotensin.
            a. The Effect of Neurotensin in the Midbrain.
            b. Neurotensin in the Terminal Regions of Dopamine Neurons.
                i. Neurotensin in the Prefrontal Cortex.
                ii. Neurotensin in the Nucleus Accumbens.
                iii. Effects of Neurotensin in the Caudate/Putamen.
        3. Implications for the Role of Endogenous Neurotensin.
    B. Effects of Dopamine on the Neurotensin System
        1. Patterns of Dopamine Effects on Striatal Neurotensin.
        2. Effects of Dopaminergic Drugs on the Striatal Neurotensin System.
        3. Data Interpretation.
IV. Behavioral Interactions between Neurotensin and Dopamine
    A. Neurotensin and Dopamine in Schizophrenia and the Mechanism of Action of Antipsychotic Drugs
        1. Effects of Antipsychotic Drugs on the Neurotensin System.
        2. Behavioral Similarities between the Effects of Antipsychotic Drugs and Centrally Administered Neurotensin.
            a. Behaviors Related to the Side Effect Potential of Antipsychotic Drugs.
                i. Catalepsy.
                ii. Vacuous Chewing Movements.
            b. Antidopaminergic Effects.
                i. Locomotion.
                ii. Stereotypy.
            c. Animal Models of Sensorimotor Gating and Selective Attention.
                i. Prepulse Inhibition of the Acoustic Startle Reflex.
                ii. The Latent Inhibition Paradigm.
    B. Neurotensin, Dopamine, and Drugs of Abuse
    C. Neurotensin and Dopamine Interactions in Other Behaviors
V. Conclusions
Acknowledgments
References

Interactions between the classical monoamine neurotransmitter dopamine (DA) and the peptide neurotransmitter neurotensin (NT) in the central nervous system (CNS) have now been investigated for over two decades. Interest in this topic has been sustained, primarily because of the potential clinical relevance of these interactions to schizophrenia and drug abuse. In the past five years, important new discoveries in the NT field have markedly expanded our previous database. Additional NT receptors have been cloned, and novel and refined techniques have contributed to a more detailed description of the anatomy of the CNS NT system. Additionally, lipophilic NT receptor antagonists, active in the CNS after peripheral administration, have rendered more facile the investigation of the physiologic importance of endogenous NT at electrophysiologic, neurochemical, and behavioral levels. In the present review, the discussion of NT/DA interactions will progress from a discussion of the anatomical interactions between these two systems, to electrophysiologic and neurochemical interactions, and finally to behavioral implicationsalways with focus toward the potential clinical relevance of the data. The discussion of interactions between NT and DA systems will be limited to those occurring within the CNS. Moreover, because the DA projections from the midbrain to the striatum account for the bulk of the DA innervation in the CNS, we will focus on NT/DA interactions within these brain regions. Last, because of the extensive literature on NT/DA interactions available in the rat, our discussion will be based primarily on studies using this species.