Cortical thinness and volume differences associated with marijuana abuse in emerging adults.

BACKGROUND: The prevalence of marijuana (MJ) use among youth and its legalization for medical or recreational use has intensified public health endeavors of understanding MJ effects on brain structure and function. Studies indicate that MJ use is related to impaired cognitive performance, and altered functional brain activation and chemistry in adolescents and adults, but MJ effects on brain morphology in emerging adults are less understood. METHODS: Fifteen MJ users (age 21.8±3.6, 2 females) and 15 non-user (NU) participants (age 22.3±3.5, 2 females) were included, demographically matched on age, education and alcohol use. High-resolution structural MR images were acquired at 3Tesla. Cortical thickness (CT) and volumetric analyses were performed using Freesurfer. A priori regions of interest (ROI) included orbitofrontal and cingulate cortices, amygdala, hippocampus and thalamus. RESULTS: Whole brain CT analysis did not result in significant group differences in a priori ROIs but revealed MJ users had significantly less CT (i.e., thinness) in right fusiform gyrus (rFG) compared to NU (p<0.05). Thalamic volume was significantly smaller in MJ users compared to NU (right, p=0.05; left, p=0.01) and associated with greater non-planning (p<0.01) and overall impulsivity (p=0.04). There were no other group differences. CONCLUSIONS: RFG cortical thinness and smaller thalamic volume in emerging adults is associated with MJ abuse. Furthermore, smaller thalamic volume associated with greater impulsivity contributes to growing evidence that the thalamus is neurobiologically perturbed by MJ use. Collectively, altered thalamic and rFG structural integrity may interfere with their known roles in regulating visuoperceptual and object information processing.

Differential influence of safe versus threatening facial expressions on decision-making during an inhibitory control task in adolescence and adulthood.

Social cognition matures dramatically during adolescence and into early adulthood, supported by continued improvements in inhibitory control. During this time, developmental changes in interpreting and responding to social signals such as facial expressions also occur. In the present study, subjects performed a Go No-Go task that required them to respond or inhibit responding based on threat or safety cues present in facial expressions. Subjects (N = 112) were divided into three age groups: adolescent (12-15 years), emerging adult (18-25 years) and adult (26-44 years). Analyses revealed a significant improvement in accuracy on No-Go trials, but not Go trials, during both safe and threat face conditions, with changes evident through early adulthood. In order to better identify the decision-making processes responsible for these changes in inhibitory control, a drift diffusion model (DDM) was fit to the accuracy and reaction time data, generating measures of caution, response bias, nondecision time (encoding + motor response), and drift rate (face processing efficiency). Caution and nondecision time both increased significantly with age while bias towards the Go response decreased. Drift rate analyses revealed significant age-related improvements in the ability to map threat faces to a No-Go response while drift rates on all other trial types were equivalent across age groups. These results suggest that both stimulus-independent and stimulus-dependent processes contribute to improvements in inhibitory control in adolescence with processing of negative social cues being specifically impaired by self-regulatory demands. Findings from this novel investigation of emotional responsiveness integrated with inhibitory control may provide useful insights about healthy development that can be applied to better understand adolescent risk-taking behavior and the elevated incidence of related forms of psychopathology during this period of life.

Citicoline enhances frontal lobe bioenergetics as measured by phosphorus magnetic resonance spectroscopy.

Citicoline supplementation has been used to ameliorate memory disturbances in older people and those with Alzheimer's disease. This study used MRS to characterize the effects of citicoline on high-energy phosphate metabolites and constituents of membrane synthesis in the frontal lobe. Phosphorus ((31)P) metabolite data were acquired using a three-dimensional chemical-shift imaging protocol at 4 T from 16 healthy men and women (mean +/- SD age 47.3 +/- 5.4 years) who orally self-administered 500 mg or 2000 mg Cognizin Citicoline (Kyowa Hakko Kogyo Co., Ltd, Ibaraki, Japan) for 6 weeks. Individual (31)P metabolites were quantified in the frontal lobe (anterior cingulate cortex) and a comparison region (parieto-occipital cortex). Significant increases in phosphocreatine (+7%), beta-nucleoside triphosphates (largely ATP in brain, +14%) and the ratio of phosphocreatine to inorganic phosphate (+32%), as well as significant changes in membrane phospholipids, were observed in the anterior cingulate cortex after 6 weeks of citicoline treatment. These treatment-related alterations in phosphorus metabolites were not only regionally specific, but tended to be of greater magnitude in subjects who received the lower dose. These data show that citicoline improves frontal lobe bioenergetics and alters phospholipid membrane turnover. Citicoline supplementation may therefore help to mitigate cognitive declines associated with aging by increasing energy reserves and utilization, as well as increasing the amount of essential phospholipid membrane components needed to synthesize and maintain cell membranes.

