Cerebral effects of nicotine during cognition in smokers and non-smokers

 For the smoker, nicotine has a positive effect on attention, cognition and mood. Conversely, nicotine abstinence is characterized by uncomfortable psychological effects such as impaired attention, but also irritability. We postulated that nicotine exerts an effect on cerebral areas important for attention and mood. Regional cerebral blood flow (rCBF), as an index for cerebral activity, was measured in both smokers and non-smokers. They were scanned during performance of a psychometric task with and without IV infusion of nicotine (1-methyl-2-[3-pyridyl1] pyrrolidine). Nicotine induced rCBF decreases in the anterior cingulate cortex and the cerebellum, and concomitant increases in the occipital cortex. The changes were similar in nature and magnitude in smokers and non-smokers. Thus, specific changes were induced in areas pertaining to the anterior attention system and to higher order visual cortex. We conclude that these effects on cerebral activity provide insights into the desired positive effects of nicotine on cognition as well as the negative effects experienced during nicotine abstinence. Received: 9 June 1997/Final version: 8 September 1997     

Behavioral effects of nicotine, amphetamine and cocaine under a fixed-interval schedule of food reinforcement in rats chronically exposed to caffeine

 Epidemiological surveys demonstrate that caffeine, the main psychoactive ingredient of coffee, is a positive correlate in drug abuse. To characterize the behavioral nature of caffeine interactions with other psychomotor stimulants, we examined the effects of chronic caffeine exposure on the behavioral responses to nicotine, amphetamine, cocaine, the selective D₁ agonist SKF-82958 and the selective D₂ receptor agonist NPA, in rats responding under a fixed interval (FI) schedule of food reinforcement. Following stabilization of rates and temporal patterns of responding (mathematically expressed as quarter-life values, QL), twenty-one Sprague-Dawley rats responding under a 5-min FI schedule of food reinforcement were divided into two groups; one (twelve rats) maintained on tap water (control) and the other (nine rats) on caffeine (3 mg/ml added to the drinking water). Following the substitution of caffeine solution for tap water, behavior was temporarily disrupted as evidenced by decreases in responding and QL values which reached a maximum after 72 h (rate 60% and QL 30% below baseline levels). Rats developed complete tolerance to these effects of caffeine over 5 days of caffeine exposure. After response rate and QL values stabilized, effects of drugs were evaluated. Nicotine (0.01–1.0 mg/kg; SC), amphetamine (0.1–5.6; IP), and cocaine (1.0–17; IP) each produced biphasic dose-dependent changes in response rate with maximum increases in response rate following intermediate doses and decreases in response rates following higher doses. The increase in rates of responding produced by amphetamine or cocaine (but not nicotine) were greater (P<0.05) in caffeine-drinking than in water-drinking rats. Both SKF-82958 (0.001–0.3 mg/kg; IP) and NPA (0.0001–0.1; IP) produced only dose-dependent decreases in rates of responding. Caffeine-drinking rats were less sensitive to the rate-depressant effects of SKF-82958 (P<0.05) than water-drinking rats. However, similar changes (P>0.05) were produced by NPA in both groups. Except for amphetamine, the remaining drugs produced similar (P>0.05) dose-dependent decreases in QL values in water- and caffeine-drinking rats. Amphetamine produced smaller decreases in QL values in caffeine-drinking rats than in water-drinking rats (P<0.05). Chronic exposure to caffeine produced complete insurmountable tolerance to the response-rate increasing (stimulant) effects of acute caffeine (3.0–17 mg/kg; IP) in caffeine-drinking rats. In conclusion, our study revealed that chronic caffeine exposure potentiates the behavioral response to amphetamine and cocaine but not to that of nicotine in rats responding under a FI schedule of food reinforcement. Thus, it is likely that these effects are mediated through different pharmacological mechanisms. Received: 3 September 1997 / Final version: 9 May 1998     

The influence of nicotine pretreatment on mesoaccumbens dopamine overflow and locomotor responses to D-amphetamine

