dizocilpine-maleate and robalzotan

The use of cannabis for therapeutic and recreational purposes is growing exponentially. Nevertheless, substantial questions remain concerning the potential cognitive and affective side-effects associated with cannabis exposure. In particular, the effects of specific marijuana-derived phytocannabinoids on neural regions such as the prefrontal cortex (PFC) are of concern, given the role of the PFC in both executive cognitive function and affective processing. The main biologically active phytocannabinoids, ∆-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), interact with multiple neurotransmitter systems important for these processes directly within the PFC. Considerable evidence has demonstrated that acute or chronic THC exposure may induce psychotomimetic effects, whereas CBD has been shown to produce potentially therapeutic effects for both psychosis and/or anxiety-related symptoms. Using an integrative combination of cognitive and affective behavioral pharmacological assays in rats, we report that acute intra-PFC infusions of THC produce anxiogenic effects while producing no impairments in executive function. In contrast, acute infusions of intra-PFC CBD impaired attentional set-shifting and spatial working memory, without interfering with anxiety or sociability behaviors. In contrast, intra-PFC CBD reversed the cognitive impairments induced by acute glutamatergic antagonism within the PFC, and blocked the anxiogenic properties of THC, suggesting that the therapeutic properties of CBD within the PFC may be present only during pathologically aberrant states within the PFC. Interestingly, the effects of PFC THC vs. CBD were found to be mediated through dissociable CB1 vs. 5-HT

Topics: Affect; Animals; Anxiety; Behavior, Animal; Benzopyrans; Cannabidiol; Dizocilpine Maleate; Dose-Response Relationship, Drug; Dronabinol; Executive Function; Male; Microinjections; Piperidines; Prefrontal Cortex; Pyrazoles; Rats; Social Behavior

Cognitive dysfunctions are common in major depressive disorder, but have been difficult to recapitulate in animal models. This study shows that Flinders sensitive line (FSL) rats, a genetic rat model of depression, display a pronounced impairment of emotional memory function in the passive avoidance (PA) task, accompanied by reduced transcription of Arc in prefrontal cortex and hippocampus. At the cellular level, FSL rats have selective reductions in levels of NMDA receptor subunits, serotonin 5-HT(1A) receptors and MEK activity. Treatment with chronic escitalopram, but not with an antidepressant regimen of nortriptyline, restored memory performance and increased Arc transcription in FSL rats. Multiple pharmacological manipulations demonstrated that procognitive effects could also be achieved by either disinhibition of 5-HT(1A)R/MEK/Arc or stimulation of 5-HT₄R/MEK/Arc signaling cascades. Taken together, studies of FSL rats in the PA task revealed reversible deficits in emotional memory processing, providing a potential model with predictive and construct validity for assessments of procognitive actions of antidepressant drug therapies.

Topics: AIDS-Related Complex; Analysis of Variance; Animals; Avoidance Learning; Benzopyrans; Brain-Derived Neurotrophic Factor; Citalopram; Depression; Disease Models, Animal; Dizocilpine Maleate; Emotions; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Exploratory Behavior; Gene Expression Regulation; Hippocampus; Immunoprecipitation; MAP Kinase Signaling System; Memory Disorders; Prefrontal Cortex; Rats; Rats, Mutant Strains; Receptors, N-Methyl-D-Aspartate; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Serotonin; Swimming

The role of the brain 5-HT1A receptor in cognition was examined in the water maze (WM) and passive avoidance (PA) tasks in the male rat. Pre-training administration of the 5-HT1A receptor agonist 8-OH-DPAT impaired WM performance and facilitated PA retention at low doses (0.01 and 0.03 mg/kg) and impaired PA retention at higher doses (0.1-1.0 mg/kg). The 5-HT1A receptor antagonist NAD-299 produced a dose-dependent facilitation of PA retention. In contrast, the 5-HT1A receptor antagonists NAD-299 and WAY-100635 failed to alter acquisition and retention in the WM. The impairments in WM and PA (but not facilitation in PA) induced by 8-OH-DPAT were blocked by NAD-299. Furthermore, NAD-299 prevented the PA impairments induced by the muscarinic antagonist scopolamine or the NMDA receptor antagonist MK-801. In contrast, NAD-299 and WAY-100635 failed to attenuate the WM impairment induced by scopolamine, probably due to the failure of 5-HT1A receptor blockade to attenuate the sensorimotor disturbances induced by scopolamine. These results indicate that 5-HT1A receptor stimulation and blockade result in opposite effects in two types of cognitive tasks in the rat, and that 5-HT1A receptor blockade can facilitate some aspects of cognitive function, probably via modulation of cholinergic and glutamatergic transmissions. This suggests that 5-HT1A receptor antagonists may have a potential role in the treatment of human degenerative disorders associated with cognitive deficits.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Analysis of Variance; Animals; Avoidance Learning; Behavior, Animal; Benzopyrans; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Male; Maze Learning; Muscarinic Antagonists; Piperazines; Pyridines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Serotonin, 5-HT1A; Scopolamine; Serotonin Antagonists; Serotonin Receptor Agonists; Spatial Behavior; Time Factors