Adolescent exposure to fluoxetine impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats.

The effects of chronic adolescent fluoxetine (FLX, Prozac®) exposure on adult cognition are largely unknown. We used a serial multiple choice (SMC) task to characterize the effects of adolescent FLX exposure on rat serial pattern learning in adulthood. Male rats were exposed to either 1.0, 2.0, or 4.0 mg/kg/day FLX for five consecutive days each week for five weeks during adolescence, followed by a 35-day drug-free period. As adults, the rats were trained in a task that required them to learn a highly structured sequential pattern of responses in an octagonal chamber for water reinforcement. In a transfer phase, the terminal element of the pattern was replaced by a violation element that was inconsistent with previously learned pattern structure. Results indicated that adolescent FLX exposure caused differential learning deficits for different types of elements in the serial pattern. Adolescent exposure to 1.0 or 4.0 mg/kg/day FLX, but not 2.0 mg/kg/day FLX, impaired chunk-boundary element learning, which is known to be mediated by stimulus-response (S-R) learning. All three doses of FLX impaired violation element learning, which is known to be mediated by multiple-cue learning. FLX did not impair within-chunk element learning, which is known to be mediated by rule-learning mechanisms. The results indicate that adolescent FLX exposure produced multiple cognitive impairments that were detectable in adulthood long after drug exposure ended.

Marine anoxia and delayed Earth system recovery after the end-Permian extinction.

Delayed Earth system recovery following the end-Permian mass extinction is often attributed to severe ocean anoxia. However, the extent and duration of Early Triassic anoxia remains poorly constrained. Here we use paired records of uranium concentrations ([U]) and (238)U/(235)U isotopic compositions (δ(238)U) of Upper Permian-Upper Triassic marine limestones from China and Turkey to quantify variations in global seafloor redox conditions. We observe abrupt decreases in [U] and δ(238)U across the end-Permian extinction horizon, from ∼3 ppm and -0.15‰ to ∼0.3 ppm and -0.77‰, followed by a gradual return to preextinction values over the subsequent 5 million years. These trends imply a factor of 100 increase in the extent of seafloor anoxia and suggest the presence of a shallow oxygen minimum zone (OMZ) that inhibited the recovery of benthic animal diversity and marine ecosystem function. We hypothesize that in the Early Triassic oceans-characterized by prolonged shallow anoxia that may have impinged onto continental shelves-global biogeochemical cycles and marine ecosystem structure became more sensitive to variation in the position of the OMZ. Under this hypothesis, the Middle Triassic decline in bottom water anoxia, stabilization of biogeochemical cycles, and diversification of marine animals together reflect the development of a deeper and less extensive OMZ, which regulated Earth system recovery following the end-Permian catastrophe.

Adolescent exposure to methylphenidate impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats.

The long-term effects of adolescent exposure to methylphenidate (MPD) on adult cognitive capacity are largely unknown. We utilized a serial multiple choice (SMC) task, which is a sequential learning paradigm for studying complex learning, to observe the effects of methylphenidate exposure during adolescence on later serial pattern acquisition during adulthood. Following 20.0mg/kg/day MPD or saline exposure for 5 days/week for 5 weeks during adolescence, male rats were trained to produce a highly structured serial response pattern in an octagonal operant chamber for water reinforcement as adults. During a transfer phase, a violation to the previously-learned pattern structure was introduced as the last element of the sequential pattern. Results indicated that while rats in both groups were able to learn the training and transfer patterns, adolescent exposure to MPD impaired learning for some aspects of pattern learning in the training phase which are learned using discrimination learning or serial position learning. In contrast adolescent exposure to MPD had no effect on other aspects of pattern learning which have been shown to tap into rule learning mechanisms. Additionally, adolescent MPD exposure impaired learning for the violation element in the transfer phase. This indicates a deficit in multi-item learning previously shown to be responsible for violation element learning. Thus, these results clearly show that adolescent MPD produced multiple cognitive impairments in male rats that persisted into adulthood long after MPD exposure ended.

What's the ROI for resolving the nursing faculty shortage?

The nursing faculty shortage will have a fundamental impact on the ability to produce nurses. For most nursing schools and states, however, concerns about the relative merits of different solutions to the nursing faculty shortage are misplaced. Without significantly increased visibility and definition, accompanied by a clear public, private, and health care organization return on investment (ROI), proposing solutions to the nursing faculty shortage is at best premature and at worst irrelevant. There is simply too much competition for resources to expect that a vaguely defined and invisible problem with no rationale for increased investment will receive sufficient support from critical decision makers and constituencies. First must come problem definition, visibility, and ROI. Only then can the case be made for implementing solutions to the nursing faculty shortage.

Adolescent exposure to nicotine impairs adult serial pattern learning in rats.

In the present study investigating the effects of adolescent nicotine exposure on adult serial pattern learning, adolescent rats received daily i.p. injections of either 1.0 mg/kg nicotine or saline for 5 days per week for 5 weeks beginning on postnatal day 25 (P25), then were allowed 35 days drug free. Rats then began training on P95 as adults on a 24-element serial pattern composed of eight 3-element chunks. Adolescent exposure to 1.0 mg/kg nicotine produced persistent retardation of learning for the first element of each 3-element chunk of the pattern, that is, for chunk boundary elements, and transient retardation of learning for elements 2 and 3 of each chunk of the pattern, that is, for the within-chunk elements. Deficits at chunk boundaries were interpreted as deficits of phrasing cue discrimination learning whereas deficits for learning responses for elements within-chunks (elements 2 and 3 of chunks) were interpreted as deficits of rule learning. These results indicate that the effects of adolescent nicotine exposure on adult learning and cognitive capacity deserve further scrutiny.

