Craig G. McDonald

A novel approach to the physiological measurement of mental workload

While performing a visuo-motor task under incrementally-varied levels of difficulty, individuals were probed with a variety of novel, task-irrelevant, auditory stimuli. To determine the effect of task load on cerebral-cortical processing of these stimuli, event-related potentials were recorded while participants performed the task. We found that N1, P2, P3 and late positive potential (LPP) component amplitudes were inversely related to task-difficulty. This suggests that a variant of the oddball paradigm - in which the stimulus stream comprises novel sounds - is capable of providing a reliable index of mental workload.

Long-term changes in fear conditioning and anxiety-like behavior following nicotine exposure in adult versus adolescent rats

Adolescent nicotine exposure is associated with long-term use, and it has been suggested that this vulnerability to addiction may relate to lasting anxiogenic effects of the drug. However, few studies have addressed long-term effects of adolescent nicotine, and fewer yet have compared adolescent to adult exposure. Male and female Long-Evans rats continuously received nicotine bitartrate or sodium tartrate via osmotic mini-pumps over 15 days either during adolescence (p28-42) or adulthood (p85-99). Initial nicotine dose (free base) was either low (1 mg/kg/day) or high (2 mg/kg/day). Open field behavior and fear conditioning were assessed in adulthood, 1 month post-dosing. Animals pretreated with nicotine during adolescence showed less center time in a novel open field than sham controls. Conversely, the two nicotine doses differentially affected fear conditioning. Animals pretreated with low nicotine during adolescence demonstrated superior acquisition of the task compared to sham control animals; however, unlike either high nicotine-pretreated or sham control animals, they failed to extinguish the learned behavior. In contrast, animals pretreated during adulthood did not behave significantly different from sham controls on either task. Overall, nicotine-pretreatment during adolescence induced effects on behaviors related to fear and anxiety in adulthood, while comparable pretreatment during adulthood failed to produce significant residual effects.

Nicotine place preference in a biased conditioned place preference design

Conditioned place preference (CPP) is often more effectively produced with nicotine using a biased procedure. Interpretation of results can be problematic, however, given that doses that produce CPP in rats have acute anxiolytic and residual anxiogenic effects. We tested three groups of male rats in a biased, 2-chambered apparatus. Over eight conditioning days, one group (paired group) received four alternating injections of nicotine paired with the non-preferred (white) chamber and of saline in the preferred (black) chamber. A second group (counterbalanced group) received two nicotine injections each paired with the black and white chambers, with saline pairings on alternate days. A third group (saline control) received saline injections paired with both chambers. Following conditioning, the paired group spent significantly more time in the initially non-preferred chamber relative to saline-treated controls, suggesting CPP. The counterbalanced group did not show a significant preference shift, providing evidence that the observed preference shift in the paired group was not due to a drug-induced unconditioned reduction in aversion. Although this finding is consistent with the notion that nicotine produced CPP through its rewarding effects, we cannot discount the possibility of a conditioned reduction in aversion to the non-preferred chamber. For the paired group, a negative correlation was found between time spent in the white chamber before conditioning and preference shift following conditioning, suggesting that animals showing greater initial aversion to a non-preferred context are more likely to form CPP.

Late emerging effects of prenatal and early postnatal nicotine exposure on the cholinergic system and anxiety-like behavior.

Animal models of prenatal nicotine exposure clearly indicate that nicotine is a neuroteratogen. Some of the persisting effects of prenatal nicotine exposure include low birth weight, behavioral changes and deficits in cognitive function, although few studies have looked for neurobehavioral and neurochemical effects that might persist throughout the lifespan. Pregnant rats were given continuous infusions of nicotine (0.96mg/kg/day or 2.0mg/kg/day, freebase) continuing through the third trimester equivalent, a period of rapid brain development. Because the third trimester equivalent occurs postnatally in the rat (roughly the first week of life) nicotine administration to neonate pups continued via maternal milk until postnatal day (P) 10. Exposure to nicotine during pre- and early postnatal development had an anxiogenic effect on adult rats (P75) in the elevated plus maze (EPM), and blocked extinction learning in a fear conditioning paradigm, suggesting that pre- and postnatal nicotine exposure affect anxiety-like behavior and cognitive function well into adulthood. In contrast, nicotine exposure had no effect on anxiety-like behaviors in the EPM in adolescent animals (P30). Analysis of mRNA for the alpha4, alpha7, and beta2 subunits of nicotinic acetylcholine receptors revealed lower expression of these subunits in the adult hippocampus and medial prefrontal cortex following pre- and postnatal nicotine exposure, suggesting that nicotine altered the developmental trajectory of the brain. These long-term behavioral and neurochemical changes strengthen the case for discouraging cigarette smoking during pregnancy and clearly indicate that the use of the patch as a smoking cessation aid during pregnancy is not a safe alternative.

Periadolescent nicotine administration produces enduring changes in dendritic morphology of medium spiny neurons from nucleus accumbens.

The objective of the current study was to examine how periadolescent nicotine exposure affects dendritic morphology of medium spiny neurons from the nucleus accumbens shell. Male Long-Evans hooded rats were chronically administered nicotine or saline for a period extending from postnatal day 22 (p22) to p69. Nicotine and saline administration was via subcutaneously implanted osmotic pumps. At p144, 75 days after conclusion of nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from the nucleus accumbens shell were digitally reconstructed. It was found that neurons from nicotine-treated animals possessed significantly longer dendrites and a greater number of dendritic segments than control animals. A branch order analysis indicated that differences in dendritic length and segment number were most pronounced in third and fourth order segments. A subsequent behavioral experiment suggests that the observed anatomical changes are associated with enduring psychomotor differences. These findings indicate that periadolescent exposure to nicotine can result in long-lasting structural changes in the nucleus accumbens shell and are consistent with behavioral data suggesting that adolescent nicotine exposure may result in vulnerability to nicotine addiction in adulthood.

