Cognitive effects of psychotomimetic drugs in rats discriminating number cues

Abstract

Rationale Deficits in memory and attention are broadly acknowledged during psychosis; however, experiments on modeled psychosis often test working memory without systematic manipulation of attentional demands. Objectives The major research goal was discovering which neurobehavioral processes, attention, or memory contributed more to drug-provoked performance deficits. Materials and methods Rats were trained to perform operant ratio discrimination (RD) tasks wherein the number of presses at a rear-wall lever was discriminated using one of two front-wall levers. Effects from four psychotomimetic drugs, the serotonin agonist 2,5-dimethoxy-4-iodoamphetamine, the noncompetitive NMDA-glutamate receptor antagonist phencyclidine (PCP), and two CB1-selective cannabinoid agonists, WIN 55,512-2 and AM 411, were assessed using a signal detection analytical overlay to dissociate cognitive from noncognitive motor and motivational disruptions. Further methods allowed dissociation of attention compromises from mnemonic deficits. Results For each test compound, at least one dose elicited decreased RD accuracy without affecting response rates, and task difficulty was shown to be a crucial dictator of accuracy effect specificities. Effects from both PCP and WIN 55,512-2 biased animals to select the response lever conditioned for denser reinforcement. The same two drugs rendered peculiar response patterns in distracter light session components, considering light blinks were included to divert subjects’ attention away from task-relevant information. The response patterns determined during distracter components of PCP/WIN testing sessions, counterintuitively, suggest performance enhancement. Conclusion Comprehensive viewing of RD performance patterns after drug administration indicates that sustained attention and transient information management are significantly impaired during the drug-induced psychosis state, while selective attention is less affected.

Stress-induced impairments in prefrontal-mediated behaviors and the role of the N-methyl-d-aspartate receptor

“…Systemic treatment with NMDAR antagonists also disrupts working memory (Jentsch et al, 1997, Aura and Riekkinen, 1999, Ko and Evenden, 2009, Willmore et al, 2009, Smith et al, 2011) and produces deficits in attentional performance that reflect increased impulsivity (Higgins et al, 2003, Higgins et al, 2005, Baviera et al, 2008, Amitai and Markou, 2009, 2010, Murphy et al, 2011, Thomson et al, 2011). These effects can be recapitulated by direct infusion of NMDAR antagonists into the mPFC (Aura and Riekkinen, 1999, Baviera et al, 2008), consistent with the hypothesis that NMDARs in this brain region are key mediators of these behaviors.…”

Disruption of Performance in the Five-Choice Serial Reaction Time Task Induced By Administration of N-Methyl-D-Aspartate Receptor Antagonists: Relevance to Cognitive Dysfunction in Schizophrenia

“…Decreased attentional performance after acute administration of PCP or dizocilpine was observed in the open-field stimulus object test [76], two-lever and three-lever choice tasks [94,98], lateralized reaction time task [88], lateralized visual signal detection task [60,103,104], and operant ratio discrimination task [64,65]. However, performance in the lateralized visual signal detection task was not altered after a period of withdrawal from repeated dizocilpine administration [120], again suggesting that attentional performance is less affected in the drug-free state after NMDA antagonist treatment than during acute drug exposure.…”

A comprehensive evaluation of adverse childhood experiences, social–emotional impairments, and neurodevelopmental disorders in cannabis-use disorder: Implications for clinical practice

“…Other studies found psychotic symptoms to be high in CUD populations, one focusing on substance-related exogenous psychosis finding ego-dystonic symptoms, which we did not investigate specifically, to constitute a significant part of both transient and persistent psychosis associated with CUD [ 64 ], another indicating the centrality of dissociative symptoms in CUD-associated psychosis [ 65 ]. It is possible that glutamatergic-cannabinoid interactions contribute to dissociation, as shown in both animals [ 66 ] and humans [ 67 ]. It is also interesting that in our sample of preCUD-onset patients there were more cases of hallucinogen use than in the NO group.…”