Brandon J. Hall

Differential Effects of Non-Nicotine Tobacco Constituent Compounds on Nicotine Self-Administration in Rats

Tobacco smoking has been shown to be quite addictive in people. However, nicotine itself is a weak reinforcer compared to other commonly abused drugs, leading speculation that other factors contribute to the high prevalence of tobacco addiction in the human population. In addition to nicotine, there are over 5000 chemical compounds that have been identified in tobacco smoke, and more work is needed to ascertain their potential contributions to tobaccos highly addictive properties, or as potential candidates for smoking cessation treatment. In this study, we examined seven non-nicotine tobacco constituent compounds (anabasine, anatabine, nornicotine, myosmine, harmane, norharmane, and tyramine) for their effects on nicotine self-administration behavior in rats. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine (0.03 mg/kg/50 μl infusion) under a fixed ratio-1 schedule of reinforcement. Each self-administration session lasted 45 min. Doses of each tobacco constituent compound were administered subcutaneously 10 min prior to the start of each session in a repeated measures, counterbalanced order two times. Anabasine displayed a biphasic dose-effect function. Pretreatment with 0.02 mg/kg anabasine resulted in a 25% increase in nicotine self-administration, while 2.0mg/kg of anabasine reduced nicotine infusions per session by over 50%. Pretreatment with 2.0mg/kg anatabine also significantly reduced nicotine self-administration by nearly half. These results suggest that some non-nicotine tobacco constituents may enhance or reduce nicotines reinforcing properties. Also, depending upon the appropriate dose, some of these compounds may also serve as potential smoking cessation agents.

Role of insular cortex D1 and D2 dopamine receptors in nicotine self-administration in rats

The insular cortex has been associated with the processing of rewarding stimuli and with the neural bases of drug addiction. Ischemic damage to the insula has been associated with decreased desire to smoke cigarettes. Which component of insular function is involved in the neural basis of cigarette smoking is not clear. Dopamine systems are crucial for the reinforcing value of addictive drugs. The DA projection from the ventral tegmental area to the nucleus accumbens (NAc) has been shown to be a vital pathway for the primary reinforcement caused by taking a variety of abused drugs. In the current set of studies, the roles of D₁ and D₂ receptors in the insular cortex in the self-administration of nicotine by rats were assessed. Adult female Sprague-Dawley rats were fitted with jugular catheters and given access to self-administer nicotine. Bilateral local infusion cannulae were implanted into the agranular insular cortex to locally administer D₁ and D₂ antagonists (SCH-23390 and haloperidol). Acute local infusions of the D₁ antagonist SCH-23390 into the insula (1-2 μg/side) significantly decreased nicotine self-administration by more than 50%. Repeated infusions of SCH-23390 into the agranular insula caused continuing decreases in nicotine self-administration without signs of tolerance. In contrast, local infusions of the D₂ antagonist haloperidol 0.5-2 μg/side did not have any discernable effect on nicotine self-administration. These studies show the importance of DA D₁ systems in the insula for nicotine reward.

Bupropion-varenicline interactions and nicotine self-administration behavior in rats.

Varenicline and bupropion each have been shown to significantly improve cessation of tobacco addiction in humans. They act through different mechanisms and the question about the potential added efficacy with their combined used has arisen. Preclinical animal models of nicotine addiction can help with the evaluation of this combined approach and what dose combinations of varenicline and bupropion may be useful for enhancing tobacco cessation. In this study, we investigated the interacting dose-effect functions of varenicline and bupropion in a rat model of nicotine self-administration. Young adult female Sprague-Dawley rats were allowed to self-administer nicotine in 1-h sessions under an FR1 reinforcement schedule. Varenicline (0.3, 1. 3 mg/kg) and bupropion (8.33, 25, 75 mg/kg) were administered alone or together 15 min before each session. The vehicle saline was the control. Higher doses of each drug alone reduced nicotine self-administration compared to control with reductions of 62% and 75% with 3 mg/kg varenicline and 75 mg/kg bupropion respectively. Lower dose varenicline which does not by itself reduce nicotine self-administration, significantly augmented bupropion effects. The 0.3 mg/kg varenicline dose combined with the 25 and 75 mg/kg bupropion doses caused greater reductions of nicotine self-administration than either dose of bupropion given alone. However, higher dose varenicline did not have this effect. Lower dose bupropion did not augment varenicline effects. Only the high bupropion dose significantly enhanced the varenicline effect. Likewise, combining 1 mg/kg varenicline with 75 mg/kg bupropion reduced self-administration to a greater extent than either dose alone. These results demonstrate that combination therapy with varenicline and bupropion may be more beneficial than monotherapy with either drug alone.

