Microinjection of a corticotropin-releasing factor antagonist into the central nucleus of the amygdala reverses anxiogenic-like effects of ethanol withdrawal.

Publisher Summary The dopamine (DA) innervation of the prefrontal cortex (PFC) differs from other mesotelencephalic DA terminal field regions in that it responds in a quantitatively different manner to a number of pharmacological and environmental manipulations. The quantitatively different response characteristics of the PFC DA system and the resultant pattern of changes across the mesotelencephalic DA terminal fields presumably reflect differences in the regulatory features of mesencephalic neurons, which give rise to the DA innervations of different forebrain regions. The regulatory controls involved in the normal impulse-dependent release of DA from the nerve terminal range from intrinsic regulatory features to extrinsic regulatory features. This chapter explores the features of mesoprefrontal cortical DA neurons that render their response characteristics to a number of pharmacological and environmental challenges different from those of other mesotelencephalic DA neurons by using stress-induced alterations in mesotelencephalic DA neurons as a model. It also examines both the similarities and differences between DA neurons projecting to the PFC and those innervating other telencephalic sites.

The determinants of stress-induced activation of the prefrontal cortical dopamine system.

In the introductory section an overview is given of the strategies which have been proposed in the search for side-effect free antipsychotics. Special attention is paid to the role of predominant 5HT2 receptor blockade over D2 blockade. Whereas D2 receptor blockade seems to be essential for the treatment of positive symptoms of schizophrenia, it also underlies the induction of extrapyramidal side effects (EPS). Predominant 5HT2 receptor blockade may reduce the EPS liability and can ameliorate negative symptoms of schizophrenia. We further report a nearly complete list of neuroleptics that are on the European market and eight new antipsychotics that recently entered clinical trial, 5HT2 and D2 receptor binding affinity (Ki values) and the rank order in affinity for various neurotransmitter receptor subtypes are also discussed. For the eight new antipsychotics and for six reference compounds the complete receptor binding profile (including 33 radioligand receptor binding and neurotransmitter uptake models) is reported. Furthermore, for a series of 120 compounds the relative affinity for D2 receptors and D3 receptors (a recently cloned new dopamine receptor subtype) is compared. Finally, original findings are reported for the new antipsychotic risperidone and for haloperidol and clozapine on the in vivo occupation of neurotransmitter receptors in various brain areas after systemic treatment of rats or guinea pigs. The receptor occupation by the drugs was measured ex vivo by quantitative receptor autoradiography. The receptor occupancy was related to the motor activity effects of the test compounds (measurements were done in the same animals) and to the ability of the drugs to antagonize various 5HT2 and D2 receptor mediated effects. With risperidone a high degree of central 5HT2 receptor occupation was achieved before other neurotransmitter receptors became occupied. This probably co-underlies the beneficial clinical properties of the drug. Antagonism of the various D2 receptor-mediated effects was achieved at widely varying degrees of D2 receptor occupancy, from just about 10% to more than 70%. For therapeutic application it may be of prime importance to carefully titrate drug dosages. Antipsychotic effects may be achieved at a relatively low degree of D2 receptor occupancy at which motor disturbances are still minimal. With drugs such as risperidone that produce shallow log dose-effect curves, differentiation between the various D2 receptor mediated effects may be made more easily, allowing EPS-free maintenance therapy of schizophrenic patients.

Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors

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 implications-always 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.

