Hooked on the nicotine addiction thesis: a response to DiFranza.

DiFranza's rebuttal to our critique of the "Hooked on Nicotine" research program misconstrues our arguments beyond recognition. The grossest misrepresentation of our critique by DiFranza is that we devise (by thwarting science) to rescue "the conventional wisdom" of the "threshold model of nicotine addiction." In fact, the difference between our positions lies elsewhere: We believe that nicotine is not an addictive drug and that its contribution to the smoking habit is secondary; DiFranza believes that nicotine is so powerfully addictive that novice smokers can lose autonomy over their smoking behavior after one cigarette or even following a single puff. Our review aimed to critically examine the empirical basis of this extreme version of the nicotine "addiction" model. In this brief commentary we illustrate how the commitment to the nicotine "addiction" theory has biased the methodology and the interpretation of the data in "Hooked on Nicotine" research program.

If the data contradict the theory, throw out the data: Nicotine addiction in the 2010 report of the Surgeon General.

The reports of US Surgeon General on smoking are considered the authoritative statement on the scientific state of the art in this field. The previous report on nicotine addiction published in 1988 is one of the most cited references in scientific articles on smoking and often the only citation provided for specific statements of facts regarding nicotine addiction. In this commentary we review the chapter on nicotine addiction presented in the recent report of the Surgeon General. We show that the nicotine addiction model presented in this chapter, which closely resembles its 22 years old predecessor, could only be sustained by systematically ignoring all contradictory evidence. As a result, the present SG's chapter on nicotine addiction, which purportedly "documents how nicotine compares with heroin and cocaine in its hold on users and its effects on the brain," is remarkably biased and misleading.

Can one puff really make an adolescent addicted to nicotine? A critical review of the literature.

RATIONALE: In the past decade, there have been various attempts to understand the initiation and progression of tobacco smoking among adolescents. One line of research on these issues has made strong claims regarding the speed in which adolescents can become physically and mentally addicted to smoking. According to these claims, and in contrast to other models of smoking progression, adolescents can lose autonomy over their smoking behavior after having smoked one puff in their lifetime and never having smoked again, and can become mentally and physically "hooked on nicotine" even if they have never smoked a puff. OBJECTIVES: To critically examine the conceptual and empirical basis for the claims made by the "hooked on nicotine" thesis. METHOD: We reviewed the major studies on which the claims of the "hooked on nicotine" research program are based. RESULTS: The studies we reviewed contained substantive conceptual and methodological flaws. These include an untenable and idiosyncratic definition of addiction, use of single items or of very lenient criteria for diagnosing nicotine dependence, reliance on responders' causal attributions in determining physical and mental addiction to nicotine and biased coding and interpretation of the data. DISCUSSION: The conceptual and methodological problems detailed in this review invalidate many of the claims made by the "hooked on nicotine" research program and undermine its contribution to the understanding of the nature and development of tobacco smoking in adolescents.

Spatio-temporal motifs 'remembered' in neuronal networks following profound hypothermia.

Surgical procedures using hypothermic temperatures have been linked to complications such as seizures, impaired mental development and impaired memory. Although there is some evidence that the profound hypothermia (<12 ( composite function)C) used in these procedures may be contributing to these neurological impairments, skepticism remains because of lack of evidence from experimental studies isolating the effects of hypothermia on neuronal networks. In order to attain a better understanding of profound hypothermia effects on neurons during surgical procedures, we applied cold to a cultured in-vitro neuronal network. The typical pattern of activity of such cultures is in the form of synchronized bursts, in which most of the recorded neurons fire action potentials in a short time period. In most cases, the bursting activity shows one or more repeating precise spatio-temporal patterns (motifs) that are sustained over long periods of time. In this experimental study, neuronal networks grown on microelectrode arrays (MEA) are subjected to profound hypothermia for an hour and the collective dynamics of the network as a whole are assessed. We show, by using a similarity analysis that compares changes in the time delays between neuronal activation at different burst motifs, that neuronal networks survive total inhibition by profound hypothermia and retain their intrinsic synchronized burst motifs even with substantial generalized neuronal degeneration. By applying multiple sessions of cold, we also show a marked monotonic reduction in the rate of burst firing and in the number of spikes of each neuron after each session.

