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Several studies have tested nicotinic receptor ligands in the 5-Choice Serial Reaction Time Task (5-CSRTT) with varying results. Some investigators have increased attentional demands by modifying task parameters or using aged or poor performing rats to observe treatment effects. This study examined the alpha4beta2 nicotinic agonist ABT-594 in the 5-CSRTT using a variety of manipulations to determine optimal conditions for observing enhancement. ABT-594 had no effect in drug-naïve adult rats that self-initiated trials. Constant trial presentation decreased accuracy and omissions, with the latter significantly attenuated by acute administration of ABT-594 (0.019-0.062 micromol/kg). Sub-chronic treatment (0.019 micromol/kg) initially impaired drug-naïve subjects, but significant improvements in accuracy and decreased omissions were observed after 5 days of dosing. In 18-22 month-old rats, attentional demands were altered by interspersing blocks of trials with different stimulus durations. Acute ABT-594 (0.062 micromol/kg) enhanced accuracy performance in poor performing rats (<70% accuracy) but not in those that performed well (>80% accuracy), while omissions were decreased in both groups. Sub-chronic treatment with (0.019 micromol/kg) decreased omissions in all rats, but enhanced accuracy primarily in poor performing rats. These experiments demonstrate that an alpha4beta2 nicotinic agonist can enhance attention, but accuracy effects may only be observed under specific conditions. Moreover, a reduction in omissions was more reliably observed than improvements in accuracy, resulting in a net increase in signals successfully detected., (2010 Elsevier Inc. All rights reserved.)

The recent development of a highly selective dopamine D4 receptor agonist, A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide), has provided a pharmacological tool with which to conduct systematic investigations into the putative role for dopamine D4 receptors in the central nervous system. These present studies evaluated the potential cognitive enhancing properties of A-412997 in rat models of ADHD (5-trial repeated acquisition inhibitory avoidance in Spontaneous Hypertensive Rat pups) and short-term memory (Social Recognition), in comparison with the less selective dopamine D4 receptor agonists PD168077 and CP226269. A-412997 showed significant dose-dependent efficacy in both models. PD168077 repeatedly improved acquisition in the 5-trial inhibitory avoidance model but failed to reach significance at any dose tested, although significantly improved social recognition was observed (albeit less potent than A-412997). CP226269 showed a significant enhancement in the 5-trial inhibitory avoidance model. These results support a role for the dopamine D4 receptor subtype in cognition.

Acute functional tolerance (AFT) manifests as rapid adaptation during a single ethanol exposure, leading to a decrease in the behavioral response to ethanol. In order to investigate the genetic and environmental components of the development of AFT, mice were selectively bred in replicate from HS/Ibg mice. High (HAFT) and low (LAFT) acute functional tolerance selected lines were bred to differ in the rate of development and magnitude of AFT to ethanol's intoxicating effects using a static dowel-balancing task. In the present set of experiments, HAFT and LAFT mice were tested for development of AFT on a fixed-speed rotarod using a protocol similar to that for which they were selected. HAFT mice developed greater AFT to ethanol than did LAFT mice. In a separate experiment, other mice from these lines were tested for initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia, and ethanol-induced incoordination in the grid test. Previous research has detected possible common genetic control of these phenotypes. No differences between lines were found in initial sensitivity to ethanol or in the development or magnitude of chronic tolerance in either test. These experiments show that genetic factors influencing the development of acute tolerance to ethanol-induced intoxication are at least partially distinct from those influencing initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia and incoordination. Furthermore, these experiments show that AFT measured by the stationary dowel generalizes to AFT measured by the fixed-speed rotarod.

Within-family selective breeding techniques have been used to create two lines of mice to be insensitive (HOT) and two lines to be sensitive (COLD) to the hypothermic effects of an acute 3.0-g/kg ethanol (EtOH) injection. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. The breeding program is currently in selected Generation 52, and the HOT and COLD mice differ by about 10 degrees C (average of both replicates) in their selected hypothermic response. Starting with selection Generation 20, separate lines of mice were inbred from the HOT-2 and COLD-2 selected lines, while selection continued for the original two replicate lines of HOT and COLD mice. To assess whether different dose treatments would produce differential tolerance development in the HOT and COLD selected lines, we administered different dose regimens across 5 days to HOT and COLD mice. The COLD mice developed tolerance while the HOT mice did not, regardless of total EtOH administered. In a separate study, we administered EtOH (3.0 g/kg) to mice for 3 days to assess a shorter tolerance paradigm. We also present here responses to the selection dose of 3.0-g/kg EtOH in the inbred HOT (IHOT-2) and COLD (ICOLD-2) mice tested after 41 generations of brother-sister mating. In addition, we report recent attempts to find doses of EtOH that would produce an equivalent initial hypothermic response in each of the six lines (HOT-1, COLD-1, HOT-2, COLD-2, ICOLD-2, and IHOT-2). When doses were selected to produce similar initial hypothermic sensitivity, tolerance was tested by giving three daily doses and examining the attenuation of the hypothermic response on the third day. All three COLD lines developed significant tolerance, while the HOT lines did not. The HOT and COLD mice provide a genetic model to study mechanisms mediating acute EtOH-induced hypothermia as well as tolerance development.

The repeated, intermittent administration of amphetamine produces a long-lasting sensitization to its behavioral activating effects. Excitatory amino acid receptors in the striatum have been implicated in the development of amphetamine sensitization, and one source of excitatory amino acid input to the striatum is the hippocampus. The purpose of this experiment, therefore, was to determine if an intact hippocampal system is necessary for either the development or expression of sensitization to the psychomotor activating effects of amphetamine. Rats received either fimbria-fornix lesions or sham lesions and approximately 2 weeks later received 10 injections of 3.0 mg/kg d-amphetamine or saline (IP) every other day. Rotational behavior was quantified as an index of amphetamine's psychomotor stimulant effects. Animals with a fimbria-fornix lesion were hyperresponsive to an acute injection of amphetamine, but animals with a fimbria-fornix lesion and control animals did not differ in the development of sensitization (i.e., the rate of sensitization). Furthermore, both groups expressed comparable sensitization (relative to their respective saline-pretreated control groups) when given a challenge injection of amphetamine. These results suggest an intact hippocampal system is not necessary for the development or expression of amphetamine sensitization.