Biomedical subjects
Publications and source records attributed to L H Tecott.
Four strains of 'knockout' mice, each with a different gene inactivated, have been found to show increased aggressive behavior. The generation of such knockout strains and quantitative trait locus analysis will help identify the genetic determinants of this complex trait.
Serotonin (5-hydroxytryptamine, 5-HT) is a monoaminergic neurotransmitter that is believed to modulate numerous sensory, motor and behavioural processes in the mammalian nervous system. These diverse responses are elicited through the activation of a large family of receptor subtypes. The complexity of this signalling system and the paucity of selective drugs have made it difficult to define specific roles for 5-HT receptor subtypes, or to determine how serotonergic drugs modulate mood and behaviour. To address these issues, we have generated mutant mice lacking functional 5-HT2C receptors (previously termed 5-HT1C), prominent G-protein-coupled receptors that are widely expressed throughout the brain and spinal cord and which have been proposed to mediate numerous central nervous system (CNS) actions of serotonin. Here we show that 5-HT2C receptor-deficient mice are overweight as a result of abnormal control of feeding behaviour, establishing a role for this receptor in the serotonergic control of appetite. Mutant animals are also prone to spontaneous death from seizures, suggesting that 5-HT2C receptors mediate tonic inhibition of neuronal network excitability.
The serotonin 5-HT3 receptor subtype has been implicated in many brain functions. Antagonists of this receptor have anxiolytic and antiemetic effects in humans and in animal models. To determine with cellular resolution the distribution of 5-HT3 receptor mRNA, in situ hybridization was performed in sections of mouse brain and dorsal root ganglia. Scattered labeled cells were observed throughout cortical regions, with highest densities in the piriform, cingulate, and entorhinal areas. Strong hybridization signals were seen in the hippocampal formation, where expression appeared primarily in interneurons. Labeled cells were most abundant in the posteroventral hippocampal region, particularly in the lacunosum moleculare layer of CA1. This distribution suggests that 5-HT3 receptors may mediate the known serotonergic inhibition of pyramidal cell populations via excitation of inhibitory interneurons. Labeled cells were also observed in the major subdivisions of the amygdaloid complex, the olfactory bulb, the trochlear nerve nucleus, the dorsal tegmental region, the facial nerve nucleus, the nucleus of the spinal tract of the trigeminal nerve, and the spinal cord dorsal horn. In the periphery, intense hybridization signals were seen in a subpopulation of cells in dorsal root ganglia. The data correlate generally with physiological, behavioral, and receptor autoradiographic studies, provide cellular resolution, and reveal regions of receptor expression not previously observed. The distribution of 5-HT3 receptor mRNA is consistent with roles for the receptor in cognition and affect and in the modulation of sensory input.
The neurotransmitter serotonin mediates diverse effects through multiple receptor subtypes. Recently, many of these receptor subtypes have been identified, molecularly cloned and characterized, advancing our understanding of their functional roles in the central and peripheral nervous systems.
The development of proenkephalin (PE) gene expression in the rat striatum was examined at the mRNA and peptide levels. Immunocytochemistry was performed with antisera generated to the PE-specific peptide product Met-enkephalin-Arg-Gly-Leu (MERGL). The distribution of immunostaining was compared with the distribution of PE mRNA, determined by in situ hybridization with an oligonucleotide probe. PE mRNA first appeared at E16 in the caudal ventrolateral striatum, followed at E17-18 by the appearance of MERGL immunoreactivity in a similar distribution. The anatomical gradients of PE gene expression were similar to the pattern of histogenesis of striatal neurons, suggesting that the timing of PE gene expression is related to the time of neuronal withdrawal from the mitotic cycle. The relation of the development of PE gene expression to the known patterns of striatal histogenesis, neurochemical compartmentalization and dopaminergic innervation is discussed.
A technique, in situ transcription, is described, in which reverse transcription of mRNAs is achieved within fixed tissue sections. An oligonucleotide complementary to proopiomelanocortin (POMC) mRNA was used as a primer for the specific synthesis of radiolabeled POMC cDNA in fixed sections of rat pituitary, thus permitting the rapid anatomical localization of POMC mRNA by autoradiography. Intermediate lobe signal intensities were sensitive to dopaminergic drugs, demonstrating that the method can be used for studies of mRNA regulation. The transcripts may also be eluted from tissue sections for a variety of uses, including the identification and cloning of autoradiographically localized cDNAs from small amounts of tissue.
Chronic administration of the neuroleptic haloperidol, the calcium channel antagonist nitrendipine, and the calcium channel antagonist neuroleptic pimozide produce differential effects on rat striatal 3H-spiperone binding. Following 7 days of 10 mg/kg i.p. administration, haloperidol significantly increases (p less than 0.01) dopamine D2 receptor binding to 123% +/- 6% of control values, whereas pimozide treatment significantly reduces (p less than 0.001) striatal 3H-spiperone binding to 46% +/- 6% of control values. Chronic administration of the calcium channel antagonist nitrendipine does not alter 3H-spiperone binding relative to control values. Saturation analysis reveals an increase in Bmax following chronic haloperidol and a decrease in Bmax following chronic pimozide treatment. No alterations in muscarinic cholinergic sites, dopamine uptake sites, or calcium channel antagonist sites result following chronic drug administration. These results are the first demonstration of a decrease in dopamine D2 binding sites after chronic neuroleptic treatment.