Effects of nicotine on cortical high voltage spindles in rats

doi:10.1016/0006-8993(93)90133-8

Brain Research

Volume 625, Issue 1, 15 October 1993, Pages 23-28

https://doi.org/10.1016/0006-8993(93)90133-8 Get rights and content

Abstract

Cholinergic systems have been shown to modulate 6–10 Hz immobility-related cortical spike wave discharges (high voltage spindles - HVS) in rats. This study reports that activation of central nicotinic receptors inhibits HVS identified from cortical EEG recordings. Nicotine (0.19–1.9 μmol/kg i.p.) significantly reduced the summed duration of HVS bursts during 20 min of waking immobility. The nicotinic antagonist mecamylamine (5.0 μmol/kg i.p.) blocked the effect of nicotine (0.62 μmol/kg i.p.) without itself significantly affecting HVS. At higher doses, mecamylamine (15.0 and 25.0 μmol/kg i.p.) increased HVS activity. Dimethylphenylpiperazinium (0.62–6.2 μmol/kg i.p.), a nicotinic agonist which does not cross the blood-brrrier, did not affect HVS, consistent with the idea that the effect of nicotine on HVS is due to an action in the central nervous system. Cotinine, the major metabolite of nicotine, did not affect HVS at doses similar to or higher than those tested for nicotine. Cotinine also did not block the effect of nicotine, indicating that this metabolite does not interfere with the modulatory effect of nicotine on HVS. These results suggest a role for nicotinic regulation of the neuronal substrates involved in the generation of HVS.

Reference (26)

ChenS. et al.
Nerve growth factor receptor-containing cholinergic neurons of the basal forebrain project to the thalamic reticular nucleus in the rat
Brain Res.
(1993)
ClarkeP.B.S.
Dopaminergic mechanisms in the locomotor stimulant effects of nicotine
Biochem. Pharmacol.
(1990)
CoenenA.M.L. et al.
Genetic models of absence epilepsy, with emphasis on the WAG/Rij strain of rats
Epilepsy Res.
(1992)
DeckerM.W. et al.
Effects of nicotine on spatial memory deficits in rats with septal lesions
Brain Res.
(1992)
LiuZ. et al.
Evidence for a critical role of GABAergic transmission within the thalamus in the genesis and control of absence seizures in the rat
Brain Res.
(1991)
LiuZ. et al.
Involvement of intrathalamic GABA_B neurotransmission in the control of absence seizures in the rat
Neuroscience
(1992)
PeetersB.W.M.M. et al.
Effects of GABA-ergic agents on non-convulsive epilepsy, EEG and behavior, in the WAG/Rij inbred strain of rats
Life Sci.
(1989)
PlowchalkD.R. et al.
A physiologically based pharmacokenetic model for nicotine disposition in the Sprague-Dawley rat
Toxicol. Appl. Pharmacol.
(1992)
RiekkinenP. et al.
EEG changes induced by acute and chronic quisqualic or ibotenic acid nucleus basalis lesions are stabilized by tacridine
Brain Res.
(1991)
RiekkinenP. et al.
Atipamezole, an alphα-2-antagonist, stabilizes age-related high-voltage spindles and passive avoidance defects
Pharmacol. Biochem. Behav.
(1992)

RyanL.J.

Cholinergic regulation of neocortical spindling in DBA/2 mice

Exp. Neurol.

(1985)

RyanL.J. et al.

Genetically determined spontaneous pentylenetrazol-induced brief spindle episodes in mice

Exp. Neurol.

(1979)

SteriadeM. et al.

Cholinergic and non-cholinergic neurons of cat basal forebrain project to reticular and mediodorsal thalamic nuclei

Brain Res.

(1987)

