Neurotensin levels in specific brain regions and hypnotic sensitivity to ethanol and pentobarbital as a function of time after haloperidol administration in selectively bred rat lines.

Evidence indicates that sensitivity to ethanol is a good predictor of the development of alcoholism. Thus, identification of neuronal processes that regulate ethanol sensitivity has been the subject of much recent research. The present studies were designed to further test the hypothesis that neurotensinergic processes mediate, in part, hypnotic sensitivity to ethanol. Single doses of haloperidol were administered to lines of rats [selectively bred for high and low sensitivity (HAS and LAS, respectively) to hypnotic effects of ethanol] to produce increases in neurotensin (NT) levels in brain regions. At 20 h after administration, haloperidol produced dose-dependent increases in NT immunoreactivity levels in nucleus accumbens (NA) and caudate putamen (CP) in both HAS and LAS lines. Levels of NT in NA and CP returned to control values at 48 h after 4 mg/kg haloperidol. These studies used two measures of hypnotic sensitivity to ethanol: duration of loss of righting reflex (sleep time) and blood ethanol concentration at regain of righting reflex (BECRR). At 20 h, but not 48 h, after haloperidol treatment, both HAS and LAS rats displayed increases in ethanol-induced sleep time with concomitant decreases in BECRR. Pentobarbital-induced sleep time was not increased 20 h after administration of 4 mg/kg haloperidol; however, hypnotic sensitivity to both pentobarbital and ethanol was increased by acute (30-min) pretreatment with 1 mg/kg. These results suggest that NT levels in NA, acting via NT receptors, enhance hypnotic sensitivity to ethanol, but not pentobarbital.

[1]  R. Deitrich,et al.  Effects of ethanol on extracellular amino acid levels in high-and low-alcohol sensitive rats: a microdialysis study. , 2000, Alcohol and alcoholism.

[2]  S. Sesack,et al.  Dopamine Terminals in the Rat Prefrontal Cortex Synapse on Pyramidal Cells that Project to the Nucleus Accumbens , 1999, The Journal of Neuroscience.

[3]  C. Nemeroff,et al.  Neurotensin studies in alcohol naive, preferring and non-preferring rats ∗ Presented in part at the 1998 ACNP Meeting. ∗ , 1999, Neuroscience.

[4]  T. Johnson,et al.  Common quantitative trait loci for alcohol-related behaviors and central nervous system neurotensin measures: hypnotic and hypothermic effects. , 1997, The Journal of pharmacology and experimental therapeutics.

[5]  R. Deitrich,et al.  Neurotensin levels and receptors in HAS and LAS rat brains: Effects of ethanol , 1996, Pharmacology Biochemistry and Behavior.

[6]  K. Fuxe,et al.  Facilitation of gaba release by neurotensin is associated with a reduction of dopamine release in rat nucleus accumbens , 1994, Neuroscience.

[7]  D. Dorsa,et al.  Differential induction of neurotensin and c-fos gene expression by typical versus atypical antipsychotics. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[8]  E. Kislauskis,et al.  Cooperative Regulation of Neurotensin/Neuromedin N Gene Expression in PC12 Cells Involves AP‐1 Transcription Factors , 1992, Annals of the New York Academy of Sciences.

[9]  B. Bunney,et al.  Actions of Neurotensin: A Review of the Electrophysiological Studies a , 1992, Annals of the New York Academy of Sciences.

[10]  T. Hökfelt,et al.  Cloning of human neurotensin/neuromedin n genomic sequences and expression in the ventral mesencephalon of schizophrenics and age/sex matched controls , 1992, Neuroscience.

[11]  C. Nemeroff,et al.  Further studies on the modulation of regional brain neurotensin concentrations by antipsychotic drugs: focus on haloperidol and BMY 14802. , 1992, The Journal of pharmacology and experimental therapeutics.

[12]  U. Ungerstedt,et al.  The effects of neurotensin on GABA and acetylcholine release in the dorsal striatum of the rat: an in vivo mirodialysis study , 1992, Brain Research.

