Most Recent Studies Published

February 2005

Fallon, J.H., Keator, D.B., Mbogori, J., Taylor, D. and Potkin, S.G. Gender: a major determinant of brain response to nicotine. International Journal of Neuropsychopharmacology, (2005),8, 17-26.

Abstract

Biological factors responsible for nicotine initiation and dependence are largely unknown. Men and women smoke differently, and may smoke for different reasons. Brain metabolic response to nicotine may explain gender differences in nicotine use. We used FDG-PET to measure brain metabolic response on placebo and following nicotine administered by patch in 42 females and 77 males (smokers and non-smokers) while performing a Continuous Performance Task (CPT) or the Bushman Competition and Retaliation Task (CRT). Nicotine administration affected brain metabolism much differently in males and females, and these differences were dependent on task and smoking history. In the placebo condition female smokers performing the CPT and female non-smokers performing the CRT consistently had higher brain metabolism than males, especially in the entire prefrontal system and the mid and anterior temporal lobe, language cortices, and related subcortical systems. The overall effect of nicotine was to decrease these gender differences in brain metabolism.

January  2005

Chattopadhyay, S., Xue, B., Collins, D., Pichika, R., Bagnera, R., Leslie, F.M., Bradley T. Christian, B.T., Shi, B., Narayanan, T.K., Potkin, S.G., and Mukherjee, J.  Synthesis and Evaluation of Nicotine ₄ß₂ Receptor Radioligand, 5-(3'-¹⁸F-Fluoropropyl)-3-(2-(S)-Pyrrolidinylmethoxy)Pyridine, in Rodents and PET in Nonhuman Primate.  J Nucl Med 2005 46: 130-140. (Press Release, Q&A, Link to Journal )

Abstract

Nicotine ₄ß₂ receptor subtypes are implicated in the study of Alzheimer’s disease, schizophrenia, substance abuse, lung cancer, and other disorders. We report the development and evaluation of a putative antagonist, 5-(3'-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (nifrolidine) as a PET agent for nicotine ₄ß₂ receptors. Methods: In vitro binding affinity of nifrolidine was measured in rat brain slices labeled with ¹²⁵I-iodoepibatidine or ¹²⁵I-bungaratoxin. Selectivity of binding was measured in the presence of cytisine. ¹⁸F radiolabeling was performed by reacting the tosylate precursor with ¹⁸F-fluoride followed by deprotection. In vitro autoradiographic studies in rat brain slices with 5-(3'-¹⁸F-fluoropropyl)-3-(2-(S)-pyrrolidinylmethoxy)pyridine (¹⁸F-nifrolidine) were read on a phosphor imager. Rats were injected with ¹⁸F-nifrolidine (3.7 MBq each), and brain regions were counted at various times (2–120 min). Blocking studies were performed by subcutaneous injection of nicotine (10 mg/kg). A PET study of ¹⁸F-nifrolidine (approximately 148 MBq) was performed on an anesthetized rhesus monkey using a high-resolution scanner.

Results: In vitro binding affinity of nifrolidine exhibited an inhibition constant of 2.89 nmol/L for the ₄ß₂ sites. Radiosynthesis and high-performance liquid chromatography purifications yielded the product in approximately 20%–40% decay-corrected radiochemical yield to provide ¹⁸F-nifrolidine specific activities of approximately 111–185 GBq/µmol. In vitro autoradiography in rat brain slices revealed selective binding of ¹⁸F-nifrolidine to the anteroventral thalamic nucleus, ventral posteriomedial thalamus, dorsolateral geniculate, and, to a lesser extent, cortex and striata, which are known to contain ₄ß₂ sites. This specific binding was completely abolished by 300 µmol/L nicotine. Ex vivo rat brain distribution studies indicated selective binding in the thalamus with a maximal thalamus-to-cerebellum ratio of approximately 3. The PET study revealed selective maximal uptake (0.01% injected dose/mL) in regions of the thalamus (anteroventral and anteromedial thalamus, ventrolateral thalamus) and extrathalamic regions such as cingulate gyrus, lateral geniculate, temporal cortex, and frontal cortex.

