Neuroticism

Anxiety
corticotropin-releasing factor receptor, subtype 1 (CRFR1) [GE]
    Corticotropin-releasing factor receptor, subtype 1 (CRFR1)-deficient mice displayed increased exploratory behavior in the elevated Plus-Maze and the Black and White test box, both models of anxiety.  These results suggested that the CRFR1 gene plays a role in anxiety.  The CRFR1 deficient mice also were impaired in spatial recognition memory, indicating that this gene is involved in cognitive biological processes, as well.  Contarino et al., Brain Res., 835:1-9, 1999.

dopamine receptor, type 2 (DR2) [HGL]
    A significantly increased incidence of migraine with aura (MWA), major depression, and generalized anxiety disorder (GAD), panic attacks, and phobia was observed in individuals with a DR2 allele NcoI C/C genotype compared with individuals with a DR2 NcoI T allele.  Peroutka et al., Mol. Med., 4:14-21, 1998.

gamma-aminobutyric acid (GABA) receptor, type A [GE]
    5-HTR1A "knock-out" mice displayed reduced binding to the GABA receptor, type A (GABA-A), impaired GABAergic transmission, and benzodiazepine-resistant anxiety.  These results suggest that a deficit in the 5-HTR1A leads to abnormalities in the GABAergic pathways which in turn results in benzodiazepine-resistant anxiety.  Sibille et al., J. Neurosci., 20:2758-2765, 2000. See entry under "serotonin receptor, subtype 1A (5-HTR1A)."

gamma-aminobutyric acid (GABA) receptor, type A, subtype alpha-2 [GE]
    Two transgenic mouse cell lines were generated in which the alpha-2 and alpha-3 GABA-A receptors were rendered insensitive to diazepam by a point mutation in the drug binding site.  Alpha-2 receptors are present in the limbic system, cerebral cortex, hippocampus, and striatum, whereas alpha-3 receptors are expressed in the brainstem reticular formation, the basal forebrain, and the reticular nucleus of the thalamus.  Both lines of transgenic mice displayed a normal response to the sedative, motor-impairing, and anticonvulsant activities of diazepam, but only alpha-2 mice did not show the behavioral disinhibition by diazepam observed in normal and alpha-3 mice.  These results indicate that the anxiolytic activity of diazepam is mediated by alpha-2 GABA-A receptors, suggesting their role, and associated pathways in the limbic system, cerebral cortex, and hippocampus, in anxiety-related disorders.  Low et al., Science, 290:131-134, 2000.

glutamic acid decarboxylase, 65 kDa isoform (GAD65) [GE]
    Glutamic acid decarboxylase (GAD) is involved in the synthesis of GABA, a neurotransmitter in the CNS.  Mice with an inactivated GAD gene showed abnormal behaviors, including increased anxiety-like behavior and reduced intermale aggression.  Stork et al., Brain Res., 865:45-58, 2000.  See, also entry under Agreeableness.

protein kinase C, gamma isoform (PKC-gamma) [GE]
    Protein kinases (PKC) are enzymes that phosphorylate proteins.  PKCs are part of the signal transduction pathway.  For instance, stimulation of a receptor by its cognate hormone or neurotransmitter can lead to the production of cAMP, which in turn activates PKC.  Activated PKC phosphorylates various substrates in the pathway, triggering various cellular responses, including, secretion, changes in membrane permeability, and gene activation.  PKC-gamma is involved in 5-HT2 and GABA-A signalling (see also, entries under "gamma-aminobutyric acid (GABA) receptor, type A").  To study the role of  the gamma isoform of PKC in behavior, mice completely lacking the gene were engineered.  Null mutant mice (deficient in both copies of the gene) displayed a decrease in baseline anxiety-related behaviors in several different test.   Locomotor activity was normal indicating that the reduced anxiety was not due to baselibne differences in it.  Bowers et al., Behav. Genet., 30:111-121, 2000.

