Psychopharmacology
November 1, 2009
Dagmar Koethe, Carolin Hoyer, F Markus Leweke
Model psychosis refers to experimentally induced symptoms resembling schizophrenia, such as withdrawal from reality, perceptual disturbances, thought disorders, delusions, and sometimes hallucinations. These altered states of consciousness help researchers understand aspects of schizophrenia. The endocannabinoid system has become a focus of investigation due to its discovery and epidemiological evidence linking cannabis use to the onset and course of schizophrenia. Most studies examine cannabis and cannabinoid effects not directly related to psychosis. This review summarizes studies relevant to or designed as model psychosis experiments, examining their contribution to understanding endocannabinoid functioning in psychosis and schizophrenia, and outlines future research directions and cross-links to other modeling approaches.
Psychopharmacology
November 1, 2009
C B Willmore, D M Krall, F M Spears et al.
Deficits in memory and attention are known in psychosis, but experiments often test working memory without systematically varying attentional demands. This study used rats trained on operant ratio discrimination tasks to determine whether attention or memory contributes more to drug-induced performance deficits. Four psychotomimetic drugs—a serotonin agonist, the NMDA antagonist PCP, and two cannabinoid agonists—were assessed. A signal detection analysis dissociated cognitive from noncognitive disruptions. At least one dose of each drug decreased accuracy without affecting response rates, and task difficulty determined the specificity of accuracy effects. PCP and one cannabinoid biased animals toward the lever associated with denser reinforcement and produced peculiar response patterns during distracter light sessions, suggesting performance enhancement. Overall, sustained attention and transient information management were significantly impaired, while selective attention was less affected.
Psychopharmacology
March 1, 2009
Mark Blagrove, Celia J. A. Morgan, H Valerie Curran et al.
Ketamine, an NMDA receptor antagonist, increases the unpleasantness of dreams for three nights after a sub-anaesthetic dose. In a placebo-controlled study with 30 healthy volunteers, those given ketamine reported significantly more unpleasant dreams, with a threefold increase in the odds of having an unpleasant dream. The number of dreams recalled did not differ between groups. People who already had frequent nightmares at home were more likely to have unpleasant dreams after ketamine. This effect may reflect a lingering psychotogenic influence or disrupted sleep physiology not captured by standard symptom questionnaires.
Psychopharmacology
December 1, 2008
Alessandro Gozzi, Hugh Herdon, Adam Schwarz et al.
Impaired NMDA receptor function may underlie schizophrenia. Drugs that activate the glycine binding site of the NMDA receptor could boost its activity and offer therapeutic benefit. In rats, the NMDA antagonist PCP activated brain circuits involved in schizophrenia. Pretreatment with D-serine (1 g/kg) or the GlyT-1 inhibitor SSR504734 (10 mg/kg) completely blocked this activation and caused weak, sustained deactivation in cortical areas. The results suggest that agents acting at the glycine co-agonist site can enhance NMDA receptor activity in the living brain and support their potential for treating schizophrenia.
Psychopharmacology
May 1, 2007
Gary S Linn, Robert T O'Keeffe, Kenneth Lifshitz et al.
Glycine treatment reversed the effects of the dissociative anesthetic PCP on stereotyped pacing in socially housed monkeys but had no effect on scanning behavior. Chronic PCP infusion in ten monkeys produced behavioral symptoms modeling both positive and negative symptoms of schizophrenia. Eight of ten animals experienced extreme motoric and physiological episodes during stressful events. The results suggest glycine may be beneficial for negative symptoms of schizophrenia, and that chronic PCP in primates could serve as a model for developing drugs targeting schizophrenia symptoms.
Psychopharmacology
May 1, 2007
Erik Pålsson, Kim Fejgin, Caroline Wass et al.
Cognitive and attentional deficits in schizophrenia, such as impaired sensory filtering measured by prepulse inhibition (PPI), can be modeled in animals using the drug phencyclidine (PCP), which disrupts PPI. Nitric oxide (NO) may mediate some of PCP's effects, as NO synthase inhibitors block PCP-induced deficits. This study tested whether blocking L-arginine transport—a step in NO production—with L-lysine could prevent PCP-induced PPI disruption in mice. Subchronic, and to some extent acute, L-lysine pretreatment blocked the PCP-induced PPI deficit without affecting baseline PPI. The results support the idea that PCP's effects in the brain involve NO and that L-arginine transport may regulate NO production.
