Benzodiazepines preferentially affect mesolimbic dopamine turnover in rats. 1992

J W van der Laan, and L Eigeman, and C Jansen van 't Land
Laboratory for Medicines and Medical Devices, National Institute for Public Health and Environmental Protection, Bilthoven, The Netherlands.

Withdrawal of benzodiazepines in man may induce hallucinatory symptoms and can evoke delusional depressions, which can be treated with dopamine-antagonistic drugs. Withdrawal of benzodiazepines in rats induces a strong hyperactivity during daytime, leaving the nighttime activity relatively undisturbed. This hyperactivity may be related to an enhanced dopaminergic activity in the mesolimbic area, especially in the nucleus accumbens. Mesolimbic dopaminergic activity may be specifically involved in the development of benzodiazepine withdrawal. Acute administration of benzodiazepines in otherwise non-treated rats, has been described not to affect the dopamine-turnover in the nucleus accumbens, measured by synthesis inhibition. However, activation by administration of haloperidol (feedback activation) can be suppressed by benzodiazepines effectively. Five different benzodiazepines viz. desmethyldiazepam (DMD), lorazepam (LRZ), brotizolam (BTZ), triazolam (TRZ) and flunitrazepam (FNZ) have been compared with respect to their acute effects. Using a 3-fold increase in dopamine turnover (determined by measuring the DOPAC-concentration), benzodiazepines were capable to reduce this increase maximally for 70-80% in the nucleus accumbens. The results point to a selective effect of benzodiazepines in the nucleus accumbens. The increase induced by haloperidol in the corpus striatum was found to be much less sensitive to benzodiazepines. In contrast to the other compounds lorazepam appeared to have no effect on haloperidol-induced increase in DOPAC concentration. Flunitrazepam and brotizolam did affect not only the haloperidol-induced DOPAC increase but also the basal DOPAC concentrations. Linear dose-response curves could not be obtained for the compounds, but minimal effective doses could be assessed. Flunitrazepam and triazolam appeared to be the most active compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

UI MeSH Term Description Entries
D008032 Limbic System A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the AMYGDALA; EPITHALAMUS; GYRUS CINGULI; hippocampal formation (see HIPPOCAMPUS); HYPOTHALAMUS; PARAHIPPOCAMPAL GYRUS; SEPTAL NUCLEI; anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)). Limbic Systems,System, Limbic,Systems, Limbic
D008297 Male Males
D009714 Nucleus Accumbens Collection of pleomorphic cells in the caudal part of the anterior horn of the LATERAL VENTRICLE, in the region of the OLFACTORY TUBERCLE, lying between the head of the CAUDATE NUCLEUS and the ANTERIOR PERFORATED SUBSTANCE. It is part of the so-called VENTRAL STRIATUM, a composite structure considered part of the BASAL GANGLIA. Accumbens Nucleus,Nucleus Accumbens Septi,Accumbens Septi, Nucleus,Accumbens Septus, Nucleus,Accumbens, Nucleus,Nucleus Accumbens Septus,Nucleus, Accumbens,Septi, Nucleus Accumbens,Septus, Nucleus Accumbens
D011919 Rats, Inbred Strains Genetically identical individuals developed from brother and sister matings which have been carried out for twenty or more generations or by parent x offspring matings carried out with certain restrictions. This also includes animals with a long history of closed colony breeding. August Rats,Inbred Rat Strains,Inbred Strain of Rat,Inbred Strain of Rats,Inbred Strains of Rats,Rat, Inbred Strain,August Rat,Inbred Rat Strain,Inbred Strain Rat,Inbred Strain Rats,Inbred Strains Rat,Inbred Strains Rats,Rat Inbred Strain,Rat Inbred Strains,Rat Strain, Inbred,Rat Strains, Inbred,Rat, August,Rat, Inbred Strains,Rats Inbred Strain,Rats Inbred Strains,Rats, August,Rats, Inbred Strain,Strain Rat, Inbred,Strain Rats, Inbred,Strain, Inbred Rat,Strains, Inbred Rat
D003342 Corpus Striatum Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE. Lenticular Nucleus,Lentiform Nucleus,Lentiform Nuclei,Nucleus Lentiformis,Lentiformis, Nucleus,Nuclei, Lentiform,Nucleus, Lenticular,Nucleus, Lentiform,Striatum, Corpus
D004298 Dopamine One of the catecholamine NEUROTRANSMITTERS in the brain. It is derived from TYROSINE and is the precursor to NOREPINEPHRINE and EPINEPHRINE. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. A family of receptors (RECEPTORS, DOPAMINE) mediate its action. Hydroxytyramine,3,4-Dihydroxyphenethylamine,4-(2-Aminoethyl)-1,2-benzenediol,Dopamine Hydrochloride,Intropin,3,4 Dihydroxyphenethylamine,Hydrochloride, Dopamine
D004305 Dose-Response Relationship, Drug The relationship between the dose of an administered drug and the response of the organism to the drug. Dose Response Relationship, Drug,Dose-Response Relationships, Drug,Drug Dose-Response Relationship,Drug Dose-Response Relationships,Relationship, Drug Dose-Response,Relationships, Drug Dose-Response
D005246 Feedback A mechanism of communication within a system in that the input signal generates an output response which returns to influence the continued activity or productivity of that system. Feedbacks
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D001569 Benzodiazepines A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring. Benzodiazepine,Benzodiazepine Compounds

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