Pretreatment with psychostimulant drugs causes sensitisation of their effects on locomotor activity and dopamine (DA) overflow in the nucleus accumbens (NAcc) and there is evidence for similarities in the mechanisms involved. This study used in vivo microdialysis in conscious freely moving rats to investigate the extent to which pretreatment with nicotine causes sensitisation to D-amphetamine. Pretreatment with nicotine (0.4 mg/kg SC daily for 5 days) caused sensitisation of the locomotor responses to D-amphetamine (0.1–0.5 mg/kg SC) but not cocaine (15 mg/kg IP). Nicotine pretreatment did not influence the increase in DA overflow into dialysis probes, located in the core of the NAcc, evoked by systemic injections of D-amphetamine or cocaine (15 mg/kg IP) but decreased the overflow evoked by the administration of D-amphetamine (1 × 10^–6M) through the dialysis probe. The results provide further evidence for a dissociation between the expression of sensitised locomotor responses to psychostimulant drugs and sensitisation of their stimulatory effects on DA overflow in the core of the NAcc. The results suggest that the sensitisation of the effects of nicotine on DA overflow in this subdivision of the NAcc may be pharmacologically specific to nicotinic drugs. Received: 23 July 1997/Final version: 19 March 1998     

Nicotine blocks latent inhibition in rats: evidence for a critical role of increased functional activity of dopamine in the mesolimbic system at conditioning rather than pre-exposure

Latent inhibition (LI) is a cognitive process whereby repeated exposure of a stimulus without consequence impedes the formation of subsequent associations with that stimulus. A number of studies in the rat have reported that LI is impaired by moderate systemic doses of amphetamine, an effect believed to be mediated via dopamine (DA) release in the nucleus accumbens. We and others have reported that nicotine has a selective effect in releasing DA in the accumbens rather than the caudate nucleus. We have therefore examined the ability of nicotine to disrupt LI, using a conditioned emotional response paradigm. Pre-exposure of a tone stimulus impaired subsequent conditioning between that stimulus and mild footshock, as indexed by suppression of licking by the tone subsequently presented alone. This LI effect was prevented, by an effect confined to the pre-exposed group, by doses of 0.4 or 0.6 mg/kg nicotine SC, which are accumbens selective, given before pre-exposure and before conditioning. The effect of nicotine in disrupting LI was prevented by prior administration of haloperidol at a dose (0.5 mg/kg) reported to reverse the disruptive effect of amphetamine on LI. Although the amphetamine effect requires two administrations, the effect of two administrations of nicotine was reproduced by a single dose of nicotine given before conditioning, but not by a single dose before pre-exposure. The results are discussed in relation to studies in human control and schizophrenic subjects, which suggest that increased DA activity in humans is also associated with impaired LI. The results indicate that nicotine does indeed increase functional DA activity in the rat accumbens; the consequent disruption of LI critically depends upon an action at the time of conditioning, and is independent of processes which occur during pre-exposure. In more general terms, this indicates the potential of drug experiments to complement behavioural studies on the mechanism of latent inhibition.     

Nicotine binding sites and their localization in the central nervous system

The resolution of racemic nicotine to provide optically pure (+)-nicotine and the synthesis of radiolabeled nicotine with high specific activity have facilitated the study of nicotine binding in brain. The actions of the stereoisomers of nicotine on the central nervous system are qualitatively similar in most tests but (−)-nicotine is more potent than the unnatural (+)-isomer by 10-fold or greater. Binding of radiolabeled nicotine to brain has both saturable and nonsaturable components. Only saturable binding is affected by incubation conditions such as time, temperature, pH and ion concentration. Excess concentrations of the stereoisomers are equally effective in displacing (−)-[³H]-nicotine from brain homogenates. Nevertheless, a direct comparison of (+)-[³H]-nicotine and (−)-[³H]-nicotine binding shows that the latter has a K_D three times lower than the former. (−)-[³H]-Nicotine is bound to the greatest degree in hypothalamus and hippocampus, areas that also exhibited the most stereoselectivity for nicotine. However, differences in the binding affinities of the two isomers were far less than the pharmacological stereospecificity observed.     

Transfer of state-dependent control of discriminative behaviour between subcutaneously and intraventricularly administered nicotine and saline

Rats were trained to choose between the side compartments of a three-chambered shock-escape apparatus according to whether they were injected with nicotine or saline. Half of the rats learned to discriminate between 0.4 mg/kg nicotine and saline administered subcutaneously, whereas the other half learned to differentiate between 644 ng nicotine or saline administered intraventricularly. The rats trained by the subcutaneous route of administration had the ability to discriminate between nicotine and saline given intraventricularly and the rats trained by the intraventricular route could differentiate when the two substances were injected subcutaneously. This transfer of state-dependent control of discriminative behaviour between subcutaneously and intraventricularly administered nicotine and saline is presented as evidence for the central origin of the nicotine-produced interoceptive cue.This work supported by a grant from the American Medical Association Education and Research Foundation.     