Psychopharmacology
June 1, 2001
M Sarter, J P Bruno, G G Berntson
The benzodiazepine receptor partial inverse agonist FG 7142, traditionally labeled anxiogenic, is proposed to model core components of schizophrenia theories. FG activates the mesolimbic dopaminergic system, disinhibiting corticopetal cholinergic projections via increased dopamine in the nucleus accumbens. This is hypothesized to mediate hyperattentional impairments contributing to psychotic cognition. FG-induced abnormal processing of conditioned stimuli explains its anxiogenic effects. In rats and monkeys, typical and atypical antipsychotic drugs attenuated FG-induced increases in cortical cholinergic activity and cognitive impairments. Compared to amphetamine and phencyclidine, FG offers an alternative psychotogenic manipulation for research on cortical and cognitive aspects of schizophrenia theories.
Psychopharmacology
March 1, 2000
J Cartmell, J A Monn, D D Schoepp
A selective activator of metabotropic glutamate receptors (mGlu2/3), LY379268, reduces specific abnormal behaviors induced by the drug phencyclidine (PCP) in rats, similar to the antipsychotic clozapine. LY379268 and clozapine dose-dependently decreased PCP-evoked falling, turning, and back pedaling. At 30 minutes after PCP, 1 mg/kg LY379268 reduced falls by 89% and turns by 53%, while 1 mg/kg clozapine reduced turning by 70%. Low clozapine doses increased PCP-induced falls. Back pedaling was completely blocked by 1 mg/kg of either drug. However, clozapine's effects occurred only at doses that worsened PCP-evoked ataxia, whereas LY379268 did not. The findings suggest mGlu2/3 receptors selectively modulate certain PCP behaviors, supporting their potential as drug targets for schizophrenia.
Psychopharmacology
September 1, 1999
Y Shiigi, D E Casey
Ketamine, a drug that blocks NMDA receptors, produced dose-related increases in parkinsonian symptoms (bradykinesia and dystonia) and salivation, along with decreases in locomotor activity and reactivity to environmental stimuli in Cebus monkeys. These effects had short time courses and steep dose-response curves. The findings suggest that ketamine-induced behavioral changes in non-human primates can serve as a model for studying the role of glutamate systems in motor and mental functions such as attention or perception.
Psychopharmacology
February 1, 1999
M Haney, A S Ward, S D Comer et al.
Dependence can develop at lower daily doses of THC than previously studied. In a 20-day residential study, 12 marijuana smokers received placebo, then 80 mg/day (20 mg four times daily) and 120 mg/day (30 mg four times daily) of oral THC. Both active doses increased ratings of "High," "Good Drug Effect," and "Willingness to Take Dose Again," and increased food intake by 35–45% while decreasing verbal interaction. Tolerance developed to subjective effects but not to effects on food intake or social behavior. Abstinence increased ratings of anxious, depressed, and irritable, reduced sleep quantity and quality, and decreased food intake by 20–30%. These changes suggest that alleviation of abstinence symptoms may contribute to maintaining daily marijuana use.
Psychopharmacology
January 1, 1998
A Mele, K M Wozniak, F S Hall et al.
Five drugs similar to phencyclidine (PCP) were tested in rats with brain lesions to see if they cause circling behavior and alter dopamine levels in the striatum. All five drugs caused the rats to turn in circles toward the side of the lesion, which typically indicates increased dopamine on the intact side. But measurements of dopamine in the striatum did not match this expectation. Only PCP itself increased dopamine levels. MK-801 caused strong circling but no dopamine increase. Dexoxadrol also caused circling without raising dopamine. TCP and SKF 10,047 raised dopamine only slightly (16% and 12%) at their peak. The authors conclude these drugs likely act through NMDA receptor blockade rather than by altering dopamine.