The effects of NMDA and GABAA pharmacological manipulations on acute and rapid tolerance to ethanol during ontogeny.

BACKGROUND: Sensitivity to several ethanol effects increases during ontogeny, perhaps in part because of a notable decline in acute tolerance. In contrast, rapid tolerance to ethanol-induced sedation emerges slowly during ontogeny. This study tested the hypothesis that ontogenetic differences in glutamate and/or gamma-aminobutyric acid systems influence tolerance expression. METHODS: Sprague-Dawley rats at postnatal day (P)26 or P70 received (+)MK-801, muscimol, or saline before ethanol (3.5 or 4.5 g/kg) or saline on day 1 and ethanol only on day 2. Loss of and time to regain the righting reflex and blood alcohol levels at recovery were recorded. The presence of acute tolerance was indicated as a positive slope of the linear regression of blood alcohol levels at recovery versus ethanol dose. Rapid tolerance was estimated on day 2 by comparing animals given ethanol only on day 2 with those given ethanol on both days. RESULTS: Acute tolerance on day 1 only was observed at P26; this was disrupted by (+)MK-801 but not muscimol. Evidence for acute tolerance also emerged in adults on day 2. Whereas both drugs increased ethanol sedation at both ages, they did not facilitate ontogenetic expression of rapid tolerance: rapid tolerance was not evident at P26 regardless of pretreatment when indexed in terms of recovery time. CONCLUSIONS: These data provide further evidence for an ontogenetic dissociation in the expression of acute and rapid tolerance to ethanol-induced sedation. Pharmacological attenuation of the expression of acute tolerance was sufficient but not necessary to delay recovery of righting after ethanol. The greater propensity of young animals to develop acute tolerance, seemingly modulated in part by NMDA receptors, may contribute to their relative resistance to ethanol, although other factors, including pharmacokinetic factors, also contribute to their more rapid recovery from ethanol sedation.

The effects of NMDA and GABAA pharmacological manipulations on ethanol sensitivity in immature and mature animals.

BACKGROUND: Sensitivity to the hypnotic effects of ethanol dramatically increases with age (Silveri and Spears, 1998). Little is known regarding the neural mechanisms that might underlie this relative resistance of young animals to ethanol. The present study used a psychopharmacological approach to examine the influence of NMDA (N-methyl-D-aspartate) and GABA (gamma-Aminobutyric acid) receptor systems in modulating age differences in ethanol responsiveness between young [postnatal day (P26)] and mature (P70) female and male Sprague-Dawley rats. METHOD: Dose response curves were established for the effects of intraperitoneal (ip) administration of the NMDA antagonist (+)MK-801 (0.75, 1.0, or 1.25 mg/kg), the GABAA agonist muscimol (0.75, 1.25, or 1.75 mg/kg), or saline on loss and regain of the righting reflex and trunk blood alcohol levels following 3.5 g/kg of ethanol. RESULTS: (+)MK-801 increased time to regain the righting reflex at both ages, maintaining the age-related increase in ethanol sensitivity typically observed, although a gender effect also emerged at P70, with females being more sensitive than males to (+)MK-801-induced increases in duration of loss of the righting reflex. In contrast to the across-age similarity in responsiveness to (+)MK-801, P26 animals were considerably more sensitive to muscimol's enhancing effect on ethanol sedation than mature animals. CONCLUSION: Although modulation of either the NMDA or GABA system enhances the sedative effects of ethanol at both ages, stimulation of the GABAA receptor is a more effective means of prolonging ethanol sedation in immature than mature animals.