Involvement of both cholinergic and catecholaminergic pathways in the central action of methylphenidate: A study utilizing lead-exposed rats

The effects of methylphenidate (MPH) and the cholinergic agonists nicotine and oxotremorine were tested on the spontaneous multiple unit activity in the mesencephalic reticular formation of two groups of rats. In control rats i.v. MPH (1 mg/kg), nicotine (0.125 mg/kg), and oxotremorine (0.5 mg/kg) all attenuated the unit activity with latencies of less than 10 min. In another group of rats, exposed to lead acetate since birth, the extent of attenuation of unit activity induced by MPH and nicotine was reduced and the latency of effect was delayed by 45–50 min. The latency of the oxotremorine effect was not changed but the attenuation of unit activity was more pronounced in the lead-treated group. Pretreatment with spiroperidol, to inhibit the aminergic receptors, diminished the inhibitory effect of MPH in the control group but not in the lead-treated group, whereas the attenuating effect of oxotremorine was not affected in either group. These data support our previous evidence that MPH exerts its action in the central nervous system by a cholinergic pathway in addition to published catecholaminergic pathways. Furthermore, the present findings indicate that chronic leadexposure in rats results in cholinergic hypofunction and supersensitivity at central cholinergic receptor sites. This alteration of central cholinergic function may be partially attributed to the malnutrition observed in the lead-exposed animals.Part of this work was presented in abstract form (Shih et al., 1976b)     

Influence of chronic administration of nicotine on the turnover and metabolism of noradrenaline in the rat brain

Chronic administration of nicotine (0.5 mg/kg, subcutaneously, 3 to 5 times a day for 6 weeks) accelerated the rate of disappearance of intraventricularly administered ³H-noradrenaline from rat brain. This was associated with normal levels of ³H-normetanephrine suggesting an increase in intraneuronal deamination.The rate constant of amine decline (k) in animals chronically treated with nicotine was significantly greater than that of controls, while the steady state level of brain noradrenaline was about equal in both groups of rats. Amphetamine, reserpine, acetylcholine, histamine, pheniprazine, pargyline, and nicotine affected the catecholamine levels in the rat brain treated with nicotine to the same degree as they did in the controls. It is concluded that chronic administration of nicotine may increase noradrenaline turnover in the brain and possibly increase the deamination of this amine.     

Serotonergic function in mouse head twitches induced by lithium and reserpine

The effects of four neural excitants (d-amphetamine, cocaine, nicotine, and strychnine) on myoclonic and clonic seizure susceptibility were investigated in two age groups (30 and 120 days) of short-sleep mice. Amphetamine and cocaine decreased susceptibility to myoclonus in young mice and increased susceptibility in mature mice. These effects were attenuated by pretreatment with haloperidol, indicating mediation by a dopaminergic system. Amphetamine did not alter clonic susceptibility in either age group of mice, whereas cocaine affected clonic susceptibility and myoclonus. These effects were not attenuated by haloperidol, indicating mediation by systems other than dopamine. Nicotine decreased susceptibility to myoclonus and increased susceptibility to clonus, whereas strychnine increased susceptibility to both types of seizure. Haloperidol, however, failed to alter any of these effects. These results are consistent with our previous work which suggests that a dopaminergic mechanism in these mice undergoes marked developmental changes between 30 and 120 days of age.     

Effect of Nicotine Treatment on the Metabolism of Nicotine in the Mouse Liver in Vitro

¹⁴C-nicotine was incubated with a 10000 × g supernatant fraction of liver homogenate from mice pretreated with nicotine for 3, 10 and 17 days respectively. The rate of metabolism was measured by the determination of the oxidative nicotine metabolite cotinine. After intraperitoneal injections of 5 mg/kg of nicotine three times daily for three days a 50% significant decrease in metabolism was observed. A 71% significant decrease in hepatic glycogen was also seen. Giving nicotine 27.8 and 24.5 mg/kg/24 hours in drinking water for 10 and 17 days respectively did not significantly change the metabolism or the hepatic glycogen levels.