[13]  Y. Cheng,et al.  Linear pharmacokinetics of haloperidol in the rat , 1992, Biopharmaceutics & drug disposition.

[14]  D. Dorsa,et al.  Haloperidol rapidly increases the number of neurotensin mRNA-expressing neurons in neostriatum of the rat brain , 1991, Brain Research.

[15]  R. Roth,et al.  Stimulation‐Induced Release of Coexistent Transmitters in the Prefrontal Cortex: An In Vivo Microdialysis Study of Dopamine and Neurotensin Release , 1989, Journal of neurochemistry.

[16]  M. Miller,et al.  Distribution of neurotensin/neuromedin N mRNA in rat forebrain: unexpected abundance in hippocampus and subiculum. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[17]  H. Fibiger,et al.  Effects of short- and long-term haloperidol administration and withdrawal on regional brain cholecystokinin and neurotensin concentrations in the rat , 1989, Brain Research.

[18]  S. McNeil,et al.  The rat gene encoding neurotensin and neuromedin N. Structure, tissue-specific expression, and evolution of exon sequences. , 1988, The Journal of biological chemistry.

[19]  A. Beaudet,et al.  Selective association of neurotensin receptors with cholinergic neurons in the rat basal forebrain , 1987, Neuroscience Letters.

[20]  P. Widdowson.  The effect of neurotensin, TRH and the δ-opioid receptor antagonist ICI 174864 on alcohol-induced narcosis in rats , 1987, Brain Research.

[21]  L. Villa-komaroff,et al.  Cloning and sequence analysis of cDNA for the canine neurotensin/neuromedin N precursor. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[22]  V. Erwin,et al.  Neurotensin selectively alters ethanol-induced anesthesia in LS/Ibg and SS/Ibg lines of mice , 1987, Brain Research.

[23]  P. Kalivas,et al.  Neurotensin: Topographical distribution in rat brain by immunohistochemistry , 1982, The Journal of comparative neurology.

[24]  P. Kalivas,et al.  Neuroanatomical site specific modulation of spontaneous motor activity by neurotensin. , 1982, European journal of pharmacology.

[25]  Ting-kai Li,et al.  Different sensitivities to ethanol in alcohol-preferring and -nonpreferring rats , 1982, Pharmacology Biochemistry and Behavior.

[26]  Joseph B. Martin,et al.  The regional distribution of somatostatin, substance P and neurotensin in human brain , 1981, Brain Research.

[27]  C. Nemeroff,et al.  Enhancement of ethanol-induced sedation and hypothermia by centrally administered neurotensin, β-endorphin and bombesin , 1981, Neuropharmacology.

[28]  S. Govoni,et al.  Increase of neurotensin content elicited by neuroleptics in nucleus accumbens. , 1980, The Journal of pharmacology and experimental therapeutics.

[29]  B. Cohen,et al.  Tissue levels of haloperidol by radioreceptor assay and behavioral effects of haloperidol in the rat. , 1980, Life sciences.

[30]  F. Bloom,et al.  Calcium-dependent release of somatostatin and neurotensin from rat brain in vitro , 1978, Nature.

[31]  A. Beaudet,et al.  Neurotensin-induced bursting of cholinergic basal forebrain neurons promotes gamma and theta cortical activity together with waking and paradoxical sleep. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[32]  R. Deitrich,et al.  Pharmacological effects of ethanol on the nervous system , 1996 .

[33]  R. Deitrich,et al.  Selective breeding of rats differing in sensitivity to the effects of acute ethanol administration. , 1992, Alcoholism, clinical and experimental research.

[34]  G. Paxinos,et al.  The Rat Brain in Stereotaxic Coordinates , 1983 .

[35]  P. Emson,et al.  The regional distribution and chromatographic characterization of neurotensin-like immunoreactivity in the rat. , 1982, Advances in biochemical psychopharmacology.

[36]  C. Nemeroff.  Neurotensin: perchance an endogenous neuroleptic? , 1980, Biological psychiatry.