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Previous studies have reported that HVSs were enhanced in striatum, globus pallidus (GP), substantia nigra recitulata (SNr), subthalamic nucleus (STN) and motor cortex after dopaminergic degeneration of the nigrostriatal pathway [35,40–45]. Moreover, it has been suggested that HVSs in cortex may be a brain oscillatory activity associated with memory impairment in aged rats [46]. So, the abnormal increased HVSs in the hippocampus may contribute to spatial cognitive deficits in 6-OHDA lesioned rats.
Cognitive decline is a common clinical symptom in Parkinson’s disease (PD) patients. Fluoxetine (FLU), a selective serotonin reuptake inhibitor, can improve cognitive deficits in demented patients. The present study investigated the effects of FLU on spatial learning and memory cognitions in 6-OHDA lesioned rats. Morris water maze (MWM) test showed that FLU significantly improved spatial cognitive deficits in rats with unilateral 6-OHDA injection at 4 and 7 weeks after 6-OHDA injection. Electrophysiological recordings demonstrated that the number and duration of high voltage spindles(HVSs)in the ipsilateral hippocampus of 6-OHDA lesioned rats were decreased by the administration of FLU. Furthermore, the spectral analysis of per frequency revealed increases in δ and θ rhythm power and decreases in α, β and γ rhythm power in the ipsilateral hippocampus of 6-OHDA lesioned rats in contrast to the saline-treated rats. Acute FLU treatment can reduce δ and θ rhythm power, and enhance α, β and γ rhythm power in the ipsilateral hippocampus of 6-OHDA lesioned rats. These findings suggest that FLU improves impaired cognition by tuning oscillatory activities in the hippocampus of 6-OHDA lesioned rats.
Cotinine impacts sensory processing in DBA/2 mice through changes in the conditioning amplitude
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Citation Excerpt :
Although nicotine and cotinine share structural similarities, their pharmacological properties, both in vitro and in vivo, are different. It has been proposed that cotinine, like nicotine, binds to, and activates nicotinic acetylcholine receptors (Dwoskin et al., 1999; Vainio and Tuominen, 2011), whereas other reports indicate no pharmacological action of cotinine (Linville et al., 1993; Radek, 1993). Cotinine has a much longer half-life (15–19 h) compared to the half-life of nicotine (2–3 h) (Davis et al., 1999; Crooks and Dwoskin, 1997) and has been proposed to be safe at doses up to 10 times greater than that attained during cigarette smoking (Hatsukami et al., 1997).
Cotinine, a major metabolite of nicotine, has produced improved learning and memory in rodents and non-human primates and corrects apomorphine-induced loss of pre-pulse startle inhibition in rats. The present study assessed cotinine, both acute and chronic (7-day), in the sensory inhibition paradigm in DBA/2 mice. These mice spontaneously show a deficit in hippocampal sensory inhibition, as assessed by the P20–N40 EEG paradigm, which models the deficit observed in schizophrenia patients. Anesthetized DBA/2 mice were recorded in the CA3 region of hippocampus for inhibition of paired, identical auditory stimuli, then administered cotinine (0.33, 0.1, 0.33, 1.0 or 3.3 mg/kg SQ) and recorded for 90 min. At doses of 0.1, 0.33 and 1.0 mg/kg, there were significant increases in conditioning amplitude, with no changes in test amplitude or TC ratio. Blockade of α4β2 nicotinic receptors with central administration of DHΒE blocked the increase in the conditioning amplitude induced by the 1.0 mg/kg dose of cotinine, as did blockade of α7 nicotinic receptors with α-bungarotoxin. Daily injections of 0.33, 1.0 or 3.3 mg/kg for 7 days produced similar increases in the conditioning amplitude on the 7th day, but only at the 0.33 and 3.3 mg/kg doses. Determination of the “carry over” effect of the previous 6 daily doses of cotinine, prior to the 7th dose, showed that there was a significant increase in the conditioning amplitude as compared to the baseline data for mice receiving the equivalent acute dose. There were no significant effects on test amplitude or TC ratio for any of the chronic doses. These data suggest that cotinine modulates the conditioning amplitude in the sensory inhibition paradigm through the α4β2 nicotinic receptor and possibly also through the α7 nicotinic receptor, as well. However the data do not suggest that cotinine is a potential therapeutic for the treatment of sensory inhibition deficits in schizophrenia.
The potential role of cotinine in the cognitive and neuroprotective actions of nicotine
2003, Life Sciences
