Impact of reduced nicotine content on behavioral economic measures of cigarette reinforcement in adolescents who smoke cigarettes.

BACKGROUND: Public health officials in the U.S. and New Zealand are considering a reduced nicotine standard for cigarettes to reduce their addictive potential. This study's aim was to evaluate the effects of nicotine reduction on the reinforcing efficacy of cigarettes in adolescents who smoke, which has implications for this policy's potential for success. METHODS: Adolescents who smoked cigarettes daily (n = 66; mean age: 18.6) participated in a randomized clinical trial assessing effects of assignment to very low nicotine content (VLNC; 0.4 mg/g nicotine) or normal nicotine content (NNC; 15.8 mg/g nicotine) cigarettes. Hypothetical cigarette purchase tasks were completed at baseline and the end of Week 3 and demand curves fit to the data. Linear regressions estimated effects of nicotine content on demand for study cigarettes at baseline and Week 3 and associations between baseline demand for cigarette consumption at Week 3. RESULTS: An extra sum of squares F-test of fitted demand curves indicated that demand (α) was more elastic among VLNC participants at baseline and Week 3 (F(2, 1016)= 35.72, p < 0.001). Adjusted linear regressions indicated demand was more elastic (ß= 1.45, p < 0.01) and maximum expenditure (Omax) lower (ß= -1.42, p-0.03) among VLNC participants at Week 3. More elastic demand for study cigarettes at baseline predicted lower consumption of cigarettes at Week 3 (p's < 0.01). CONCLUSIONS: A nicotine reduction policy may reduce the reinforcing value of combustible cigarettes among adolescents. Future work should investigate likely responses to such a policy among youth with other vulnerabilities and evaluate the potential for substitution to other nicotine containing products.

Associations Between Nicotine Knowledge and Smoking Cessation Behaviors Among US Adults Who Smoke.

INTRODUCTION: Misperceptions about nicotine's contribution to smoking-related health harms could complicate efforts to reduce the public health burden of smoking. Study goals were to describe nicotine knowledge among adults who smoke and investigate whether misperceiving nicotine as a source of health harm was associated with beneficial health behaviors, or lower uptake of using less harmful sources of nicotine to support smoking cessation attempts. METHOD: This study used longitudinal data from 9140 adults who participated in four waves of the Population Assessment of Tobacco and Health Study and were current smokers during the first wave. Logistic regressions estimated odds ratios for correct responses across six aspects of nicotine knowledge assessed in Wave 4. Longitudinal models estimated associations between misperceptions and cigarette consumption, and odds of making a quit attempt; self-reported cessation; e-cigarette use; and use of NRT or e-cigarettes to support quit attempts. RESULTS: Participants who were non-White, older, and had lower educational attainment or income tended to be least knowledgeable about nicotine. Misperceiving nicotine as harmful to health was associated with increased odds of quit attempts (AOR: 1.12, 95% CI: 1.03, 1.23), lower odds of cessation success (AOR: 0.84, 95% CI: 0.73, 0.98) and e-cigarette use (AOR: 0.79, 95% CI: 0.72, 0.86), and lower odds of using NRT (AOR: 0.84, 95% CI: 0.71, 0.99) or e-cigarettes to support quit attempts (AOR: 0.59, 95% CI: 0.49, 0.71). CONCLUSION: Harm reduction efforts may be impeded by misperceptions about nicotine. Further work should evaluate the effects of correcting such misperceptions through public education. IMPLICATIONS: This study provides longitudinal evidence that among adult smokers, misperceiving nicotine as a primary cause of smoking-related diseases may be associated with reduced cessation success and lower likelihood of using less harmful nicotine products. These misperceptions may therefore impede efforts to encourage smokers ready to quit to use evidence-based cessation support such as nicotine replacement during quit attempts and limit the success of policies designed to shift smokers to less harmful sources of nicotine. Further work should evaluate the longitudinal effects of correcting nicotine misperceptions through public education targeted toward adults who smoke.

d-amphetamine increases choice of cigarette smoking over monetary reinforcement.

RATIONALE: Psychomotor stimulants previously have been found to increase the frequency of cigarette smoking, but it is unclear whether this is due to a non-specific increase in general activity or a specific increase in the reinforcing effects of smoking. OBJECTIVES: To investigate whether d-amphetamine increases the relative reinforcing effects of cigarette smoking. METHODS: Ninety minutes after d-amphetamine (7.5, 15 mg/70 kg) or placebo administration, 13 male and female subjects participated in 3-h sessions during which they could make a maximum of 20 choices between cigarette smoking (two puffs per choice), earning money ($0.25 per choice), or neither. In separate sessions, using the same subjects, the effects of d-amphetamine on the frequency of ad libitum smoking was assessed. RESULTS: During choice sessions, d-amphetamine dose-dependently increased smoking choices from 4.2 +/- 0.6 to 5.7 +/- 0.6. During sessions in which subjects smoked ad libitum, d-amphetamine increased number of cigarettes smoked from 2.8 +/- 0.4 to 3.8 +/- 0.6. Breath carbon monoxide (CO) levels, a measure of smoke exposure, showed corresponding dose-related increases. CONCLUSIONS: These results are consistent with previous findings that d-amphetamine increases smoking and provide evidence that this effect is due to a drug-produced increase in the relative reinforcing effects of cigarette smoking.

