Biphasic dose‐related responses of the CNV (contingent negative variation) to I.V. nicotine in man.

Abstract

-upon-Tyne NE2 4AB1 The effects of intravenous injections of nicotine bitartrate, given as intermittent 'shots', on the magnitude of the contingent negative variation (CNV) were studied in twelve male volunteers. 2 In one series of experiments in five subjects, a fixed dose of nicotine was used. In three of these subjects nicotine 500 ,ug or 750 ,ug produced a reproducible increase in magnitude of the CNV. In two subjects nictone 750 ug produced a reproducible decrease in magnitude of the CNV. 'The direction and magnitude of the CNV changes could be reproduced by cigarette smoking. 3 In another series of experiments in eight subjects, dose-response relationships for the effect of nicotine on the CNV were measured using a range of doses from 12.5 to 800 ,ug. Individual and mean dose-response curves were found to be biphasic so that whilst smaller doses produced an increase of CNV magnitude (stimulant effect), larger doses produced a decrease of the CNV (depressant effect). 4 The results are discussed in relation to the possible mechanism of action on the brain of nicotine as obtained by inhaling cigarette smokers.

The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man.

“…As shown in Figures 3 and 4, CNV magnitude was increased after 2.5 mg All-IC in introverted subjects and in those with high N scores, and after 10 mg in extraverted subjects and those with low N scores. Similar increases in CNV magnitude have been shown to occur after central stimulant drugs such as caffeine, methamphetamine, pemoline, low doses of nicotine and LSD (Ashton et al, 1974(Ashton et al, , 1980Kopell et al, 1974;Walter, 1964). Conversely, CNV magnitude was decreased after 2.5 mg A9THC in extraverted subjects and in those with low N scores, and after 10 mg in introverted subjects and in those with high N scores.…”

“…The depressant effect of A9THC on CNV magnitude could be due to dose and personality-related actions in the opposite direction on the same brain system or to separate depressant effects on different systems. Biphasic dose-related Braden, Stillman & Wyatt (1974), and the direction of CNV response to nicotine is influenced by both dose and personality (Ashton et al, 1974(Ashton et al, , 1980Eysenck & O'Connor, 1979). Skin conductance reactivity also showed both stimulant and depressant effects, and these were dependent on the starting state.…”

“…Conversely, CNV magnitude was decreased after 2.5 mg A9THC in extraverted subjects and in those with low N scores, and after 10 mg in introverted subjects and in those with high N scores. Such decreases in CNV magnitude occur after central depressant drugs such as ethanol, benzodiazepines, barbiturates, chlorpromazine and high doses of nicotine (Ashton et al, 1974(Ashton et al, , 1980Kopell, Tinklenberg & Hollister, 1972;Kopell et al, 1974;Halblitz & Borda, 1973;Tecce, Cole & Savignano-Bowman, 1975). The stimulant effect of A9THC on CNV magnitude may possibly reflect an increase in sensory traffic into the reticular activating system, which is known to be involved in the genesis of the CNV (Rebert, 1972).…”

Acute Nicotine-Induced Tachyphylaxis Is Differentially Manifest in the Limbic System

“…Reports that nicotine decreased cerebral blood flow in the hippocampus while increasing it in the thalamus and visual cortex in human smokers (Domino et al, 2000(Domino et al, , 2004Zubieta et al, 2005) are also in accord with these data. In addition, the biphasic nicotine effects observed in this study are consistent with earlier electroencephalographic data, which demonstrated that moderate doses of nicotine increased (ie, stimulant effect), while high doses decreased cortical activation (ie, depressant effect) in human subjects (Ashton et al, 1974(Ashton et al, , 1980 and preclinical studies (Armitage et al, 1969;Guha and Pradhan, 1976). Admittedly, the neuroanatomical sources of these electroencephalographic observations remain to be elucidated, although the involvement of the limbic system was implicated (Ashton et al, 1980).…”

Bimodal Concentration-Response of Nicotine Involves the Nicotinic Acetylcholine Receptor, Transient Receptor Potential Vanilloid Type 1, and Transient Receptor Potential Ankyrin 1 Channels in Mouse Trachea and Sensory Neurons

“…Effects that decrease or revert into the contrary at supramaximal concentration or dosage are a classic hallmark of the nicotine concentration/doseresponse relationship and have been demonstrated in many animal and human experimental models (Ashton et al, 1980;Nakamura et al, 1986;Clarke 1990;Perkins et al, 1994;Krebs et al, 1994;Rowell and Li, 1997;Picciotto 2003;Matta et al, 2007). The phenomenon has unanimously been attributed to the well-known fast and complete homologous desensitization/ tachyphylaxis of the nAChR that is particularly evident at high agonist concentrations (Jinks and Carstens 1999;Liu and Simon 1996;Dessirier et al, 2000;Rau et al, 2005).…”