Cotinine is a primary metabolite of nicotine that has been suggested in many studies in animals and in humans to exert measurable effects on aspects of on-going behavior or on cognitive function. Much of the interest in cotinine derives from its long pharmacological half-life (15–19 hours) relative to nicotine (2–3 hours). Despite decades of study focusing on nicotine as the predominant behaviorally active component of tobacco, there continue to be aspects of the pharmacology of the drug that have yet to be explained. For example, nicotine can evoke a protracted behavioral response, i.e., in great excess of the presence of the drug in the plasma. Also, there is often a striking differential between the potency for nicotine-induced behavioral responses in humans and animals, and its potency as a cholinergic agonist, neurochemically. One possibility that may explain one or more of these properties of nicotine is the presence of a long-lived bioactive metabolite or breakdown product of nicotine such as cotinine. Preliminary data in support of this hypothesis are consistent with the ability of cotinine to improve performance accuracy on delayed matching task by macaque monkeys, and in reversing apomorphine-induced deficits in prepulse inhibition of acoustic startle in rats. The drug also was shown to be as potent as nicotine in the ability to act as a cytoprotective agent in cells that express a neuronal cholinergic phenotype. This new appreciation for the role of cotinine in nicotine's actions, and as a pharmacological agent in its own right, particularly in aspects of cognitive function and for neuroprotection, ultimately may be applied towards the treatment of Alzheimer's disease and related disorders, and for various psychiatric syndromes.
The effects of cholinergic drugs on rat neocortical high-voltage spindles in ketanserin-treated rats
1996, European Journal of Pharmacology
To investigate the roles of the cholinergic system and 5-HT₂ receptors in the modulation of thalamocortical oscillations, we studied the effects of systemic (s.c.) administration of anticholinesterases (physostigmine, tetrahydroaminoacridine) and muscarinic acetylcholine receptor agonists (pilocarpine, oxotremorine) on spontaneous thalamically generated rhythmic neocortical high-voltage spindles in adult rats pretreated with either saline or ketanserin, a 5-HT₂ receptor antagonist. Ketanserin at 20.0 mg/kg increased the number of high-voltage spindles. In saline-treated rats, tetrahydroaminoacridine 3.0 and 9.0 mg/kg was able to decrease high-voltage spindles, whereas in ketanserin 20.0 mg/kg-treated rats only the highest dose of tetrahydroaminoacridine (9.0 mg/kg) decreased high-voltage spindles. Both doses of physostigmine, 0.12 and 0.36 mg/kg, decreased high-voltage spindles in both saline and ketanserin 20.0 mg/kg-treated rats. Lower doses of tetrahydroaminoacridine (1.0 mg/kg) and physostigmine (0.06 mg/kg) were ineffective in both saline- and ketanserin 20.0 mg/kg-treated rats. Pilocarpine 3.0 mg/kg and oxotremorine 0.1 and 0.9 mg/kg decreased high-voltage spindles in saline-treated rats. However, in rats treated with ketanserin 20.0 mg/kg, only the lower doses of pilocarpine (0.3 and 1.0 mg/kg) and oxotremorine (0.03 mg/kg) were able to decrease the high-voltage spindles. The results suggest that activation of the cholinergic system and activation of 5-HT₂ receptors have additive effects in the suppression of thalamocortical oscillations and related neocortical high-voltage spindles in rats, thus maintaining effective information processing in thalamocortical networks.
Suppression of neocortical high-voltage spindles by nicotinic acetylcholine and 5-HT<inf>2</inf> receptor stimulation
1996, European Journal of Pharmacology
To investigate the roles of the nicotinic acetylcholine receptor and the serotonin (5-hydroxytryptamine; 5-HT) subtype 2 receptor in the modulation of rat thalamocortical oscillations, the effects of systemic (s.c.) administration of nicotine, a nicotinic acetylcholine receptor agonist, and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT₂ receptor agonist, on neocortical high-voltage spindle activity occurring during quiet waking-immobility behavior in aged (28 months of age) and adult (7 months of age) rats were studied. Nicotine 0.1 and 0.3 mg/kg alleviated the age-related increase of neocortical high-voltage spindles, whereas in adult rats only nicotine 0.3 mg/kg was effective. DOI 0.3, 1.0 and 2.0 mg/kg suppressed high-voltage spindles in both aged and adult rats. In aged rats, a combination of subthreshold doses of nicotine (0.03 mg/kg) and DOI (0.1 mg/kg) decreased neocortical high-voltage spindles, whereas in adult rats two different subthreshold dose combinations (nicotine 0.03 or 0.1 mg/kg + DOI 0.1 mg/kg) had no effect. p-Chlorophenylalanine (400 mg/kg/day i.p. for 3 consecutive days) treatment decreased brain serotonin concentration (> 80% reduction), but did not affect high-voltage spindles. However, in both aged and adult rats, p-chlorophenylalanine treatment blocked the decrease in high-voltage spindle activity produced by DOI 0.3 mg/kg, though not the decrease produced by higher doses of DOI (1.0 and 2.0 mg/kg). It is important that, in adult rats, p-chlorophenylalanine treatment was able to abolish the decrease in high-voltage spindle activity seen after a relatively high dose of nicotine (0.3 mg/kg). The results suggest that nicotinic acetylcholine and 5-HT₂ receptors may act in concert to suppress neocortical high-voltage spindling in rats, and that intact brain serotonergic systems may be important for some of the therapeutic effects of nicotine.
Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions
2021, Frontiers in Behavioral Neuroscience

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Effects of nicotine on cortical high voltage spindles in rats

Abstract

Brain Res.

Biochem. Pharmacol.

Epilepsy Res.

Brain Res.

Brain Res.

Neuroscience

Life Sci.

Toxicol. Appl. Pharmacol.

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Exp. Neurol.

Exp. Neurol.

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