Effects of Chronic Nicotine Treatment on the Accumulation of [³H]Tetraphenylphosphonium by Cerebral Cortical Synaptosomes

Abstract

Chronic exposure of rats to nicotine increases the number of [3H]nicotine binding sites in the brain; however, it is not clear whether nicotinic cholinergic receptor function is altered as well. In this study, we have used [3H]tetraphenylphosphonium as a probe of synaptosomal membrane potential to investigate whether exposure to nicotine in vivo alters the ability of cerebral cortical synaptosomes to maintain a potential difference and to depolarize in response to in vitro nicotine. Treatment of rats for 14 days with 0.475 mg of nicotine baselday via subcutaneously implanted minipumps resulted in a decrease in the synaptosoma1 accumulation of [3H]tetraphenylphosphonium in physiological buffer, corresponding to a decrease in estimated membrane potential from -55 mV to -50 mV. The onset of the decrease in membrane potential occurred after 7 days of in vivo nicotine treatment and was significantly correlated with an increase in [3H]nicotine binding to cerebral cortical synaptosomal (P2) membranes. Nicotine, at in vitro concentrations of 3-1,000 pM, decreased [3H]tetraphenylphosphonium accumulation in cerebral cortical synaptosomes from control animals. When compared to accumulation in buffer alone, in vitro nicotine and other nicotinic agonists did not significantly decrease [3H]tetraphenylphosphonium accumulation in cerebral cortical synaptosomes prepared from rats treated with nicotine in vivo. These studies provide evidence that chronic treatment with nicotine results in an average lower membrane potential in cerebral cortical synaptosomes and in functional down-regulation of the depolarization response to nicotinic cholinergic receptor stimulation.

Upregulation of [3H]methyllycaconitine binding sites following continuous infusion of nicotine, without changes of α7 or α6 subunit mRNA: an autoradiography andin situhybridization study in rat brain

“…We found an extensive upregulation of [ 3 H]nicotine binding sites in the brain of nicotine‐treated rats, in agreement with many authors (Marks et al ., 1986; Romanelli et al ., 1988; Nordberg et al ., 1989; Collins et al ., 1990; Zhang et al ., 1994; Wall et al ., 2000). Only a few studies, however, reported the effect on [ 3 H]nicotine binding sites of constant infusion of nicotine, and at doses similar to those used in the present work (Morrow et al ., 1985; Fung & Lau, 1988; Hillard & Pounds, 1993; Sanderson et al ., 1993). Our data are consistent with those of Morrow et al .…”

“…Only a few studies, however, reported the effect on [ 3 H]nicotine binding sites of constant infusion of nicotine, and at doses similar to those used in the present work (Morrow et al ., 1985; Fung & Lau, 1988; Hillard & Pounds, 1993; Sanderson et al ., 1993). Our data are consistent with those of Morrow et al . (1985), Hillard & Pounds (1993) and Sanderson et al .…”

Dose‐Response Relationship for Nicotine‐Induced Up‐Regulation of Rat Brain Nicotinic Receptors

“…In contrast to the studies using periodic injections, the infusion of 1.5-4 mg/kg/day nicotine has resulted in less consistent increases in nAChR density, particularly in the striatum. Fung and Lau (1988), Drasdo and Wonnacott (1991), and Sanderson et al (1993) have reported little or no effect on striatal nAChR density from con-stant nicotine infusion, although others have found that nAChR density in the hippocampus and cortex appears to be increased by infusion of these doses (Morrow et al, 1985;Hillard and Pounds, 1993;Sanderson et al, 1993).…”

The nicotinic acetylcholine receptor: smoking and alzheimer's disease revisited

“…Nevertheless, regular use of tobacco products creates chronic exposure to nicotine. Research from several laboratories demonstrates that chronic nicotine exposure creates a loss of nicotine-sensitive nAChR functional activity in the brain that can last for days in vivo (117), (118), (59), (60), (44), (42), (75), (76), (38). Through a process call “persistent inactivation,” the functions of nAChRs are lost due to chronic nicotine exposure in a time- and dose-dependent manner that is specific for each subtype.…”

“…Many small trials have been conducted which demonstrate that subcutaneous and intravenous administration of nicotine has mild benefits in cognition in AD subjects, especially in areas of short-term memory, attention, and information processing (82), (90), (112), (48). Nicotine patches have also been found to have positive effects on attention in AD (107), (42), (105) (47). Large trials of ABT- 418, a nicotinic agonist have been undertaken (143).…”