Cocaine and development: a retrospective perspective.

Neurobehavioral alterations evident in offspring of Sprague-Dawley rat dams exposed to 40 mg/kg/day cocaine subcutaneously from gestational days 8-20 are reviewed. Consequences for offspring are often age dependent: for instance, reliable deficits in classical conditioning are evident during the early postnatal period, whereas cognitive effects are less pervasive in adulthood, although apparent in tasks such as reversal training. Gender of offspring is another variable of importance, particularly when testing animals in adulthood, with adult male offspring being more likely than their female counterparts to exhibit alterations following the prenatal exposure regimen. Characteristics of the test situation likewise influence detection of outcome effects, with effects particularly likely to emerge under stressful testing conditions or other challenges to the organism. Under these circumstances, alterations in responsiveness to stressors also sometimes emerged in offspring of pair-fed (PF) dams (whose food intake was restricted to match that of cocaine-exposed [COC] dams); these findings perhaps should not be surprising given that pair feeding is a stressor and prenatal stress is known to alter later stressor responsiveness. Although several approaches to equate food intake or avoid pair feeding have yielded disappointing findings, one promising approach is to initiate cocaine administration prior to mating followed by exposure throughout gestation. Premating exposure to cocaine was sufficient to eliminate anorexic effects of drug delivery during pregnancy, although it remains to be seen how similar the pattern of neurobehavioral alterations that emerge with this extended exposure regimen will be to effects seen following more restricted gestational exposure.

Acute, rapid, and chronic tolerance during ontogeny: observations when equating ethanol perturbation across age.

BACKGROUND: Sensitivity to the motor-impairing and hypnotic effects of ethanol (EtOH) increases notably during development. Less is known, however, about the ontogeny of EtOH tolerance and the ontogenetic relationship among different types of tolerance. Consequently, we compared the ontogenetic development of acute, rapid, and chronic tolerance to EtOH-induced motor impairment and hypothermia in a swim task. METHODS: Preweanling, adolescent, and adult female and male Sprague-Dawley rats were given chronic saline (control group), five daily EtOH exposures before EtOH on test day (chronic group), one EtOH exposure before test day (rapid group), or EtOH exposure only on test day (acute groups). Separate groups of animals in the acute groups were tested at 15, 60, or 105 min after injection to estimate acute tolerance development via calculating slopes of the linear regression of impairment relative to brain alcohol levels at each postinjection interval. Initial EtOH perturbation of swim performance was equated across age by varying EtOH dose. RESULTS: Acute tolerance was evident to the motor-impairing effects of EtOH at all ages. When impairment was indexed relative to brain alcohol levels, rapid and chronic tolerance to the motor-impairing effects of EtOH on latency to reach the start was seen across age, although this tolerance tended to be more pronounced in adults. Somewhat different ontogenetic patterns of tolerance development were observed with EtOH-induced hypothermia, a dependent measure for which EtOH perturbation was not equated across age. CONCLUSIONS: The degree of initial perturbation by EtOH seems to be an important predictor of tolerance expression during ontogeny. That is, ontogenetic profiles of tolerance development differ significantly when EtOH-induced motor impairment is equated across age rather than dose of EtOH administered. The role of target response measures and context stress should also be considered when exploring ontogenetic expression of EtOH tolerance.

Ethanol as a reinforcer in the newborn's first suckling experience.