Conclusion: Binding of ¹⁸F-nifrolidine to ₄ß₂ receptor-rich regions in rats and monkeys indicates promise as a PET agent. Additionally, the thalamus-to-cerebellum ratio approached a plateau of 1.7 in 120 min, indicating relatively faster kinetics compared with previously reported imaging agents.

October 2004

Nicotine's Addictive Hold Increased With Other Chemical In Tobacco Smoke, UCI Tobacco Use Research Center Study Finds

Belluzzi, J.D., Wang, R.H. and Leslie, F.M.  Acetaldehyde enhances nicotine reinforcement in adolescent rats.  Neuropsychopharmacology, doi:10.1038/sj.npp.1300586 (Press Release, Q & A, & Link to Journal)

Abstract

Tobacco use has one of the highest rates of addiction and relapse of any abused drug. Paradoxically, however, in animal models of reinforcement nicotine appears weak compared to other abused drugs. We report here that acetaldehyde, a major component of tobacco smoke, enhances nicotine self-administration. Juvenile and adult male rats were implanted with intravenous catheters and tested for self-administration 4 days later at postnatal day 27 or 90, respectively. Animals were tested, without prior response training, in five daily 3-h sessions where each nose-poke delivered an intravenous injection followed by a 60-s timeout. Animals (11-13/group) were offered one of the following solutions: nicotine (30 g/kg/injection), acetaldehyde (16 g/kg/inj), nicotine (30 g/kg/inj)+acetaldehyde (16 g/kg/inj), or saline. The youngest animals responded significantly more for nic+acet than for saline or for either drug alone. Responding at the reinforced hole was significantly higher than at the nonreinforced hole or at the reinforced hole during noncontingent injections of nic+acet. Tests with receptor antagonists indicated that these drug effects are mediated by central, but not peripheral, nicotinic receptors. There was an age-related decline in self-administration of nic+acet, but not for cocaine. Taken together, these results indicate that acetaldehyde, at the low concentrations found in tobacco smoke, interacts with nicotine to increase responding in a stringent self-administration acquisition test where nicotine alone is only weakly reinforcing, and that adolescent animals are more sensitive to these actions than adults. Animal models of tobacco addiction could be improved by combining acetaldehyde, and possibly other smoke components, with nicotine to more accurately reflect the pharmacological profile of tobacco smoke.

June 2004

Adolescent development of forebrain stimulant responsiveness: insights from animal studies.

Leslie, F.M., Loughlin, S.E., Wang, R., Perez, L., Lotfipour, S. and Belluzzi, J.D. (2004) Adolescent development of forebrain stimulant responsiveness: Insights from animal studies. Ann. N.Y. Acad. Sci., 1021:148-59. (Link to Presentation, Paper, & Journal)

Abstract
Although initiation of drug abuse occurs primarily during adolescence, little is known about the central effects of nicotine and other abused drugs during this developmental period. Here evidence, derived from studies in rodents, is presented that suggests that tobacco use initiation during early adolescence results from a higher reward value of nicotine. The developmental profiles of the rewarding effects of other abused drugs, such as cocaine, differ from that of nicotine. Using in situ hybridization to quantify mRNA levels of the immediate early gene, cfos, the neuronal activating effects of nicotine in limbic and sensory cortices at different developmental stages are evaluated. Significant age changes in basal levels of cfos mRNA expression in cortical regions are observed, with a peak of responding of limbic cortices during early adolescence. A changing pattern of nicotine-induced neuronal activation is seen across the developmental spectrum, with unique differences in both limbic and sensory cortex responding during adolescence.

An attentional set-shifting task was also used to evaluate whether the observed differences during adolescence reflect early functional immaturity of prefrontal cortices that regulate motivated behavior and psychostimulant responding. The finding of significantly better responding during adolescence suggests apparent functional maturity of prefrontal circuits and greater cognitive flexibility at younger ages.

