Knockout and Transgenic Mice

Several genes coding for adrenergic receptors or proteins implicated in the synthesis or metabolism of NE have been deleted from mice with the knockout technique. Most of the initial studies have focused on the cardiovascular functions of these knockout mice, and only few behavioral experiments performed on these animals have yet been described.

1. Dopamine b-Hydroxylase (DBH) Knockout Mice

Most DBH—/— mice die in utero. However, survival can be enhanced by perinatal administration of dihydroxyphenylserine (DOPS), a direct precursor of NE (see Fig. 3). DBH—/— mice have impaired adaptation to cold and have elevated basal metabolic rates without abnormalities in thyroid hormone levels. A deficit in maternal behavior in DBH—/— females may also exist. The results of cross-fostering between DBH—/— females and DBH + /— females suggest that an important interaction mediated by NE occurs between the dam and the neonate during the first 24 hr for establishing maternal behavior.

The results of behavioral tests indicate that NE plays an important role in motor learning and performance and in the retention of several behaviors. Restoration of NE with DOPS eliminates the motor deficits and improves fertility in males, indicating that these differences are due to the physiological absence of NE rather than lasting developmental defects secondary to NE deficiency. More recently, it was found that DBH—/— mice exhibit altered ethanol-induced behavioral and physiological responses. DBH—/— mice exhibit a reduced ethanol preference in a two-bottle choice paradigm and delayed extinction in the ethanol-conditioned test aversion. They are hypersensitive to the sedative and hypothermic effects of systemic alcohol administration. Interestingly, NPY—/— mice show increased consumption and less sensitivity to the hypnotic effects of ethanol, whereas NPY-overexpres-sing mice decrease their consumption of ethanol. This suggests that NPY, which, as previously mentioned, is colocalized with NE in LC cells (see Section II.B), counterbalances NE effect.

2. NE Transporter Knockout Mice

Although such animals have been already obtained and seem to survive at normal Mendelian ratios, data concerning their phenotypes are scarce. There is no doubt that mice lacking the NE transporter will be an interesting tool to use to approach the different roles of NE, especially if one considers that NET is a major target site for most antidepressants and psychostimulants. Recent data indeed indicate that mice lacking NET are hypersensitive to behavioral effects of psychostimulants.

3. a2-Adrenergic Receptor Transgenic Mice

Mice with the deletion of a2A-, a2B-, or a2C-adrenergic receptor genes, as well as point mutation of the a2A gene and a 3-fold overexpression of the a2C gene, have been generated and facilitated the assignment of different functions of a2-adrenergic receptors to specific subtypes because subtype-specific agonists and antagonists were lacking. Studies with these mice indicate that most of the classical physiological functions mediated by the a2-adrenergic receptors, such as hypotension, sedation, analgesia, and hypothermia, are mediated by the a2A subtype. The a2B subtype, the principal mediator of the hypertensive response to a2-agonists, appears to play a role in salt-induced hypertension and may be important in developmental processes.

The a2C subtype appears to be involved in many central nervous system processes, such as the startle reflex, stress response, and locomotion. In particular, a2C-knockout mice show an increased locomotor response to amphetamine, whereas mice overexpres-sing the a2C gene show decreased activity in response to the drug. In an isolation-induced aggression paradigm, a2C knockout mice present decreased attack latency, whereas mice overexpressing the a2C gene increase attack latency. a2C overexpression increases and lack of a2C-adrenergic receptor decreases the immobility of mice in the forced swimming test, i.e., a2C-adrenergic receptor expression appears to promote the development of behavioral despair. a2C-adrenergic receptor is also involved in spatial learning. In the Morris water maze, a2C-adrenoreceptor over-expressing mice develop an ineffective thigmotaxic search pattern characterized by swimming close to the pool walls during both spatial and nonspatial water maze training, whereas their swimming pattern is normal when no cognitive component is required. In the T-maze delayed alternation task, a2C-knockout mice present lower performance than wild-type mice due to a higher number of perseverative errors.

Both a2A and a2C subtypes are important in the presynaptic inhibition of NE release and appear to have distinct regulatory roles. However, simultaneous disruption of both a2A and a2C genes leads to far more severe deficits than the single disruption of either of these genes.

4. a1-Adrenergic Receptor Knockout Mice

Only data on a1B-adrenergic receptor knockout mice were published at that time. The mutants have no apparent phenotype changes except a decreased phe-nylephrine-induced blood pressure response. However, interestingly, experiments have indicated that these knockout mice exhibit locomotor responses to psychostimulants, such as cocaine or amphetamine, that are dramatically decreased when compared to those obtained with wild-type congeners. Because it has been claimed that psychostimulants exert their behavioral effects through an increase in subcortical dopaminergic transmission, such data suggest, as previously mentioned, the presence of coupling between noradrenergic and subcortical dopaminergic systems. In other words, it cannot be excluded that psychostimulants exert some of their behavioral effects through the noradrenergic stimulation of a1B-adre-nergic receptors.

5. /(-Adrenergic Receptor Knockout Mice

Ninety percent of b1-adrenoreceptor (—/—) mice die in utero between days 10.5 and 18.5 of gestation. Surviving mice appear normal and are fertile. b2-adre-noreceptor(—/—) knockout mice are normal and fertile. Physiological responses (blood pressure and heart rate) of the mice to b-adrenergic agonists and antagonists were tested and confirmed their absence of effects. Behavioral experiments have not been reported yet.

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