Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Reexamination Certificate
1998-10-15
2001-06-26
Clark, Deborah J. R. (Department: 1633)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
C800S003000, C800S008000, C800S009000, C800S021000, C800S025000, C435S320100, C435S325000, C435S455000, C536S023500
Reexamination Certificate
active
06252131
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to transgenic mammals characterized by 5-HT
3
receptor over-expression in the central nervous system (CNS). In particular, the invention relates to such transgenic mammals having a significantly reduced desire for alcohol as compared to mice of the corresponding non-transgenic line.
1. Field of the Invention
5-HT
3
receptors belong to a group of receptor subtypes for 5-hydroxytryptophan (serotonin). 5-HT
3
receptors are primarily located presynaptically, and are known to modulate the release of a number of neurotransmitters, including GABA, acetylcholine, and dopamine. The receptors are ion-channel-coupled receptors, the only known receptors of this type in the serotonin family.
It is not yet clear how neurotransmitters such as serotonin regulate neuronal cell function. However, 5-HT
3
receptors are believed to play a role in neurochemical reward pathways associated with the phenomena of drug abuse and other clinical conditions by modulating dopamine release in the mesolimbic pathway.
2. Discussion of Related Art
Many drugs of abuse, including alcohol, result in the release of dopamine in the nucleus accumbens of the brain, a region associated with motivation and reward. 5-HT
3
receptor antagonists have been shown to cause a dose-dependent decrease in alcohol-stimulated dopamine release in the nucleus accumbens (
Eur. J. Pharmacol.
87: 287-289, 1990;
Alcohol
9: 17-22), and it appears that certain 5-HT
3
agonists can stimulate dopamine release in the nucleus accumbens (
Brain Res.
513: 156-160, 1990). Nicotine and opiates such as morphine also release dopamine in the nucleus accumbens, and this release can be blocked by 5-HT
3
receptor antagonists (
Eur. J. Pharmacol.
164: 515-519, 1989).
Animal studies have demonstrated that 5-HT
3
receptor antagonists can decrease alcohol self-administration (
Alcohol
26: 107-110, 1991; and others). In human studies, 5-HT
3
receptor antagonists decreased pleasurable effects of alcohol and increased abstinence in mild alcoholics (
Psychopharmacol.
112: 142-144, 1993;
Alcohol Clin. Exp Res.
18: 879-855, 1994). Also, 5-HT
3
antagonists enhanced the subjective feeling of intoxication produced by ethanol in at least one study (
Biol. Psychiatry
40: 514-521, 1996).
5-HT
3
antagonists have been proposed for treatment of drug withdrawal syndromes, chemotherapy and drug-induced nausea and emesis, and as antimigraine, anxiolytic, and antipsychotic agents (reported in U.S. Pat. No. 5,057,519 to Suberg, et al.).
Studies of the 5-HT
3
receptor have, however, been hampered by the low level of their normal expression in the CNS. 5-HT
3
receptors are expressed throughout the forebrain in extremely low amounts. The highest amounts of 5-HT
3
receptors appear to be present in the cingulate cortex, entorhinal cortex, hippocampus, and amygdala; the last has also been associated with drug abuse, but 5-HT
3
receptors in this brain region have been less well characterized than those in the nucleus accumbens, where 5-HT
3
receptors are particularly scarce.
SUMMARY OF THE DISCLOSURE
The inventions comprise transgenic mammals carrying an exogenous 5-HT
3
transgene in their genome for over-expression in the CNS, particularly the forebrain. The inventions further comprise mammalian embryos carrying the 5-HT
3
transgene capable of developing into viable transgenic animals whose progeny carry the transgene after breeding forward by sexual reproduction. The inventions additionally include DNA constructs comprising selected promoter+intron +5-HT
3
CDNA or DNA segments cloned into plasmids for ultimate insertion into the genome of a mammal.
The transgenic mammals of the invention are characterized by a high density of functional 5-HT
3
receptors in the CNS of the mammals. They also exhibit a decreased desire for alcohol as compared to genetically similar non-transgenic mammals and decreased aggressiveness.
REFERENCES:
patent: 5057519 (1991-10-01), Suberg
Eur. J. Pharmacol. 187:287-289, 1990.
Alcohol 9: 17-22.
Brain. Res. 513: 156-160, 1990.
Eur. J. Pharmacol. 164: 515-519, 1989.
Alcohol 26: 107-110, 1991.
Psychopharmacol. 112: 142-144, 1993.
Psychopharmacol. 112: 503-510, 1993.
Alcohol Clinic. Exp. Res. 18: 879-855, 1994.
Biol. Psch. 40: 514-421, 1996.
Maricq et al Science 254: 432-437, 1991.
Pharmacol. Biochem. Behavior 51; 835-842-1995.
Engel, et al, Psychopharmacology, 1998.
Wall RJ Theriogenology 45:57-68, 1996.*
Kappel et al. Current Opinion in Biotechnology 3:358-353 1992.*
Robert et al, Biol. Physchiatry 40:514-521, 1996.
Allan Andrea M.
Engel Sharon R.
Lyons Clifford R.
Clark Deborah J. R.
Kaushal Sumesh
Ownbey Nancy E.
Slusher Stephen A.
University of New Mexico
LandOfFree
Transgenic mammal having 5-HT3 transgene overexpression in... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Transgenic mammal having 5-HT3 transgene overexpression in..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transgenic mammal having 5-HT3 transgene overexpression in... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2531314