Reevaluating the nicotine delivery kinetics hypothesis.

RATIONALE: The view of smoking as an addiction to nicotine implies that nicotine is an addictive drug and a primary reinforcer. However, nicotine other than in tobacco does not appear to be very rewarding for smokers. This potential anomaly to the nicotine addiction thesis is resolved by the proposition that the reward associated with smoking depends on "high-nicotine boli." According to the nicotine delivery kinetics hypothesis, smoked nicotine reaches the brain in 5-10 s in high concentrations, which provide reinforcing "hits" of nicotine to the brain. OBJECTIVES: Because of its essential role in the nicotine addiction thesis, this review set out to examine the current empirical basis of the nicotine delivery kinetics hypothesis. MATERIALS AND METHODS: We reviewed studies that bear on two questions: First, does nicotine from cigarettes reach the brain significantly faster than from other nicotine delivery devices? Second, is there a relationship between delivery kinetics and any rewarding effects of nicotine? RESULTS: There is little empirical support for the nicotine delivery kinetics hypothesis. Several studies found that arterial nicotine levels associated with smoking are much lower than predicted by the nicotine delivery kinetics thesis and not higher than with other nicotine delivery devices. More importantly, comparisons of nicotine delivery devices with varying speeds of delivery do not suggest any correlation between nicotine delivery profile and subjective reward. CONCLUSIONS: This review indicates that the wide endorsement of the nicotine delivery kinetics hypothesis is unjustified. Critical research is required to resolve the anomalies within the nicotine addiction theory of smoking.

Euphoriant effects of nicotine in smokers: fact or artifact?

RATIONALE: The claim that nicotine in cigarettes is euphoriant to smokers is largely based on two studies (Pomerleau and Pomerleau, Psychopharmacology, 108:460-465, 1992; Tobacco Control, 3:374, 1994) in which smokers were instructed to respond to sensations of rush, buzz, or high while smoking low-nicotine or regular cigarettes. However, the assumption that these sensations are pleasurable was not tested and may have biased the results. OBJECTIVES: The aim of this study was to re-examine the claim that smoked nicotine is euphoriant to smokers. METHODS: Study 1 surveyed the frequency and pleasantness of the smoking-related sensations of rush, buzz, and high in a sample of smokers. Study 2 replicated Pomerleau and Pomerleau (Psychopharmacology, 108:460-465, 1992) with two sets of instruction. One set, as in the original study, defined these sensations as pleasurable, whereas the other defined them as unpleasant. RESULTS: Study 1 found that whereas rush and high were perceived as pleasant, buzz was unpleasant to most smokers. Study 2 found that under both sets of instructions, smokers reported more sensations when smoking the regular, as compared to the low-nicotine cigarette. Additionally, the sensations of rush, buzz, and high were rated as more pleasant under the pleasant instructions as compared to the unpleasant instructions. Finally, in the pleasant instructions condition, many participants reported having pressed the button to indicate a pleasurable sensation despite having actually experienced that sensation as unpleasant. CONCLUSIONS: Our results suggest that the findings of Pomerleau and Pomerleau (Psychopharmacology, 108:460-465, 1992; Tobacco Control, 3:374, 1994) may have been biased by the experimental instructions and cannot be taken as evidence that smoked nicotine is euphoriant to smokers.

Study of hypothermia on cultured neuronal networks using multi-electrode arrays.

Efficient and safe use of hypothermia during various neuro-medical procedures requires sound understanding of low temperature effects on the neuronal network's activity. In this report, we introduce the use of cultivated dissociated neuronal networks on temperature controlled multi-electrode arrays (MEAs) as a simple methodology for studying the long-term effects of hypothermia. The networks exhibit spontaneous activity in the form of synchronized bursting events (SBEs), followed by long intervals of sporadic firing. Through the use of our correlation method, these SBEs can be clustered into sub-groups of similar spatio-temporal patterns. Application of hypothermia to the network resulted in a reduction in the SBE rate, the spike intensity and an increase in inter-neuronal correlations. Within 2h following the cessation of hypothermia, the cultured network returned to its initial spatio-temporal SBE structure. These results suggest that the network survived cold exposure and demonstrate the feasibility of long-term continuous neural network recording during hypothermic conditions.