Effects of abstinence on cigarette smoking among outpatients with schizophrenia.

The authors of this study examined the effects of brief smoking abstinence on smoking among 6 individuals with schizophrenia or schizoaffective disorder. Before 6 of 12 experimental sessions, participants were required to provide breath carbon monoxide (CO) samples indicative of smoking abstinence; before the remaining sessions, participants provided CO samples indicating no abstinence. During sessions, participants obtained smoking opportunities (2 puffs/opportunity) under either fixed ratio-1 or progressive ratio (PR) schedules of reinforcement. Abstinence increased smoking under both schedules and increased breakpoint for smoking under the PR schedule. These data offer further evidence that smoking by individuals with schizophrenia is orderly, operant behavior that is modulated, at least in part, by variables that also affect smoking in people without major mental illness.

Effects of response requirement and the availability of an alternative reinforcer on cigarette smoking by schizophrenics.

Cigarette smoking and other forms of drug abuse are more prevalent among schizophrenics than the general population. Despite the clinical importance of this problem, there has been relatively little experimental study of schizophrenic drug use. We examined under controlled laboratory conditions the effects of response requirement and the availability of an alternative (monetary) reinforcer on cigarette smoking by schizophrenics. Subjects were six heavy smokers with diagnoses of schizophrenia or schizoaffective disorder. Before each session, subjects provided carbon monoxide samples indicating recent smoking abstinence. During 3-h sessions, subjects obtained opportunities to smoke (2 puffs/opportunity) under a fixed ratio (FR) schedule of reinforcement, which varied across sessions from FR50 to FR6400. In half of the sessions, subjects also were able to earn a small amount of money ($0.25/ratio completed) under an FR400 schedule. Increasing the response requirement for smoking decreased smoking and increased smoking-maintained responding. The availability of the monetary reinforcer decreased smoking and smoking-maintained responding by approximately half. These results are consistent with those seen previously in community volunteers without major mental illness studied under the same experimental conditions, suggesting that smoking by these two populations is controlled, at least in part, by a common set of determinants.

Drug discrimination in methamphetamine-trained monkeys: agonist and antagonist effects of dopaminergic drugs.

The involvement of D1 and D2 subtypes of dopamine receptors in behavioral effects of methamphetamine was studied in squirrel monkeys using a two-lever drug discrimination procedure. In monkeys that discriminated i.m. injections of 0.3 mg/kg methamphetamine from saline, methamphetamine (0.03-0.3 mg/kg), cocaine (0.1-1.0 mg/kg) and the selective dopamine uptake inhibitor, GBR 12909 (3.0-17.8 mg/kg) produced dose-related increases in responding on the methamphetamine-associated lever and, at the highest doses, full substitution. In contrast, the norepinephrine and serotonin uptake inhibitors, tomoxetine (1.0-17.8 mg/kg) and fluoxetine (0.3-10.0 mg/kg), respectively, did not substitute appreciably for methamphetamine. Substitution for methamphetamine also was observed with the D1 receptor agonists, SKF 81297, SKF 82958 and dihydrexidine, and the D2 receptor agonist, (+)-PHNO in the majority of monkeys. Lower-efficacy D1 or D2 agonists substituted for methamphetamine either partially (SDZ 208-911) or not at all (SKF 77434, SDZ 208-912). Pretreatment with dopamine receptor blockers [D1 (SCH 39166, 0.1 mg/kg) or D2 (remoxipride, 3.0 mg/kg and nemonapride, 0.003 mg/kg)] and low-efficacy agonists [D1 (SKF 77434; 3.0 mg/kg) or D2 (SDZ 208-911 and SDZ 208-912; 0.01-0.03 mg/kg)] antagonized the discriminative-stimulus effects of methamphetamine. In separate studies, comparable doses of each of these drugs, except SKF 77434, induced significant levels of catalepsy-associated behavior. These results support the view that both dopaminergic D1 and D2 mechanisms mediate the discriminative-stimulus effects of methamphetamine; further, they indicate that selected dopamine D1 partial agonists may have antagonist actions at doses that do not produce undesirable effects associated with dopamine receptor blockade.

Psychiatric symptom severity in cocaine-dependent outpatients: demographics, drug use characteristics and treatment outcome.