regulator of G-protein signaling-2 (rgs2) [GE]
    Regulator of G-protein signaling-2 (rgs2) is a member of a family of genes which accelerate the GTPase activity of G-proteins, components of signal transduction pathways.  They contain a conserved RGS domain of about 120 amino acids.  rgs2 is up-regulated in the central nervous system after stimuli which evok long-term neuronal plasticity and also in activated T-cells.  To investigate its in vivo role, rgs2-deficient mice were generated.  The rgs2 deficieny had no apparent effect on motor responses, exploratory behavior, spatial learning, or memory.  However, mice lacking the rgs2 gene completely (rgs2-/rgs2-) showed reduced male aggression when compared to heterozygous (rgs2-/rgs+) littermates.  The aggressive response of female mice deficient in rgs2 was normal.  In addition to aggression, rgs2-deficient mice showed increased anxiety as compared to heterozygous littermates (data comparing males and females in the anxiety test were not presented.)  Differences in the CA1 hippocampal neursons were observed in rgs-deficient mice as compared to controls.  Oliveira-dos-Santos et al., Proc. Natl. Acad. Sci., 97:12272-12277, 2000.  See, also entry under Agreeableness.

serotonin receptor, subtype 1A (5-HTR1A) [GE]
    Transgenic mice were created by gene-targeting strategy which lack a functional type 1A serotonin receptor (5-HTR1A).  Homozygous mutants displayed a consistent pattern of responsies indicative of increased anxiety levels in open-field, elevated-zero maze, and novel-object assays.  Heisler et al., Proc. Natl. Acad. Sci., 95: 15049-54, 1998.  Similar results in Parks et al., Proc. Natl. Acad., 95:10734-9, 1998.  5-HTR1A "knock-out" mice also showed benzodiazepine-resistant anxiety.  Binding to the GABA(A) receptor was reduced and GABAergic transmission was impaired in the mutant mice.  Sibille et al., J. Neurosci., 20:2758-2765, 2000.

serotonin receptor, subtype 1B (5-HTR1B) [GE]
    Mice deficient in subtype 1B serotonin receptor show reduced anxiety and are hyperactive throughout their life.  Pups lacking 5-HTR-1B were more hyperactive than wild-type pups.  5-HTR-1B deficient mothers spent 20% more time out of the nest than wild-type mothers.  They showed elevated hyperactivity, rearing and climbing to the edge of the cage more than the normal control mothers.  Brunner et al., Behav. Neurosci., 113:587-601, 1999.

serotonin transporter gene (5-HTT or SERT)+ [HGL]
    A polymorphism in the promoter region of the 5-HTT gene was detected in humans.  A long and short version of the gene was identified, depending on whether it contained a DNA insertion.  The short variant of the polymorphism results in decreased expression of 5-HTT and a decrease in serotonin uptake.  This polymorphism was associated with increased increased anxiety in sample of human subjects.  Lesch et al., Science, 274(5292):1526-1531, 1996.  See, also, Murakami et al., J. Human Genetics, 1:15-17, 1999.   These results have not been replicated by others. Jorm et al., Mol. Psychiatry, 3:449-451, 1998; Ohara et al., Biol. Psychiatry, 44:550-554, 1998.

Obsessive-compulsive disorders
dopamine receptor, type 1 [GE]
    The cholera toxin gene was placed under the control of the dopamine receptor, type 1 (DR1), promoter.   Cholera toxin gene expression was restricted to CNS neurons.  Variations in the regional expression of the gene was observed in different transgenic lines.   Expression of the cholera toxin gene resulted in stimulation of the G-protein signal transduction pathway, including cAMP synthesis.  In one transgenic line studied, in which expression was observed in the piriform cortex layer II, the somatosensory cortex, and the amygdala,  a constellation of behaviors were observed that strongly resembled compulsive disorders, such as obsessive- compulsive disorder (OCD).   These abnormal behaviors included repetitive non-aggressive biting and leaping.  Campbell et al., J. Neurosci., 19:5044-5043, 1999.

serotonin transporter gene (5-HTT or SERT) [HGL]
    The "L" SLC6A4 allele of the 5-HTT gene was associated with obsessive-compulsive disorder (OCD).  McDougle et al., Mol. Psychiatry, 3: 270-273, 1998.

Panic disorder
serotonin transporter (5-HTT or SERT)* [HGL]
    No association between a functional polymorphism in the promoter of the 5-HTT gene and panic disorder.  Hamilton et al., Psychiatr. Genet., 9:1-6, 1999.