Psychopharmacology
January 1, 1998
F Sams-Dodd
Phencyclidine (PCP) induces behaviors in rats that model aspects of schizophrenia, including hyperactivity, stereotyped behavior, and social isolation. Over a 3-day regimen, dopamine D1-receptor agonists had limited effects on these PCP-induced behaviors, while the D1-antagonist SCH 23391 reduced PCP-induced social isolation, though tolerance developed after 21 days of treatment. The D2/D3/D4-agonist quinpirole worsened and mimicked PCP's social deficits, and the D2/D3-antagonist (-)sulpiride reduced PCP-induced stereotyped behavior and social isolation. A D4-antagonist had no effect. However, similar effects occurred in vehicle-treated rats, suggesting non-specific influences may have been involved.
Psychopharmacology
August 1, 1996
G D Ellison, A S Keys
Phencyclidine (PCP) can cause a psychosis resembling schizophrenia and dementia that sometimes persists long after the drug is stopped. In rats, a five-day continuous 'binge' of PCP caused lasting increases in brain glucose metabolism, especially in limbic regions (retrosplenial, piriform, and entorhinal cortex, hippocampus, and olfactory tubercle). These increases were still present 10 days after the drug was removed, indicating that the metabolic changes persist. The findings suggest a brain basis for the prolonged psychosis that can follow PCP use.
Psychopharmacology
February 1, 1995
P J Armstrong, C Morton, W Sinclair et al.
Inhaling nitrous oxide at concentrations as low as 3% impairs long-term memory recall, while short-term recall is affected only at 15%. Attention and psychomotor performance are impaired at 15%, and subjective sedation occurs at that dose. These findings suggest that memory consolidation is especially vulnerable to disruption from central nervous system depression.
Psychopharmacology
April 1, 1994
J P Zacny, G Sparacino, P Hoffmann et al.
In nine healthy volunteers, isoflurane and nitrous oxide produced similar subjective effects like feeling drunk and spaced out, but isoflurane uniquely increased confusion, sedation, and carefreeness while reducing perceived control over thoughts and body; it also had an unpleasant odor. Psychomotor performance was more impaired by isoflurane than by nitrous oxide, but recovery from both was rapid and complete within five minutes. Both drugs impaired immediate and delayed free recall. The findings suggest isoflurane may be less suitable than nitrous oxide for conscious sedation due to its greater psychomotor effects and unpleasant odor.
Psychopharmacology
January 1, 1991
G E Evoniuk, R P Hertzman, P Skolnick
A simple method detects behavioral effects of dissociative anesthetics like phencyclidine (PCP) and dizolcipine in mice. These drugs, which bind to NMDA-coupled cation channels, caused a dose-related increase in the percentage of mice falling from a circular arena on a 60 cm platform. Other compounds, including competitive NMDA antagonists and sigma-receptor ligands with low PCP receptor affinity, did not produce this behavior. Pretreatment with glycine reduced falls caused by a maximally effective dose of dizolcipine in a dose-dependent manner. This procedure may aid rapid detection of dissociative anesthetics and evaluation of PCP antagonists.
Psychopharmacology
June 1, 1982
Lynne M. Adams, Mark A. Geyer
Rats given 20–30 μg/kg LSD avoided a novel holeboard chamber during the first half of a 1-hour session, reducing all activity measures such as crossovers, rearings, and hole pokes. In the second half, LSD-treated rats maintained steady responding while controls continued to decline. Despite initial avoidance, LSD-treated rats made consistently longer hole pokes into floor holes and showed more diverse locomotion patterns than controls. Most notably, they failed to develop the stereotyped excursion routes from the home cage to the holeboard that controls established. The authors suggest LSD potentiates both neophobic avoidance and investigatory responses by slowing behavioral habituation.
Psychopharmacology
March 1, 1982
R. L. Commissaris, R. H. Rech
Diazepam dramatically increased punished responding in rats, while the hallucinogens LSD and DOM produced only modest increases, and quipazine had no significant effect. Metergoline pretreatment did not affect punished responding or alter diazepam's effects, but it antagonized LSD's weak increase. Diazepam, quipazine, LSD, and DOM all decreased unpunished responding in a dose-dependent manner. Metergoline shifted the dose-response curves for quipazine and DOM rightward but shifted diazepam's curve leftward. These results suggest that changes in brain serotonin activity do not underlie diazepam's large effect on punished behavior, and that the drugs reduce unpunished responding through different neuropharmacological mechanisms.