Effects of tobacco smoke constituents, anabasine and anatabine, on memory and attention in female rats.

Nicotine has been well characterized to improve memory and attention. Nicotine is the primary, but not only neuroactive compound in tobacco. Other tobacco constituents such as anabasine and anatabine also have agonist actions on nicotinic receptors. The current study investigated the effects of anabasine and anatabine on memory and attention. Adult female Sprague-Dawley rats were trained on a win-shift spatial working and reference memory task in the 16-arm radial maze or a visual signal detection operant task to test attention. Acute dose-effect functions of anabasine and anatabine over two orders of magnitude were evaluated for both tasks. In the radial-arm maze memory test, anabasine but not anatabine significantly reduced the memory impairment caused by the NMDA antagonist dizocilpine (MK-801). In the signal detection attentional task, anatabine but not anabasine significantly attenuated the attentional impairment caused by dizocilpine. These studies show that non-nicotine nicotinic agonists in tobacco, similar to nicotine, can significantly improve memory and attentional function. Both anabasine and anatabine produced cognitive improvement, but their effectiveness differed with regard to memory and attention. Follow-up studies with anabasine and anatabine are called for to determine their efficacy as therapeutics for memory and attentional dysfunction.

Heterogeneity across brain regions and neurotransmitter interactions with nicotinic effects on memory function.

Nicotinic acetylcholine receptors have been shown in many studies to be critically involved in memory function. The precise roles these receptors play depend on the receptor subtype, their anatomic localization, their interactions with other parts of the neural systems underlying cognition and the particular domain of cognitive function. Nicotinic agonists can significantly improve learning, memory, and attention. Nicotinic receptors in the hippocampus are innervated by cholinergic projections from the medial septum and diagonal band. Local infusions of either α7 or α4β2 nicotinic antagonists into either the dorsal or ventral hippocampus produce amnestic effects in rats navigating about a radial arm maze. There is cholinergic innervation of nicotinic receptors in other components of the limbic system as well. In the basolateral amygdala and the anterior thalamus, similar amnestic effects of nicotinic α7 and α4β2 antagonists are seen. Interestingly, there are no additive amnestic effects observed in these limbic areas when α7 and α4β2 receptor antagonists are combined. The particular expression patterns of α7 and α4β2 nicotinic receptors in these limbic and cortical areas may explain this nonadditivity, but further research is needed to determine the specific cause of this phenomenon. Nicotinic receptor mechanisms in the limbic system play an important role in cognitive impairment for a variety of neurological disorders, including Alzheimers disease and schizophrenia. Alzheimers disease results in a dramatic decrease in hippocampal nicotinic receptor density, affecting α4β2 receptor expression most prominently. In schizophrenia, there are anomalies in α7 nicotinic receptor expression, which seem to be crucial for the cognitive impairment of the disorder. Chronic nicotine exposure, such as seen with tobacco use, results in an increase in nicotinic receptor density in the limbic system. This effect appears to be related to the desensitization of nicotinic receptors seen after agonist application. Open questions remain concerning the role of desensitization versus activation of nicotinic receptors in cognitive improvement.

The ventral hippocampal muscarinic cholinergic system plays a key role in sexual dimorphisms of spatial working memory in rats

&NA; Sex differences in cognitive processing and function have been documented in human and animal studies. Females have been found to perform better than males on non‐spatial memory tasks, while males tend to outperform females on spatial memory tasks. The neural mechanisms underlying these sexual dimorphisms are unclear. However, it is known that the cholinergic system is critically involved in memory processes, and there are notable differences between males and females in cholinergic system function and receptor expression. In particular, there are sex differences in the processing of information in the frontal cortex and hippocampus. In this study, we examined the roles of muscarinic and nicotinic acetylcholine receptors in the medial frontal cortex (MfC) and ventral hippocampus (VH) on spatial working memory in male and female rats. Local infusions of scopolamine (SCOP) and mecamylamine (MEC) (10, 20, 50 &mgr;g/side) were used to antagonize these receptors in each respective brain region during performance in the 16‐arm radial arm maze. Infusions of SCOP into the VH caused a significant increase in memory errors in female rats, but had no significant effect on males, while infusions of MEC into the VH had no effect on either sex. Infusions of both SCOP (50 &mgr;g/side) and MEC (20 &mgr;g/side) into the MfC caused working memory impairments in both sexes. These results show that muscarinic acetylcholine receptors in the VH are differentially vulnerable to spatial memory impairments in females. Ventral hippocampal muscarinic acetylcholine receptors may play a key role in male‐female differences in spatial memory. HighlightsVentral hippocampal scopolamine (SCOP) impaired memory in female but not male rats.Ventral hippocampal mecamylamine (MEC) had no effect on memory in either sex.Medial frontal cortical SCOP or MEC infusions impaired memory in both sexes.Ventral hippocampal muscarinic receptors may be key in sex differences in memory.

