Psychopharmacology
August 1, 2018
Masaki Domoto, Hitoki Sasase, Shintaro Wada et al.
5F-AMB, a synthetic cannabinoid abused worldwide, reduces both excitatory and inhibitory signaling in layer V pyramidal neurons of the medial prefrontal cortex by activating CB1 receptors on presynaptic terminals. Bath application of 5F-AMB decreased the frequency of spontaneous and miniature excitatory and inhibitory postsynaptic currents, an effect blocked by the CB1 antagonist AM251. The suppression of excitatory transmission was greater than that of inhibitory transmission, shifting the balance toward net inhibition of these neurons. This inhibitory effect may contribute to the memory and consciousness impairments observed after inhalation of 5F-AMB.
Psychopharmacology
February 1, 2018
Liana Fattore, Alessandro Piva, Mary Tresa Zanda et al.
A review of preclinical and clinical data examines whether cannabinoids and ketamine can modulate the reconsolidation of maladaptive memories, a process that may underlie their potential therapeutic use in post-traumatic stress disorder and substance use disorders. The authors propose that memory reconsolidation modulation is a hypothetical process explaining the efficacy of these substances, and they report findings that support or do not support this working hypothesis. Metaplasticity is suggested as a common process mediating the effects of cannabinoids and ketamine on maladaptive memories.
Psychopharmacology
August 1, 2017
Amy W M Ewald, Peter J Bosch, Aimee Culverhouse et al.
Two novel analogues of salvinorin A, EOM Sal B and β-THP Sal B, were tested in rats for their ability to reduce cocaine-related behaviors and their side effects. EOM Sal B dose-dependently reduced drug-seeking behavior in a reinstatement model and, along with β-THP Sal B, attenuated cocaine-induced hyperactivity without affecting general locomotion. Neither compound produced anxiety-like or depressive-like effects in the elevated plus maze or forced swim tests. However, β-THP Sal B caused aversion in the conditioned place aversion test. EOM Sal B showed no effect on sucrose self-administration, indicating selectivity for cocaine-related behaviors. EOM Sal B was more potent than salvinorin A and β-THP Sal B with fewer side effects.
Psychopharmacology
July 1, 2017
Rainer Kraehenmann, Dan Pokorný, Leonie Vollenweider et al.
Lysergic acid diethylamide (LSD) produces waking mental imagery that resembles dreaming, an effect driven by activation of the 5-HT2A receptor. In a study with 25 healthy subjects, LSD (100 mcg orally) significantly increased cognitive bizarreness in guided mental imagery reports compared with placebo, and this increase correlated with a loss of self-boundaries and cognitive control. Both the imagery changes and altered state of consciousness were fully blocked by the 5-HT2A antagonist ketanserin (40 mg orally). The findings suggest that LSD-induced dreamlike imagery depends specifically on 5-HT2A receptor activation.
Psychopharmacology
April 1, 2016
Adam L Halberstadt, Natalia Slepak, James Hyun et al.
Methoxetamine (MXE), a ketamine analog sold online, produces behavioral effects in rats that closely resemble those of other dissociative anesthetics like phencyclidine (PCP) and ketamine. In Sprague-Dawley rats, MXE disrupted prepulse inhibition (PPI) of acoustic startle at doses of 3 and 10 mg/kg, with a potency ranking (PCP > MXE > S-(+)-ketamine > NANM > R-(-)-ketamine) that matches their affinities for the PCP binding site on NMDA receptors. In the behavioral pattern monitor, 10 mg/kg MXE caused locomotor hyperactivity, reduced rearing, increased path roughness, and perseverative locomotion—effects similar to those of PCP. These findings indicate MXE acts as a dissociative drug with abuse potential comparable to PCP and ketamine.
Psychopharmacology
March 1, 2016
HeeSeung Lee, Grace Y. Wang, Louise E. Curley et al.
A single oral dose of either TFMPP or dexamphetamine significantly reduced the P300 amplitude, a measure of brain electrical activity related to attention and information processing. A similar trend was observed with BZP alone. However, the combination of BZP and TFMPP had no effect on P300 amplitude. Neither P300 latency nor reaction time was affected by any drug treatment, nor were earlier sensory components P100 and P200. The findings suggest that BZP and TFMPP, but not their combination, affect auditory sensory-evoked P300 potential in a manner similar to dexamphetamine.
Psychopharmacology
March 1, 2016
Michael J Wesley, Joshua A Lile, Colleen A Hanlon et al.
Long-term heavy cannabis users who are not acutely intoxicated show diminished brain responses in the medial prefrontal cortex (mPFC) when consciously evaluating emotional images, compared to non-users. Both groups judged the same stimuli as emotional and had similar activations in visual, midbrain, and middle cingulate cortices. However, controls showed additional amygdalar and inferior frontal gyrus activations, while cannabis users showed mPFC deactivations during emotional evaluation. Between-group comparisons found mPFC activity during positive and negative evaluation was significantly hypoactive in cannabis users. This abnormal neural processing of affective content extends to conscious evaluation and resembles attenuated mPFC responses found during increased non-affective cognitive load.
Psychopharmacology
October 1, 2013
Katja Clarissa Ward, Halima Zainab Khattak, Louise Richardson et al.
Low doses of the NMDA receptor antagonists ketamine and phencyclidine impair visual grouping in rats, requiring higher signal quality to discriminate patterns, without affecting discrimination of undistorted images. Higher doses impair task performance even with clear images, linked to stereotypic behavior and impulsivity. A new rodent task using Glass patterns differentiates perceptual effects from motor or memory effects, enabling quantification of cognitive psychosis that translates to human psychometric functions.
Psychopharmacology
March 1, 2013
Theresa M Carbonaro, Michael J Forster, Michael B Gatch
The hallucinogen DiPT, known for causing auditory distortions, produces discriminative stimulus effects in rats that are similar to those of other synthetic hallucinogens like LSD, DOM, and MDMA, but only partially similar to DMT and not similar to methamphetamine. Rats learned to distinguish DiPT from saline in about 60 training sessions. DiPT caused dose-dependent increases in drug-appropriate responding, reaching 99% at the highest dose. The effects began within 5 minutes and faded within 4 hours. The results suggest that DiPT's auditory effects do not make its discriminative stimulus profile distinct from other hallucinogens.
Psychopharmacology
November 24, 2012
R. A. Sewell, Ashley Schnakenberg, Jacqueline Elander et al.
Intravenous THC, at doses from 0.015 to 0.05 mg/kg, produces time overestimation and underproduction in seconds-range tasks, indicating an increased internal clock speed. This effect is not dose related and is blunted in frequent cannabis smokers, who show no differences in time perception compared to infrequent or nonsmokers. Chronic cannabis use does not alter baseline time perception.
Psychopharmacology
February 1, 2011
David M Thomson, Allan McVie, Brian J Morris et al.
Cognitive problems in schizophrenia are not well treated by current drugs. The drug PCP is often used in animals to model these problems. In rats, a single dose of PCP increased impulsive, anticipatory responses 30 minutes after injection, but this effect disappeared within 24 hours. Repeated PCP treatment caused lasting delays in cognitive processing speed, which were partly improved by the antipsychotic clozapine. Clozapine also modified a measure of risk-taking versus caution (lnBeta) that was persistently altered by repeated PCP. The findings suggest that repeated PCP treatment combined with signal detection analysis provides a useful method for testing new cognitive enhancers.
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
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
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
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
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
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
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
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
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
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.