Psychiatric symptom severity and associated characteristics were assessed in 185 individuals seeking outpatient treatment for cocaine dependence. The sample was divided into groups of low, medium and high psychiatric symptom severity based on Addiction Severity Index psychiatric composite scores. Patients with high symptom severity reported poorer pre-treatment functioning and more adverse consequences of cocaine use than the lower severity groups. Relationships between psychiatric severity and treatment outcome variables were assessed in a subset of 123 patients who received one of three 24-week psychosocial treatments for cocaine abuse: (i) behavioral treatment with a voucher-based incentive program; (ii) the same behavioral treatment without vouchers; (iii) or drug abuse counseling. Psychiatric symptom severity failed to influence treatment outcome with any of these treatments. Thus, in this study the authors found no evidence to indicate that high psychiatric severity predicts poor response to psychosocial treatment for cocaine abuse.

Acquisition of cocaine self-administration after social stress: role of accumbens dopamine.

Exposure to either aversive or rewarding environmental stimuli increases extracellular dopamine (DA) concentrations in terminal areas of the mesocorticolimbic dopamine system. Furthermore, behavioral reactivity to an environmental stressor has been shown to correlate with latency to initiate self-administration of psychomotor stimulant drugs. The present study examined the behavioral and dopaminergic responses of rats to social defeat stress and compared latencies to initiate cocaine self-administration in defeated and non-defeated rats. In vivo microdialysis was used to examine the effects of social defeat stress on DA concentrations in nucleus accumbens of freely-moving rats. During the experimental session, dialysate and video recording samples were collected from previously-defeated and non-defeated "intruder" rats in consecutive phases, while (1) in the home cage, (2) when placed in the empty, soiled cage of a resident rat which had previously defeated them, and (3) when exposed to threat of defeat by the resident. Immediately following threat of defeat, previously-defeated and non-defeated intruders were given the opportunity to self-administer cocaine IV. When exposed to the olfactory cues of an aggressive resident, extracellular DA levels in nucleus accumbens increased to approximately 135% of baseline in previously defeated rats versus 125% of baseline in non-defeated rats. When exposed to social threat by the resident, DA levels further increased to 145% of baseline in previously defeated rats versus 120% in non-defeated rats. Previously defeated rats acquired cocaine self-administration in approximately half the time of non-defeated rats, consistent with the hypothesis that prior stress exposure may induce a cross-sensitization to the rewarding effects of cocaine. These results are consistent with the idea that exposure to stress may induce changes in central dopaminergic activity, which may render an individual more vulnerable to acquiring psychomotor stimulant self-administration.

Social defeat stress selectively alters mesocorticolimbic dopamine release: an in vivo microdialysis study.

Exposure to various aversive stimuli ('stressors') as well as positively-reinforcing stimuli has been shown to increase extracellular dopamine concentrations in terminal areas of the mesocorticolimbic dopamine system. The magnitude and site specificity of the dopaminergic response may depend on the nature of the aversive stimulus. In the present study, in vivo microdialysis was used to examine the effects of an ethologically relevant stressor, namely threat of social defeat, on dopamine concentrations in nucleus accumbens, striatum, and prefrontal cortex of freely-moving male Long-Evans rats. During the test session, dialysate and video recording samples were collected from previously-defeated 'intruder' rats in consecutive phases, while (1) in the home cage, (2) when placed in the empty, soiled cage of a resident rat which had previously defeated them, (3) when exposed to threat of defeat by the resident, and (4) when returned to their home cages. Control animals were not defeated; in this group of rats video recording and dialysate samples were obtained when they were placed into an empty, clean novel cage and later returned to their home cage. The results indicated that levels of dopamine were elevated to approximately 130% of baseline in nucleus accumbens and prefrontal cortex when rats were placed into either the resident or novel cage. In defeated intruders, extracellular dopamine levels in accumbens and prefrontal cortex were increased further (approximately 160% of baseline), during social threat; these biochemical changes were synchronous with high levels of orienting toward the resident but not with heightened motor activity. Extracellular dopamine levels in lateral striatum were not affected by either manipulation. These results suggest that altered accumbens and cortical extracellular dopamine concentrations during social threat are not secondary to motor activation but instead reflect increased attention to the provocative stimulus or attempts by the intruder to 'cope' with the stimulus.

Effects of SKF 38393 and quinpirole on aggressive, motor and schedule-controlled behaviors in mice.

The respective roles of D1 and D2 dopamine receptors in mediating motor functions, aggressive behaviors and reinforcement processes have not been specified. The present experiments examined conditioned and unconditioned behaviors of mice under different demands and reinforcing contingencies. We compared the behavioral effects of the D2 agonist quinpirole and the D1 partial agonist SKF 38393 on motor activities, aggressive behaviors and schedule-controlled responses in male mice that were either pair-housed with a female for 4 weeks or singly-housed. Singly-housed mice were found to be more active than pair-housed mice both when alone in the home cage and in the presence of a male intruder. However, the effects of both quinpirole and SKF 38393 were substantially similar for both singly- and pair-housed mice. Quinpirole decreased motor activity, aggressive behavior, and schedule-controlled responding. In contrast, SKF 38393 decreased schedule-controlled responding at doses that did not affect either motor or aggressive behaviors. The relative behavioral specificity of SKF 38393 suggests that D1 activation alters the temporal patterning of behavior, while D2 activation appears to cause a more general suppression of behavior in mice.