Effects of contingent and noncontingent nicotine on lever pressing for liquids and consumption in water-deprived rats.

Nicotine has been proposed to be a primary reinforcer and a reinforcement enhancer. To date, no studies have examined whether nicotine enhances consummatory behaviors or only operant responding (appetitive behaviors). Experiments were designed to test whether contingent and noncontingent nicotine enhance lever pressing for and consumption of fluids in water-deprived rats. Animals were water-deprived throughout all experiments. They were trained to press two levers under a variable interval (VI-20, 1-35s). Their lever pressing and water consumption were measured after noncontingent subcutaneous (s.c.) injection of nicotine (1mg/kg), and in 3 choice conditions (water and quinine solution (18µg/ml); water and nicotine (32µg/ml) solution; quinine (18µg/ml) and nicotine (32µg/ml) solutions) where nicotine was thus delivered contingently upon lever pressing. The effects of nicotine (1mg/kg; s.c.) on the consumption of water in a time-limited free access (1h) paradigm were assessed. Nicotine significantly increased lever pressing and the number of earned reinforcements on both levers in the two choice conditions and when administered s.c. compared to all groups that did not receive nicotine. However, under no condition did animals consume more fluids than baseline. Under the time-limited free access condition nicotine reduced water consumption. Although our findings do not support a reinforcing effect for nicotine, they are consistent with the incentive-amplification hypothesis. Its relevance for human smoking is yet unclear.

Craving to smoke in orthodox Jewish smokers who abstain on the Sabbath: a comparison to a baseline and a forced abstinence workday.

RATIONALE: Previous studies suggest that craving for cigarettes is substantially influenced by non-nicotine mechanisms such as habits, cues, and expectations. As orthodox Jews must refrain from smoking during the Sabbath, examining their craving levels during this habitual abstinence may be informative in separating smoking deprivation from other determinants of craving and withdrawal. OBJECTIVE: To examine the extent to which the habitual abstinence of Orthodox Jews during the Sabbath is associated with craving to smoke and with other reactions to smoking abstinence. METHODS: Twenty orthodox Jewish heavy smokers were assessed three times: on a workday when smoking as usual, on a Sabbath when they never smoke, and on a forced abstinence workday. Craving, irritability, and other commonly reported smoking withdrawal symptoms were assessed retrospectively at several time points during the preceding 24 h. RESULTS: Craving to smoke, and to a lesser extent, irritability, was lower during the Sabbath than during the two other test days. Self-reported difficulty in abstaining was also lower on the Sabbath than on the workday. Craving in the evening preceding the test day was always significantly higher than in the next morning, despite the overnight abstinence before the morning assessment. CONCLUSIONS: These results support previous findings in showing that craving to smoke is determined to a large extent by smoking-related habits, cues, and expectations.

The effect of past-injury on pain threshold and tolerance.

Forty male veterans who had been injured during their military service in the Israeli Defense Forces were assessed for pain threshold and tolerance in a thermal pain procedure. Based on their medical records, subjects were classified by three independent judges as having been either severely or lightly injured. Veterans who had been severely injured had much higher threshold and tolerance for thermal pain as compared to lightly injured veterans. These results are interpreted as supporting adaptation-level theory, which implies that painful experiences can change the internal anchor points for the subjective evaluation of pain.

Development of thermal nociception in rats.

In the present study, we show that hypersensitivity to noxious thermal stimulation can be seen clearly in developing rats. Rats, at postnatal days 3, 6, 9, 12, 15, 21 and 90 were tested for reflex responsiveness to noxious heat, using tail withdrawal from hot water as the assay. Thermal nociceptive thresholds are considerably lowered, relative to adults, up to postnatal day 12. Thresholds were 39, 37.5, 40.8, 43.3, 46.5, 45.2 and 47.2 degrees C for the respective age groups. Enhanced sensitivity to suprathreshold noxious stimuli is seen in neonates up to postnatal day 15 (but not on day 9). Starting on day 21, sensitivity to noxious stimuli decreases with increasing age, as can be seen by the decrease in the slope of the temperature-response curve (system gain). Spinal transections at postnatal days 13, 17, 20, 60, or 100 did not produce a change in nociceptive thresholds in any of the age groups. In contrast, sensitivity to noxious stimulation (system gain) was enhanced by spinalization in rats 20 days of age or older. Based on these results we suggest that threshold elevation with increasing age most probably reflects changes in local spinal properties, while changes in responsiveness to suprathreshold noxious stimuli involves maturation of both spinal and descending supraspinal structures.