Neurotensin and Dopamine Interactions

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2893%2981509-X

Cloning and expression of a complementary DNA encoding a high affinity human neurotensin receptor

https://www.cell.com/trends/pharmacological-sciences/pdf/0165-6147(85)90095-1.pdf

Neurotensin-dopamine interactions in the CNS

Pihoker Catherine, Scott T. Cain and Charles B. Nemeroff: Postnatal Development of Regional Binding of Corticotropin-releasing Factor and Adenylate Cyclase Activity in the Rat Brain. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1992: 16 (4) : 581–586. 1. 1. Corticotropin-releasing factor (CRF) plays a major role in the endocrine, autonomic and behavioral responses to stress. The distribution of CRF and CRF receptors in hypothalamic and extra-hypothalamic brain regions is consistent with its stress-related functions. 2. 2. In most brain regions, CRF acts primarily, if not exclusively, through activation of the adenylate cyclase systems. 3. 3. While previous studies have demonstrated the prenatal presence of CRF receptors, in the early postnatal period the abundance of CRF receptors relative Co the magnitude of CRF-stimulated cAMP production suggests that CRF receptors are not fully linked to adenylate cyclase. 4. 4. Because of our interest in the possible involvement of CRF signal transduction in the development of the neonatal stress response, we have examined postnatal development of CRF receptors in relation to adenylate cyclase activity in the rat. 5. 5. CRF binding decreased significantly in the hippocampus and striatum from postnatal days 7–21. Basal adenylate cyclase activity peaked in the second-third week of postnatal life in each brain region. Preliminary studies suggest that early stress can alter the maturation of second messenger systems in the frontal cortex.

Postnatal development of regional binding of corticotropin-releasing factor and adenylate cyclase activity in the rat brain

Chronic Continuous or Intermittent Infusion of Cocaine Differentially Alter the Concentration of Neurotensin-like Immunoreactivity in Specific Rat Brain Regions

Corticotropin-releasing-factor-like immunoreactivity (CRF-LI) was measured in a number of subcellular fractions from rat brain using a highly sensitive and specific radioimmunoassay. CRF-LI was highly enriched in the crude synaptosomal/mitochondrial fraction (P2) relative to the homogenate, P1, S1, and S2 fractions. Separation of the P2 fraction into synaptosomal, myelin, and mitochondria-enriched subfractions on a rapid one-step sucrose gradient revealed that CRF-LI was present at higher concentration in the synaptosomal fraction than in the mitochondrial and myelin fractions. The distribution of CRF-LI paralleled that of synapsin, a synaptic vesicle marker phosphoprotein, but not that of pyruvate dehydrogenase, a mitochondrial phosphoprotein. These results are consistent with a nerve terminal localization of CRF and a potential role for this peptide as a central nervous system neurotransmitter.

Subcellular distribution of corticotropin-releasing-factor-like immunoreactivity in rat central nervous system.

The emphasis of this chapter is on the mechanisms and functional significance of the interaction of neuropeptides with the putative neurotransmitter dopamine in the central nervous system (CNS). Accumulating evidence supports the contention that these interactions are of physiological importance and have added a novel dimension to our concepts of the pathophysiology of psychiatric disorders and the mechanisms of psychotropic drug action. Primary emphasis has been placed on findings from our laboratories and those of others concerning interactions between the tridecapeptide neurotensin (NT) and dopamine neurons. Where appropriate, the influence of other neuropeptides on dopamine mechanisms are discussed. We (Nemeroff et al., 1982a, 1983a, 1984) and others (Goedert, 1984) have previously reviewed the neuropharmacological, neuroanatomical and neurochemical literature supporting a functional interaction between NT-containing and dopamine-containing cells in the CNS and the interested reader is referred to these articles for a more comprehensive review than is intended here. The major objective of this chapter is to integrate recent data concerning the molecular basis of NT-dopamine interactions into the developing concept of the functional significance of such interactions.

Scott T. Cain

Papers

Neurotensin-dopamine interactions in the CNS

Postnatal development of regional binding of corticotropin-releasing factor and adenylate cyclase activity in the rat brain

Chronic Continuous or Intermittent Infusion of Cocaine Differentially Alter the Concentration of Neurotensin-like Immunoreactivity in Specific Rat Brain Regions

Subcellular distribution of corticotropin-releasing-factor-like immunoreactivity in rat central nervous system.

Neuropeptide-Dopamine Interactions: Focus on Neurotensin