A comparison of the discriminative stimulus properties of phencyclidine, given intraperitoneally or intraventricularly in rats

Rats trained to discriminate intraperitoneally injected phencyclidine (PCP) from saline in a two-lever operant procedure distributed most of their responses on the phencyclidine lever after administration of 150 or 300 μg of phencyclidine into a lateral ventricle. This demonstrated that the discriminative stimulus properties of phencyclidine were centrally mediated. On the other hand, the potency of phencyclidine was increased by no more than about 7-fold from intraperitoneal to intraventricular administration. This suggests that either periventricular sites are not involved in mediating the discriminative stimulus properties of phencyclidine or that absorption of phencyclidine to relevant sites in the brain is not markedly enhanced by intraventricular administration.     

Modification of the behavioral effects of phencyclidine by repeated drug exposure and body weight changes

In the first experiment, the effects of phencyclidine (PCP) on intake of sweetened condensed milk by rats were compared before and during a period of repeated daily injections of PCP or saline. A shift to the right in the PCP dose-effect function was found in rats receiving daily PCP injections indicating tolerance development to the effects of PCP on milk intake. The dose-effect function of PCP was shifted to the right in animals receiving daily saline as well. However, when body weight changes were controlled for in this groups of animals, the effects of PCP were the same as they had been initially, implicating body weight as a determinant of the behavioral effects of PCP. In the second experiment, a direct comparison of the behavioral effects of PCP in high- and low-weight animals revealed diminished effects of PCP in high-weight animals. When these animals were treated with ³H-PCP, brain total radioactivity as well as ³H-PCP in the high-weight animals were significantly lower than those in the low-weight animals.     

Multispectral analysis of magnetic resonance images

Magnetic resonance (MR) imaging systems produce spatial distribution estimates of proton density, relaxation time, and flow, in a two dimensional matrix form that is analogous to that of the image data obtained from multispectral imaging satellites. Advanced NASA satellite image processing offers sophisticated multispectral analysis of MR images. Spin echo and inversion recovery pulse sequence images were entered in a digital format compatible with satellite images and accurately registered pixel by pixel. Signatures of each tissue class were automatically determined using both supervised and unsupervised classification. Overall tissue classification was obtained in the form of a theme map. In MR images of the brain, for example, the classes included CSF, gray matter, white matter, subcutaneous fat, muscle, and bone. These methods provide an efficient means of identifying subtle relationships in a multi-image MR study.     

Intravenous self-administration of abused solvents and anesthetics in mice

Volatile organic solvents, fuels and anesthetics are subject to abuse. The aim of the present study was to evaluate i.v. self-administration of several of these chemicals in drug- and experiment-naive mice using a commercially available vehicle, intralipid. Two strains of mice (DBA/2 and Swiss) were allowed to self-administer toluene (0.0017-0.17 micromol/infusion), 1,1,1-trichloroethane (0.006-0.19 micromol/infusion), ethanol (0.32-1.6 micromol/infusion), cyclohexane (0.0017-0.052 micromol/infusion), propofol (0.01-0.53 micromol/infusion) and flurothyl (0.00042-0.072 micromol/infusion) or their vehicles during 30-min tests. During the test, each nose-poke of the master mouse resulted in a 1.88-microl i.v. infusion to the master mouse and a yoked control mouse. When the delivery line was loaded with a reinforcing drug solution, the number of nose-pokes of the master mice significantly exceeded that for yoked control mice. In the present experiments, significant differences in rates of nose-poking were observed between mice receiving response-contingent and response-noncontingent deliveries of ethanol and toluene in both strains of mice and of 1,1,1-trichloroethane in Swiss mice. These data suggest that the reinforcing effects of abused inhalants can be studied using i.v. self-administration procedures.     

Analyzing the acquisition of drug self-administration using growth curve models

Current approaches to studying acquisition of drug self-administration have modest power to detect individual differences in the pattern of acquisition or to efficiently and accurately describe trajectories of behavior change. Methodological advances in human research have elucidated approaches to describing repeated measure data that focus on modeling the behavior of individual subjects. In this article, we re-analyzed data published in using growth curve modeling to characterize the acquisition of nicotine-taking in rats. Change over time in the infusion rate was examined, revealing that the acquisition process could be described with a quadratic equation represented by intercept, slope, and acceleration parameters. Unit dose of nicotine, sex and fixed ratio (FR) schedule of reinforcement had significant effects on the acquisition curves. Dose altered the absolute rate of infusions, but not the slope or acceleration, indicating that, when an effective dose was available, the shape of acquisition trajectories was not affected by dose. In addition, dose impacted acquisition by moderating the disruption in infusion rates after an increase in the response requirement. Thus, the role of a higher dose may not be to accelerate the acquisition process but to lead to behavior that is more resistant to change. Trajectories differed between males and females at the smallest dose, but these differences dissipated by the end of acquisition. Growth curve modeling captures the process of acquisition of drug self-administration and facilitates a greater understanding of the individual differences in change in drug-taking behavior over time.     

Affinity and specificity of <Emphasis Type="Italic">N</Emphasis>-methyl-<Emphasis Type="SmallCaps">D</Emphasis>-aspartate channel blockers affect their ability to disrupt prepulse inhibition of acoustic startle in rats

Abstract Rationale. Phencyclidine (PCP) binds with high affinity to a site located within the ionophore of N-methyl-D-aspartate (NMDA) receptors. Previous studies have demonstrated that PCP and other high-affinity NMDA channel blockers reliably disrupt prepulse inhibition (PPI) of acoustic startle, an animal model of sensorimotor gating used to study attentional deficits associated with schizophrenia. Recently, a number of low-affinity NMDA channel blockers that exhibit minimal PCP-like effects in humans at therapeutic doses have been developed. Objectives. The purpose of this study was to evaluate the effects on PPI of NMDA channel blockers with varying affinities for the channel site as well as different specificities for NMDA receptors. Methods. Sprague-Dawley rats were presented with multiple stimulus presentation trials, including pulse-alone and PPI trials. Results. As expected, the high-affinity ligands dizocilpine and dextrorphan disrupted PPI at doses that did not affect the response during pulse-alone trials. Low-affinity drugs produced a mixed pattern of results. Whereas dextromethorphan and memantine disrupted PPI, orphenadrine, amantadine, desipramine, and alaproclate did not affect this response. Ibogaine also disrupted PPI, but only within a dose range that severely decreased the startle response during pulse-alone trials. Conclusions. These results suggest that not all NMDA channel blockers share PCP's effect of PPI disruption. In addition, they suggest caution in the use of supratherapeutic doses of these compounds and in their use in vulnerable populations (e.g., schizophrenic patients). Electronic Publication