The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduces temporal summation of second pain in man.

Oral doses of dextromethorphan (DM), a common cough suppressant and N-methyl-D-aspartate (NMDA) receptor antagonist, and their vehicle control were given on a double-blind basis to normal volunteer human subjects who rated intensities of first and second pain in response to repeated painful electric shocks and repeated 52 degrees C heat pulses. Doses of 30 and 45 mg, but not 15 mg, were effective in attenuating temporal summation of second pain, a psychophysical correlate of temporal summation of C afferent-mediated responses of dorsal horn nociceptive neurons, termed 'wind-up'. By contrast, neither first nor second pain evoked by the first stimulus in a train of stimuli were affected by any of these doses of DM. These results further confirm temporal summation of second pain as a psychophysical correlate of wind-up by providing evidence that DM selectively reduces temporal summation of second pain, as has been shown for wind-up.

Continuous co-administration of dextromethorphan or MK-801 with morphine: attenuation of morphine dependence and naloxone-reversible attenuation of morphine tolerance.

N-Methyl-D-aspartate (NMDA) receptor antagonists have been repeatedly shown to attenuate the development of opiate tolerance and dependence in rodents. In the present experiments, continuous subcutaneous infusion of either MK-801 (0.01 mg/kg/h but not 0.005 mg/kg/h) or DM (0.133, 0.67 and 1.33 mg/kg/h) reliably prolonged the antinociceptive effect of continuous subcutaneous infusion of morphine sulfate (2.0 mg/kg/h), indicating attenuation of the development of morphine tolerance. Furthermore, this prolonged antinociception was completely reversible by naloxone (10 mg/kg, i.p.). Doses of MK-801 and DM that were equipotent in attenuating morphine tolerance (0.01 mg/kg/h and 1.33 mg/kg/h, respectively) revealed different profiles of effects, however, on locomotor activity and naloxone-precipitated abstinence/withdrawal symptoms. With regard to locomotor activity, rats having received continuous (48 h) subcutaneous infusion of morphine sulfate and MK-801, but not rats having received morphine sulfate and DM, displayed a reliable and striking increase in locomotor activity as compared with rats having received morphine alone. With regard to naloxone-precipitated withdrawal symptoms, continuous (48 h) subcutaneous co-infusion of either MK-801 (0.01 mg/kg/h) or DM (1.33 mg/kg/h) with morphine attenuated naloxone-precipitated hyperalgesia as compared with rats infused with morphine alone. MK-801 (0.01 mg/kg/h) was more effective than DM (0.133, 0.67, or 1.33 mg/kg/h), however, in reducing other naloxone-precipitated withdrawal symptoms (teeth chattering, jumping and wet dog shakes). The effects of MK-801 on all withdrawal symptoms were confounded, however, by the appearance of flaccidity following naloxone administration to rats having received MK-801 and morphine. These results extend previous observations by showing that the prolonged antinociception observed following co-administration of morphine and an NMDA antagonist is completely naloxone-reversible, supporting the notion that this antinociception reflects prolongation of an opioid receptor-mediated effect. The different profiles of side effects associated with MK-801 and DM, however, suggest that (1) attenuation of naloxone-precipitated withdrawal symptoms by MK-801 may be an artifact of toxicity, and (2) DM may prove clinically useful for the prevention of morphine tolerance, given its lack of observable side effects when administered concurrently with morphine to rodents.

Do smokers self-administer pure nicotine? A review of the evidence.

