Allosteric regulation of neuronal acetylcholine nicotinic receptor: implication for short-term plasticity, brain pathology and neuropharmacology

• Forschungsstelle: EU FRP
• Projektnummer: 96.0295-2
• Projekttitel Englisch: Allosteric regulation of neuronal acetylcholine nicotinic receptor: implication for short-term plasticity, brain pathology and neuropharmacology

Schlüsselwörter (Englisch)

Structure; function; neuronal; nicotinic; acetylcholine; receptor; regulation; plasticity; neuropharmacology

Alternative Projektnummern (Englisch)

EU project number: BIO4CT96-0236

Forschungsprogramme (Englisch)

EU-programme: 4. Frame Research Programme - 4.1 Biotechnology

Kurzbeschreibung (Englisch)

See abstract

Weitere Hinweise und Angaben (Englisch)

Full name of research-institution/enterprise:
Glaxo Wellcome Experimental Research SA

Partner und Internationale Organisationen (Englisch)

Dept Biotechnologie, Institut Pasteur, Parsi, (F); LOCT, Univ München, (D); Dept. Physiologie, Univ Genève, (CH); Dept Bioscience, Karolinksa Inst., Stockholm, (S)

Abstract (Englisch)

Determination of the neuropharmacological substrates of nicotine actions and development of therapeutic agents directed toward neuronal targets of nicotine dependence are critical goals for international public health. Neuronal nicotinic acetylcholine receptors (nAChrs) are a heterogeneous family of pentameric ligand-gated ion channels composed of a and b subunits (a2-a7 and b2-b4) which combine to form functional receptor subtypes with differing pharmacology and distribution throughout the central nervous and which mediate the pharmacological properties of nicotine. Determination of the subunit composition of nAChrs involved in nicotine reinforcement is critical to the understanding of nicotine's role in dependence. Acquisition and maintenance of self-administration involves multiple brain systems and nAChrs of differing subunit composition are distributed throughout the neuronal circuits that underlie this complex behavior. Methods which aim to determine the contributions of a particular nAChr subunit to a selected nicotine action must distinguish the effect of a mutation on the target action (nicotine reinforcement) from its effects on separate but related actions (e.g. learning, memory, motor coordination, etc.), to the extent that these actions are empirically separable. Transgenic mice lacking genes encoding specific nAChr subunits were tested in a mouse model of intravenous drug self-administration. Because nAChr mutant mice lack responsiveness to nicotine, a substitution procedure was employed. Mice were first trained to self-administer cocaine to stability. Cocaine was then substituted with nicotine to determine if nicotine could maintain self-administration in wild type (WT) and mutant (Mut) mice. A separate group of WT mice received saline substituted for cocaine to demonstrate extinction of self-administration in a relevant control group. b2 Mut and WT mice acquired cocaine self-administration in approximately the same number of sessions and earned approximately the same number of cocaine injections per session. WT mice maintained active nose-poke responding during five days of nicotine substitution. However, b2 Mut mice showed a significant decrease in active nose-poke responses across the same five-day period, a significant loss of discrimination between active and inactive nose-pokes, and responding similar to that in WT mice receiving saline substituted for cocaine. The role of b2-containing nAChrs appears to be specific to nicotine reinforcement because b2 Mut mice acquired a cocaine-reinforced discriminated operant response. This conclusion is supported by evidence that natural reinforcers (food) maintained normal lever-press responding in b2 Mut mice. Knowledge of the particular subunit composition of nAChrs involved in specific behavioral functions or pathological conditions may lead to the development or discovery of highly selective therapeutic compounds with profiles explicitly targeted to disorders involving different types of nAChrs or nAChr dysfunction.

Datenbankreferenzen (Englisch)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 96.0295-2