Dextromethorphan interactions with histaminergic and serotonergic treatments to reduce nicotine self-administration in rats

Combining effective treatments with diverse mechanisms of action for smoking cessation may provide better therapy by targeting multiple points of control in the neural circuits underlying addiction. Previous research in a rat model has shown that dextromethorphan, which has α3β4 nicotinic and NMDA glutamatergic antagonist actions, significantly decreases nicotine self-administration. We have found in the rat model that the H1 histamine antagonist pyrilamine and the serotonin 5HT2C agonist lorcaserin also significantly reduce nicotine self-administration. The current studies were conducted to determine the interactive effects of dextromethorphan with pyrilamine and lorcaserin on nicotine self-administration in rats. Young adult female rats were fitted with jugular IV catheters and trained to self-administer a nicotine infusion dose of 0.03-mg/kg/infusion. In an initial dose-effect function study of dextromethorphan, we found a monotonic decrease in nicotine self-administration over a dose range of 1 to 30-mg/kg with the lowest effective dose of 3-mg/kg. Then, with two separate cohorts of rats, dextromethorphan (0, 3.3, and 10-mg/kg) interactions with pyrilamine (0, 4.43, and 13.3-mg/kg) were investigated as well as interactions with lorcaserin (0, 0.3125 and 0.625-mg/kg). In the pyrilamine-dextromethorphan interaction study, an acute dose of pyrilamine (13.3-mg/kg) as well as an acute dose of dextromethorphan caused a significant decrease in nicotine self-administration. There were mutually augmenting effects of these two drugs. The combination of dextromethorphan (10-mg/kg) and pyrilamine (13.3-mg/kg) significantly lowered nicotine self-administration relative to either 10-mg/kg of dextromethorphan alone (p<0.05) or 13.3-mg/kg of pyrilamine alone (p<0.0005). In the lorcaserin-dextromethorphan study, an acute dose of lorcaserin (0.312-mg/kg) as well as an acute dose of dextromethorphan (10-mg/kg) caused a significant decrease in nicotine self-administration replicating previous findings. Augmenting interactions were observed with dextromethorphan and pyrilamine as well as lorcaserin. These findings suggest that combination therapy may be more effective smoking cessation treatments than monotherapy.

Critical developmental periods for effects of low-level tobacco smoke exposure on behavioral performance

HighlightsLate gestational TSE exposure increased errors in the initial training on the radial‐arm maze in female offspring.In attentional testing, males exposed to TSE during gestation showed hypervigilance during low‐motivating conditions.Gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window.Long‐lasting behavioral effects were seen at TSE levels modeling secondhand smoke. ABSTRACT Tobacco exposure during development leads to neurobehavioral dysfunction in children, even when exposure is limited to secondhand smoke. We have previously shown in rats that developmental exposure to tobacco smoke extract (TSE), at levels mimicking secondhand smoke, starting preconception and extending throughout gestation, evoked subsequent locomotor hyperactivity and cognitive impairment. These effects were greater than those caused by equivalent exposures to nicotine alone, implying that other agents in tobacco smoke contributed to the adverse behavioral effects. In the present study, we examined the critical developmental windows of vulnerability for these effects, restricting TSE administration (0.2 mg/kg/day nicotine equivalent, or DMSO vehicle, delivered by subcutaneously‐implanted pumps) to three distinct 10 day periods: the 10 days preceding mating, the first 10 days of gestation (early gestation), or the second 10 days of gestation (late gestation). The principal behavioral effects revealed a critical developmental window of vulnerability, as well as sex selectivity. Late gestational TSE exposure significantly increased errors in the initial training on the radial‐arm maze in female offspring, whereas no effects were seen in males exposed during late gestation, or with either sex in the other exposure windows. In attentional testing with the visual signal detection test, male offspring exposed to TSE during early or late gestation showed hypervigilance during low‐motivating conditions. These results demonstrate that gestational TSE exposure causes persistent behavioral effects that are dependent on the developmental window in which exposure occurs. The fact that effects were seen at TSE levels modeling secondhand smoke, emphasizes the need for decreasing involuntary tobacco smoke exposure, particularly during pregnancy.