RATIONALE: Nicotine is almost universally believed to be the primary agent motivating tobacco smoking and the main impediment to cessation. A principal argument in support of the presumed reinforcing properties of nicotine is that smokers self-administer pure nicotine. However, the evidence for nicotine self-administration in smokers has not been critically examined. OBJECTIVES: To review and examine the empirical basis for the assertion that smokers self-administer pure nicotine. METHODS: We reviewed all the studies we were able to locate that are cited as demonstrating self-administration of nicotine, isolated from tobacco, in normal smokers and non-smokers. These studies investigated self-administration of intravenous nicotine, nicotine gum and nicotine spray. Using the authors' own criteria, we examined whether these studies in fact demonstrate nicotine-self administration. RESULTS: None of the studies we reviewed demonstrated nicotine self-administration in smokers. Both smokers and non-smokers failed to show preference for nicotine over placebo in any of these studies, including in a series of six reports of overnight abstinent smokers having access to nicotine nasal spray, a rapidly absorbed form of nicotine. CONCLUSIONS: The common statement that smokers self-administer pure nicotine lacks empirical support. Smokers in fact do not administer pure nicotine in any of the forms studied to date, even when abstinent and presumably nicotine-deprived. This conclusion necessitates a critical re-examination of the nicotine addiction thesis.

The influence of alcohol on behavioral recovery after mTBI in mice.

In the United States 258,000 people were injured in 2004 in motor vehicle accidents that were caused by drivers under the influence of alcohol. The majority of these drivers were binge drinkers, most notably young people who tend to drink heavily during the weekends, but rarely drink alcohol during the week. Since a large proportion of the injuries involved head injuries, the present study aimed at investigating the influence of binge alcohol drinking on mild traumatic brain injury (mTBI) in an animal model. Mice had access to 0%, 7.5%, 15%, or 30% alcohol solutions for 48 consecutive hours once a week for 4 weeks as the sole source of fluids (the remaining time they drank water). Three experiments were done. For the first one (alcohol-mTBI-alcohol) the animals were subjected to a controlled mTBI injury by applying a closed-head weight drop, or a sham procedure. After the mTBI/sham-mTBI the animals got alcohol and /water for the same regimen for 4 additional weeks. In the second experiment (alcohol only) after the 4 weeks of drinking blood samples were collected, at the same time as the animals that underwent sham-mTBI or mTBI procedures. In the third experiment (mTBI-alcohol) the mice were subjected to mTBI/sham-mTBI without any treatment, and after mTBI they had alcohol for 4 weeks in the same regimen as in the previous experiments. At the end of the pharmacological treatment all animals were assessed using different behavioral tests. mTBI mice exhibited lower memory ability in the Y-maze, higher anxiety in the elevated plus maze, and lower retention in the passive avoidance test than sham-mTBI animals. Alcohol reversed these effects at all doses. The results suggest that alcohol drinking before trauma might have a protective effect on recovery from brain trauma, but not if consumed after the trauma.

The craving to smoke in flight attendants: relations with smoking deprivation, anticipation of smoking, and actual smoking.

In the study, the authors examined the effects of smoking deprivation, anticipation of smoking, and actual smoking on the craving to smoke. Flight attendants who were light to heavy smokers rated their craving to smoke at predetermined time points during a 2-way short flight (each leg 3-5.5 hr) and a 1-way long flight (8-13 hr). In both short and long flights, craving increased gradually and peaked as landing approached. Craving levels at the end of the 1st leg of the short flights were equal to those at the end of the long flight and were much higher than those at the parallel time point in the long flight. In the short flight, craving levels at the beginning of the 2nd leg dropped relative to the end of the 1st leg, both for participants who smoked during the intermission and for those who did not, though the drop was steeper for the former. The results provide additional evidence for the role of psychological factors in determining the craving to smoke in a naturalistic setting.

Antifreeze protein suppresses spontaneous neural activity and protects neurons from hypothermia/re-warming injury.

Antifreeze proteins (AFP) are associated with protection from freezing. We measured the effect of type I antifreeze protein on spontaneous bursting of mixed neuronal/glial cultures using a multi-electrode array culture system. Antifreeze protein (10mg/ml) reversibly depressed bursting activity without inhibiting mitochondrial oxidative capacity. The effect of antifreeze protein on cold/re-warming injury was investigated in rat hippocampal slice cultures. Compared to bovine serum albumin at a similar concentration, antifreeze protein protected hippocampal neurons from 8h of profound hypothermia at (4 degrees C) followed by re-warming. The protection observed is believed to be associated with the inhibitory effect of antifreeze protein.