These findings in rodent models suggest that adolescence is a period of altered sensitivity to environmental stimuli, including abused drugs. Further efforts are required to overcome technical challenges in order to evaluate drug effects systematically in this age group

May 2004

Animal Study Suggest First Exposure To Nicotine May Change Adolescents' Brain and Behavior.

Belluzzi JD, Lee AG, Oliff HS, Leslie FM.  (2004) Age-dependent effects of nicotine on locomotor activity and conditioned place preference in rats. Psychopharmacology, 174, 389-395. (Press Release , Q&A,  & Link to Journal)

Abstract
RATIONALE. Most adult smokers start smoking during their adolescence. This adolescent initiation may be due to multiple factors, but little evidence is available regarding whether their brains are differentially sensitive to the addictive effects of nicotine during adolescence.

OBJECTIVE. To test the hypothesis that adolescents are more sensitive than adults to nicotine's rewarding actions.

METHODS. An unbiased, counterbalanced, place-conditioning procedure was used to examine drug-induced reward and locomotor activity. Early adolescent (postnatal day 28), late adolescent (P38) and adult (P90) rats received either saline or nicotine (0.125, 0.25 or 0.5 mg/kg, s.c.) and were tested for place conditioning. RESULTS. During early adolescence, a single nicotine injection (0.5 mg/kg) induced significant conditioned place preference (CPP). In contrast, during late adolescence or adulthood, nicotine did not induce CPP after either one or four conditioning trials. Initial locomotor responses to acute nicotine administration during the first conditioning trial also differed with age, with no effect at P28, but substantial inhibitory responses at all doses studied (0.125-0.5 mg/kg) at later ages. Although not differing in their initial locomotor response to nicotine, there was a significantly greater tolerance/sensitization during the second and subsequent drug exposures in late adolescents than in adults.

CONCLUSIONS. These findings provide evidence that adolescent brain is differentially sensitive to both the acute and repeated effects of nicotine relative to adult brain. Furthermore, there are significant differences in nicotine sensitivity between early and late phases of adolescence.

February 2004

Nicotine Study Provides First Results Showing Personality Traits, Brain Activity and Cigarette Addiction Link.

Fallon, J.H., Keator, D., Mbogori, J. and Potkin, S.G. (2004) Hostility differentiates the brain metabolic effects of nicotine. Cognitive Brain Research. 18, 142 -148. 

(Press Release, More On Study, &  Media Coverage)

Abstract
The brain mechanisms underlying the cause of nicotine dependence are unknown, however, hostility traits are associated with increased susceptibility to nicotine dependence. We used FDG PET to measure brain metabolic response to nicotine administered by patch while the subject performed the Bushman aggression task in 86 high- and low-hostility subjects. Low-hostility trait subjects demonstrated no significant change in brain metabolic response to nicotine. In marked contrast, high-hostility non-smokers subjects demonstrated dramatic metabolic changes to low dose (3.5 mg patch) as did high-hostility smokers to high dose nicotine (21 mg patch) throughout the brain bilaterally ( p < 0.025).

Correlational analyses demonstrated greater metabolic changes in response to nicotine in subjects with greatest hostility trait measures. The observed differences were not a consequence of plasma nicotine or cotinine levels. These metabolic changes were not observed when subjects performed a sustained attentional task (continuous performance task; CPT).

Behaviorally, high-hostility subjects had higher ratings of anger, impatience, irritability and nervousness, and lower ratings of happiness, relaxation and curiosity than low-hostility subjects. Smokers had significantly greater scores on impatience and restlessness than non-smokers. This PET study demonstrates a conspicuous lack of the brain metabolic response to nicotine in low-hostility non-smokers in contrast to a dramatic brain response to nicotine in high hostility subjects. This biological difference in brain metabolic response to nicotine between high and low hostility trait subjects may explain differences in susceptibility to nicotine dependence. 2003 Elsevier B.V. All rights reserved