Morphine withdrawal aggression: modification with D1 and D2 receptor agonists.

Morphine withdrawal increases aggressive behaviors, induces explosive motor behaviors, and disrupts homeostatic functions in mice and rats. While many of these effects appear to result from altered dopaminergic activity during morphine withdrawal, the relative contributions of the D1 and D2 receptor subtypes remain unclear. In the present experiments, the D1 agonist SKF 38393 and the D2 agonist quinpirole were administered to male "resident" Swiss-Webster mice 5 h after the removal of a subcutaneously-implanted morphine or placebo pellet. These mice were then observed alone to determine changes in various motor activities and in confrontation with a group-housed male "intruder" to assess changes in aggressive behaviors. SKF 38393 decreased the display of aggressive behaviors by placebo and morphine-withdrawn mice without consistently altering walking or rearing. Quinpirole greatly decreased the display of aggressive behaviors by placebo mice and decreased aggressive behaviors in morphine-withdrawn mice to a lesser degree. The inhibitory effects of quinpirole were not specific to aggressive behaviors; low quinpirole doses also decreased the display of walking and rearing. In mice which received a low dose of SKF 38393 preceding quinpirole injection, pretreatment with the D1 agonist did not alter the effects of the D2 agonist quinpirole on motor activities but maintained high levels of aggression in morphine-withdrawn mice. The differential modification of aggressive and motor behaviors by selective dopaminergic agonists during morphine withdrawal further supports the suggestion that aggressive and motor behaviors are controlled independently; furthermore, D1 receptor stimulation appears to have particular relevance for the display of aggressive behaviors during morphine withdrawal.

Heightened aggressive behavior during morphine withdrawal: effects of d-amphetamine.

The morphine withdrawal syndrome is composed of profound short- and long-term changes in autonomic, somato-motor and affective functions. In mice, morphine withdrawal produces heightened aggressive behavior and alterations in motor behavior; however, it is unclear whether these changes in behavior occur in unison and are dependent on a common mechanism or occur independently. In order to characterize the morphine withdrawal syndrome in mice, male Swiss-Webster mice were housed with female partners for 3-4 weeks before being implanted subcutaneously with morphine or placebo pellets. The pellets were removed 72 h after implantation and behavioral measurements were conducted 5, 48 and 96 h after pellet removal. During these tests, mice received d-amphetamine (0.3-10 mg/kg) or saline after which they were assessed for changes in motor behavior and for changes in aggressive behavior while confronting a group-housed male "intruder". In morphine-withdrawn mice, frequency of attack behavior was increased by approximately 30% and this effect persisted for at least 4 days. In contrast, explosive jumping was increased and walking and rearing were greatly decreased at the onset of the withdrawal period but declined within the first 24 h and returned to control levels within 48 h of pellet removal. d-Amphetamine maintained the elevated level of aggressive behavior and sharply increased locomotion in morphine-withdrawn mice; in placebo-pelleted mice, d-amphetamine dose-dependently decreased aggressive behaviors while increasing locomotion. The differential time course and the differential modification by d-amphetamine suggest that heightened aggressive behavior is a long-lasting consequence of morphine-withdrawal based on separate mechanisms than the short-lived alterations in motor activity.

Amphetamines: aggressive and social behavior.

Clinical case reports and survey data point to incidences of intense violence in certain individuals self-administering high doses of amphetamine via the intravenous route. It is unclear how common this amphetamine effect is, what circumstances promote its occurrence, and which characteristics predispose an individual to exhibit this effect. Amphetamine may engender a dose-dependent biphasic effect on aggressive behavior in experimental situations, both with human and animal subjects, as, for example, in subjects that have habituated to an aggression-provoking stimulus. Most often, however, amphetamines disrupt social, sexual, maternal, and aggressive behavior patterns in a dose-dependent manner; neither tolerance nor sensitization appears to develop to these disruptive effects. Amphetamine consistently enhances defensive and flight reactions in various experimental situations and animal species. This effect appears to be mediated by brain dopaminergic systems. So far, no dopaminergic, noradrenergic, or opioid antagonists have been found that attenuate, reverse, or prevent the disruptive effects of amphetamines on social and aggressive behavior. The evidence from opioid-withdrawn subjects strongly suggests a profound modulatory influence by opioid peptides on the aggression-altering effects of amphetamines.