Adolescent reward system perseveration due to nicotine: studies with methylphenidate.

Previous data suggests adolescent nicotine exposure permanently disrupts reward systems. Behavioral pharmacological methods were used to assess the effects of adolescent nicotine exposure on methylphenidate (MPD) sensitivity and reward from adolescence to adulthood. For experiment one, testing was performed on adult mice exposed to nicotine (0.3 and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (PND 25-57). After a 28-day drug-free, time-off period, the locomotor effects (30 min, 30 cm traveled) of MPD (5, 10, 20, and 40 mg/kg, IP) were measured. Thereafter, mice underwent condition-place-preference testing (CPP). MPD (20 mg/kg) was paired with the subject's non-preferred side and saline with the preferred side. Conditioning sessions were conducted for 8 days with a drug-free post-test on the day following the final conditioning session. A second experiment was conducted to determine if adolescent mice respond differently to MPD compared to adult mice. The study compared adolescent mice (PND 25-46) to adult mice (PND 77-98) using identical MPD testing procedures as in experiment one. Adult subjects exposed to nicotine during adolescence behaved remarkably similar to adolescent subjects receiving only MPD. Both nicotine exposed subjects and naïve adolescents exhibited increased response to MPD's motor activating effects and a decreased response to MPD's rewarding effects. Taken together it appears that adolescent nicotine exposure retards the development of reward systems, thus, maintaining an adolescent state indefinitely, which could result in increased vulnerability to substance abuse problems throughout adulthood.

Long-term, low-level adolescent nicotine exposure produces dose-dependent changes in cocaine sensitivity and reward in adult mice.

Cigarette smoking by adolescents is a strong predictor of future drug use, abuse, and dependence. While this "gateway drug effect" is assumed to be related to psychosocial factors, data from our laboratory suggests that adolescent nicotine use may permanently disrupt reward systems through changes in dopamine receptor function. Behavioral pharmacological methods known to be indirectly (motor activity) and directly (conditioned-place-preference) related to drug reinforcement were used to examine changes in cocaine sensitivity. Testing was performed on adult mice that were exposed to nicotine (0.3, 1.0, and 3.0 mg/kg, SC, M-F, b.i.d.) or saline during adolescence (postnatal days 25-57). Prior to testing, subjects had a 28 day drug-free, time-off period. After acclimation to the testing apparatus, the locomotor effects (30 min, 30 cm traveled) of cocaine (5, 10, and 20 mg/kg, IP) were measured daily; cocaine tests were preceded and followed by saline control tests. Following the acute dose-response curve, mice received saline followed by 5 days of 20.0 mg/kg cocaine. Thereafter, mice underwent condition-place-preference testing. A pre-test was performed to determine compartment preference (i.e., no injection, 20 min test). Cocaine (10 mg/kg, IP) was paired with the subjects non-preferred side and saline with the other. Conditioning sessions were conducted for 8 days with the order of drug/saline injections counter-balanced across subjects. A drug-free, post-test occurred on the day following the final conditioning session. A dose-dependent relationship between adolescent nicotine exposure and cocaine reward was noted in the adult mice across both test conditions. Subjects exposed to nicotine showed an increased response to cocaine's motor activating effects and a decreased response to cocaine's rewarding effects. A follow-up study was undertaken to evaluate dopamine D1, D2, and D3 receptor function in adult mice exposed to the highest dose of nicotine from the first study. While both interesting and revealing, the results of motor activity tests with dopamine agonist only approached significance. Further research will be required to more fully examine the mechanism of action for the observed changes in cocaine reward. In summary, this is the first study to demonstrate a dose-response relationship between adolescent nicotine exposure and changes in cocaine reward and sensitivity during adulthood.

Differential neurosensitivity to the discriminative stimulus properties of ethanol in C57BL/6J and C3H/He mice.

BACKGROUND: A large body of evidence suggests that the interoceptive cue associated with ethanol intoxication is complex and dependent on a number of environmental and biological factors. Despite the fact that mice have been widely used to study genetic influences on sensitivity to various actions of ethanol, few studies have used mice to examine sensitivity to the discriminative stimulus effects of ethanol. The purpose of this study was to compare sensitivity to the discriminative stimulus effects of ethanol in two inbred mouse strains, namely C57BL/6J and C3H/He mice. METHODS: Adult male C57BL/6J and C3H/He mice were trained to discriminate between ethanol and saline using a two-lever food reinforcement operant procedure. Once criterion discrimination performance was achieved, dose-response functions were determined from generalization tests. Additional experiments were conducted to determine whether differences in discrimination performance were related to differential blood/brain ethanol levels in the two mouse strains. RESULTS: A greater proportion of C57BL/6J mice acquired the discrimination and required fewer trials to achieve criterion performance compared with C3H/He mice with a 1.0 g/kg ethanol training dose. This deficit in acquisition was overcome when the training dose was increased to 2.0 g/kg for C3H/He mice. In a second experiment, a 1.5 g/kg training dose of ethanol was used for both strains. Again, a greater proportion of C57BL/6J mice acquired the discrimination and required fewer training trials to achieve criterion performance compared with C3H/He mice. Blood ethanol levels did not differ between the strains after administration of the 1.5 g/kg training dose. However, blood and brain ethanol levels did differ between the strains after doses of ethanol were administered that produced equivalent discrimination performance. CONCLUSIONS: Results indicate that ethanol discrimination was more readily acquired and maintained in C57BL/6J mice than C3H/He mice. Ethanol dose-response functions generated from generalization tests also clearly demonstrated greater sensitivity to the discriminative stimulus properties of ethanol in C57BL/6J mice compared with the C3H/He strain. This differential sensitivity to the interoceptive cue produced by ethanol does not seem to be related to learning or pharmacokinetic differences between the two inbred strains.