BACKGROUND: Recent evidence suggests that human infants prefer alcohol-flavored milk when fed through a bottle. Animal models also indicate a surprising predisposition for neonatal and infant rats to voluntarily and willingly ingest ethanol. These findings suggest high susceptibility to the reinforcing properties of ethanol early in ontogeny. METHODS: A surrogate nipple technique-a highly effective tool for investigation of the reinforcing properties of different fluids-was applied in the present study. Tests of ethanol reinforcement were accomplished in terms of two basic paradigms of Pavlovian conditioning. In one paradigm, the conditioned stimulus (CS) was the surrogate nipple, and in the other, the CS was a novel odor. RESULTS: Newborn rats showed sustained attachment to the nipple providing 5% ethanol, and later reproduced this behavioral pattern toward the empty nipple (CS alone). Ingestion of ethanol yielding appetitive reinforcement was accompanied by detectable blood alcohol concentrations, with most in the range of 20-30 mg/dl. The reinforcing efficacy of ethanol was also confirmed in the classical olfactory conditioning paradigm: following pairing with intraoral ethanol infusions, the odor (CS) alone elicited sustained attachment to an empty nipple. Females showed better olfactory conditioning with low concentrations of ethanol, whereas males were effectively more conditioned to high concentrations. Although there were no reinforcing consequences of intraperitoneally injected ethanol [as an unconditioned stimulus (US)] when a neutral odor was the CS, when paired with ingestion of water from a nipple, the injection of ethanol had a reinforcing effect. CONCLUSIONS: The present series of experiments revealed ethanol reinforcement in the newborn rat. Two varieties of Pavlovian conditioning established that ethanol can serve as an effective US, and hence reinforcer, in such a way as to increase the approach and responsiveness toward stimuli paired with that US, indicating appetitive reinforcement.

Effects of prenatal cocaine on behavioral adaptation to chronic stress in adult rats.

Prenatal exposure to cocaine in rats has previously been shown to alter the behavioral and hormonal responses to acute stressors, although no work has yet examined stress adaptation in these animals in adulthood, a possibility examined in this experiment. Male and female offspring of Sprague-Dawley rat dams given 40 mg/kg/3 ml subcutaneously daily from gestational days 8-20 (C40), saline injected and pair-fed dams (PF), and non-treated dams (NT) were tested in adulthood (90-120 days). Offspring were given a 5-min open field test 24 h following the last of 1 (Acute), 9 (Chronic) or 0 (control) daily 15-min intermittent footshock sessions. Substantially more behavioral adaptation was evident in NT offspring than in C40 and PF animals. The attenuated stress adaptation seen in C40 offspring extends prior work showing altered stress responsiveness in these animals, although the PF data caution against the conclusion that this lack of stress adaptation necessarily reflects gestational exposure to cocaine per se.

Acute effects of ethanol and the first suckling episode in the newborn rat.

BACKGROUND: In humans, early postnatal experience with alcohol is far from rare and includes exposure to alcohol through breast milk or through the bottle to attain sedative effects (Croce, 1987). Exposure to alcohol though mother's milk alters the infant's suckling behavior. However, acute effects of alcohol on suckling behavior using animal models remain to be investigated. METHODS: The present study was designed to examine the effects of neonatal alcohol exposure on attachment to a surrogate nipple and ingestion of milk in rat pups, naive both to suckling and to maternal care. Cesarean-delivered rat pups were pre-exposed to four dosages of ethanol (0, 1, 2, and 3 g/kg intragastrically) and tested 30 min after ethanol administration. RESULTS: Suckling behavior was impaired only in pups exposed to a dosage of 3 g/kg of ethanol. Pups in this group demonstrated longer latency to attach followed by less efficient suckling--the pups maintained contact with the nipple but showed decreased ingestion of milk from it. Pups treated with 1 g/kg of ethanol showed the greatest suckling efficiency, ingesting far more milk per minute attached to the surrogate nipple than pups in all other groups. At the same time, nonevoked motor activity was significantly suppressed by all three dosages of ethanol. Blood alcohol levels showed a linear relationship with dose at 30 min postintubation. CONCLUSIONS: These findings suggest a dissociation between acute ethanol effects on suckling and overall motor activity, with suckling apparently less sensitive to suppressive and more sensitive to activating effects of ethanol.

Ontogeny of ethanol elimination and ethanol-induced hypothermia.

Ontogeny of ethanol elimination rates and ethanol-induced hypothermia were examined as possible mechanisms contributing to the marked reduction in ethanol sensitivity early in life (Little et al., 1996; Silveri & Spear, 1998) and the notable gender difference in ethanol sleep-time seen in adult animals (Silveri & Spear, 1998). Elimination rates and brain/blood ethanol levels were determined following doses of 1.5 or 4.5 g/kg ethanol in male and female Sprague-Dawley rats at postnatal days (P)16, 26, 36, or 56. Animals were sacrificed at 40, 80, or 160 min post-injection, with ethanol elimination rates estimated from the slope of the regression of blood and brain alcohol levels across the three sampling periods. P16 animals exhibited the slowest rate of ethanol metabolism, while no gender effects were evident at any age. Observed ontogenetic increases in ethanol hypothermia were not systematically related to the ontogeny of ethanol metabolism. Factors other than ontogenetic changes in ethanol metabolism, hypothermia, or the distribution of ethanol between brain and blood must underlie the relative insensitivity to ethanol often reported in young and adolescent organisms, a fruitful area for future studies given the frequent use and misuse of alcohol by human adolescents.