Adolescent nicotine induces persisting changes in development of neural connectivity.

Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part through D1DR receptors, in a network activated by nicotine. The adolescent nicotine effects reviewed here suggest that modification of late CNS development constitutes a hazard of adolescent nicotine use.

Evidence for elevated nicotine-induced structural plasticity in nucleus accumbens of adolescent rats.

Male Long-Evans rats were administered nicotine bitartrate or sodium tartrate either during adolescence (p29-43) or adulthood (p80-94). Route of administration was via subcutaneously implanted osmotic pump (initial dose 2.0 mg/kg/day, free base). Five weeks following nicotine administration, brains were processed for Golgi-Cox staining. Medium spiny neurons from nucleus accumbens (NAc) shell were digitally reconstructed for morphometric analysis. Total dendritic length and branch number were greater in medium spiny neurons from animals pretreated with nicotine during adolescence. A branch order analysis indicated that increased branch number was specific to higher order branches. Mean branch lengths did not differ with respect to treatment as a function of branch order. Thus, nicotine-induced increases in total dendritic length were a function of greater numbers of branches, not increased segment length. In contrast, adult nicotine exposure did not significantly alter total dendritic length or branch number of medium spiny neurons. Total dendritic length and branch number of a second morphological type, the large aspiny neuron, did not differ following either adolescent or adult pretreatment. The age-dependent alteration of accumbal structure was associated with qualitatively different behavioral responses to drug challenge. These data provide evidence that drug-induced structural plasticity in nucleus accumbens is considerably more pronounced during adolescence.

Alcohol exposure during adolescence impairs auditory fear conditioning in adult Long-Evans rats

Few studies have examined long-term effects of ethanol on auditory fear conditioning, and fewer still have examined whether adolescence represents a unique period of vulnerability. We investigated the impact of ethanol consumption during adolescence and adulthood on fear conditioning, following an extended abstinence period. Male and female Long-Evans rats (N = 80) consumed 10% ethanol or water (control) in a limited-access drinking paradigm (1 h) between postnatal (P) days 28-45 (adolescent) and P80-97 (adult). After the abstinence period (30 days), ethanol and control groups were assessed on the auditory fear-conditioning task. Alcohol consumption impaired tone conditioning in the male and female adolescent group. There were no persisting effects of adult dosing. In addition, adolescent rats consumed more ethanol than adults. These data provide evidence that ethanol consumption during adolescence produces enduring effects on auditory fear conditioning. The age-specific effect of ethanol may be attributable to an interplay of higher ethanol intake and the unique neurobiological characteristics of adolescents.

The N2 ERP component as an index of impaired cognitive control in smokers

Impaired cognitive control has been proposed as a hallmark of nicotine dependence and is thought to arise, in part, from synaptic alterations in anterior cingulate cortex (ACC), a primary component of the dopamine reward pathway. The N2 component of the event-related potential (ERP) appears to index a cognitive control process in paradigms such as the visual go/no-go task. Moreover, as dipole-modeling has suggested that the neural generator of the N2 component can be localized to the ACC, this component may prove useful for investigating impairments of cognitive control in smokers. Given conflicting reports of whether the N2 is reduced in smokers (as compared to non-smoker controls), the current study further examined the suitability of this component as an index for impaired cognitive control in smokers. Smokers and non-smokers performed a visual go/no-go task while electroencephalogram (EEG) was recorded. As predicted, the no-go N2 of smokers was significantly smaller than that of non-smoker controls, while the no-go P3 did not differ between groups. Importantly, behavioral performance (reaction time and accuracy) did not differ between smokers and nonsmokers, which might reflect the low levels of nicotine dependence (assessed by the Fagerstrom test) in our sample. The observed N2 modulation in the absence of behavioral impairments provides evidence for the utility of the N2 component as a sensitive measure of impaired cognitive control in smokers, even in those with low levels of nicotine dependence.

Chronic Nicotine Exposure Produces Lateralized, Age-Dependent Dendritic Remodeling in the Rodent Basolateral Amygdala

This study investigated the dendritic morphology of neurons located in the right and left basolateral amygdala (BLA) and infralimbic (IL) cortex following chronic nicotine exposure during adolescence or adulthood. Sprague–Dawley rats were administered subcutaneous injections of nicotine (0.5 mg/kg; free base) or saline three times per week for 2 weeks (six total injections). The dose period began on either postnatal day (P) 32 (adolescent) or P61 (adult). Twenty days following the end of dosing, brains were processed for Golgi‐Cox staining, and dendrites from principal neurons in the BLA and pyramidal neurons in the IL were digitally reconstructed in three dimensions. Morphometric analysis revealed a contrasting pattern of BLA dendritic morphology between the adolescent and adult pretreatment groups. In the adult control group, basilar dendritic length did not differ with respect to hemisphere. Nicotine induced robust hemispheric asymmetry by increasing dendritic length in the right hemisphere only. In contrast, adolescent nicotine exposure did not produce significant alteration of basilar dendritic morphology. There was, however, an indication that nicotine eliminated a naturally existing hemispheric asymmetry in the younger cohort. At both ages, nicotine produced a reduction in complexity of the apical tree of principal neurons. Chronic nicotine did not affect the dendritic morphology of pyramidal neurons from the IL in either age group, indicating another dimension of anatomical specificity. Collectively, these data implicate the BLA as a target for lasting neuroplasticity associated with chronic nicotine exposure. Further, hemispheric differences in dendritic morphology were uncovered that depended on the age of nicotine exposure, a finding that underscores the importance of considering laterality when investigating neurodevelopmental effects of drug exposure. Synapse 64:754–764, 2010.