Ontogeny of rapid tolerance to the hypnotic effects of ethanol.

BACKGROUND: Alcohol use typically begins during adolescence. Little is known regarding the antecedents and impact of this early alcohol use, although age-related changes in the neural systems modulating alcohol sensitivity could contribute to the propensity of adolescents to consume alcohol. We have previously observed a marked ontogenetic decline in acute tolerance to ethanol (EtOH), with preweanling pups exhibiting the most acute tolerance (Silveri and Spear, 1998). The objective of this study was to assess whether rapid tolerance shows a similar ontogenetic profile. METHODS: In Experiment I of the present study, female and male Sprague-Dawley preweanling rats at postnatal day (P) 16 or young adults at P56 were examined. On Day 1, preweanlings were pretreated with saline, 1.5, 3.5, or 5.0 g/kg EtOH and adults were pretreated with saline or 3.5 g/kg EtOH. This was followed by challenge with 3.5 g/kg EtOH and assessment of ethanol-induced sleep time on Day 2. In Experiment II, adolescents at P36 were pretreated with saline, 3.5, or 5.0 g/kg EtOH on Day 1 before Day 2 assessment of sleep time after 3.5 g/kg EtOH. Upon awakening, animals were killed and whole brains removed and analyzed for brain alcohol levels (BrALs). RESULTS: Rapid tolerance was observed in P36 and P56 animals, with EtOH-pretreated animals exhibiting significantly shorter sleep times than age-matched animals treated with saline. In contrast, no evidence for rapid tolerance was seen after any pretreatment dose at P16. Interestingly, although EtOH-pretreated adults woke at higher BrALs than saline-treated adults, this pattern was not evident in the adolescents, which suggests that at this age, metabolic tolerance may play a prominent role in the expression of rapid tolerance. Thus, it seems as though the ability to develop rapid tolerance to EtOH hypnosis emerges during adolescence and continues into adulthood. CONCLUSIONS: Together with previous findings that adolescent animals also display substantial acute tolerance to alcohol (Silveri and Spear, 1998), the propensity of adolescents for developing these two forms of tolerance may have important implications for the increased voluntary consumption of alcohol at this age relative to other ages.

Decreased sensitivity to the hypnotic effects of ethanol early in ontogeny.

Sensitivity to the hypnotic effects of ethanol was examined in Sprague-Dawley male and female rats at 16, 26, 36, 46, 56, or 96 days postnatally. Following administration of 3.5, 4.0, 4.5, or 5.0 g/kg of a 17% v/v ethanol solution, sleep times were recorded and blood alcohol levels (BALs) and brain alcohol levels (BrALs) were measured upon awakening. In addition to examining ethanol sleep time during ontogeny, data were used to estimate acute tolerance (indexed by the slope of the linear regressions of waking BALs and BrALs as a function of dose) and initial brain sensitivity to ethanol (indexed by calculating the y-intercept from the linear regression of BrALs as a function of sleep time). The results showed a marked increase in sensitivity to ethanol hypnosis during ontogeny, with young animals exhibiting shorter ethanol-induced sleep times and high waking BALs and BrALs. This ontogenetic increase in ethanol sensitivity was associated with a developmental decline in acute tolerance, with acute tolerance being most pronounced at postnatal day (P) 16 and evident only up to P36. Initial sensitivity conversely increased with age, with P16 pups showing lower initial brain sensitivity to ethanol than at all other ages. Gender differences emerged in adulthood, with males sleeping significantly longer than females at P56 and P96. These findings suggest that the marked insensitivity of young animals to the hypnotic effects of ethanol is related to both pronounced acute tolerance, as well as reduced initial brain sensitivity to ethanol early in life.