piperidines 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

The effects of the HT(1A) receptor antagonist NAD-299 on extracellular acetylcholine (ACh) and glutamate (Glu) levels in the frontal cortex (FC) and ventral hippocampus (HPC) of the awake rats were investigated by the use of in vivo microdialysis. Systemic administration of NAD-299 (0.3; 1 and 3micromol/kg s.c.) caused a dose-dependent increase in ACh levels in FC and HPC (peak value of 209% and 221%, respectively) and this effect was comparable to that induced by donepezil (2.63micromol/kg s.c.). Moreover, the ACh levels in the FC increased even after repeated (14days) treatment with NAD-299 and when NAD-299 was injected locally into the nucleus basalis magnocellularis or perfused through the microdialysis probe implanted in the cortex. In contrast, NAD-299 failed to alter the extracellular levels of glutamate after systemic (3micromol/kg s.c.) or local (100microM) administration. The present data support the hypothesis that cholinergic transmission in cortico-limbic regions can be enhanced via blockade of postsynaptic 5-HT(1A) receptors, which may underlie the proposed cognitive enhancing properties of NAD-299 in models characterized by cholinergic deficit.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Acetylcholine; Animals; Area Under Curve; Benzopyrans; Cholinesterase Inhibitors; Donepezil; Dose-Response Relationship, Drug; Extracellular Fluid; Frontal Lobe; Glutamic Acid; Hippocampus; Indans; Male; Microdialysis; Neostigmine; Piperidines; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Serotonin Receptor Agonists; Wakefulness

Selective 5-HT(1A) receptor antagonists enhance the effect of selective serotonin reuptake inhibitors (SSRIs) on presynaptic 5-HT function, and have potential as antidepressant augmentation therapies. The present study tested the effect of different selective 5-HT(1A) receptor antagonists (WAY 100635, NAD-299, p-MPPI and LY 426965) in combination with a SSRI (paroxetine), on postsynaptic 5-HT function measured by increased expression of the immediate early gene, Arc. Paroxetine (5 mg/kg s.c.) combined with WAY 100635 (0.3 mg/kg s.c.) increased Arc mRNA in frontal, parietal and piriform cortices, and caudate putamen. Paroxetine (5 mg/kg s.c.) plus NAD-299 (1 or 5 mg/kg s.c.) had a similar effect. None of these drugs increased Arc mRNA when administered alone. Paroxetine (5 mg/kg s.c.) plus p-MPPI (8.5 mg/kg s.c.) also increased Arc mRNA but p-MPPI itself elevated Arc mRNA in many regions. Whilst LY 426965 (3 or 10 mg/kg s.c.) had no effect alone, when combined with paroxetine (5 mg/kg s.c.), the drug increased Arc mRNA in caudate putamen but not cortical regions.In conclusion, this study demonstrates that four 5-HT(1A) receptor antagonists augment the effect of an SSRI on Arc mRNA expression, which is suggestive of increased postsynaptic 5-HT function. However, the data reveal certain differences in the 5-HT(1A) receptor antagonists not recognised in models of presynaptic 5-HT function.

Topics: Aminopyridines; Animals; Apoptosis Regulatory Proteins; Benzopyrans; Brain Chemistry; Gene Expression; Male; Muscle Proteins; Paroxetine; Piperazines; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; RNA, Messenger; Selective Serotonin Reuptake Inhibitors; Serotonin Antagonists

1. Ejaculatory problems and anorgasmia are well-known side-effects of the SSRI antidepressants, and a pharmacologically induced increase in serotonergic neurotransmission inhibits ejaculatory behaviour in the rat. In the present study the role of 5-HT1A and 5-HT1B receptors in the mediation of male rat ejaculatory behaviour was examined by use of selective agonists and antagonists acting at these 5-HT receptor subtypes. 2. The 5-HT1A receptor agonist 8-OH-DPAT (0.25-4.00 micromol kg(-1) s.c.) produced an expected facilitation of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the new selective 5-HT1A receptor antagonist (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5 -carboxamide hydrogen (2R,3R) tartrate monohydrate (NAD-299) (1.0 micromol kg(-1) s.c.). NAD-299 by itself (0.75-3.00 micromol kg(-1) s.c.) did not affect the male rat ejaculatory behaviour. 3. The 5-HT1B receptor agonist anpirtoline (0.25-4.00 micromol kg(-1) s.c.) produced a dose-dependent inhibition of the male rat ejaculatory behaviour, and this effect was fully antagonized by pretreatment with the 5-HT1B receptor antagonist isamoltane (16 micromol kg(-1) s.c.) as well as by the new and selective antagonist (R)-(+)-2-(3-morpholinomethyl-2H-chromene-8-yl)oxymethylmorphol ino methansulphonate (NAS-181) (16 micromol kg(-1) s.c.). Isamoltane (1.0-16.0 micromol kg(-1) s.c.) and NAD-181 (1.0-16.0 micromol kg(-1) s.c.) had no, or weakly facilitatory effects on the male rat ejaculatory behaviour. The non-selective 5-HT1 receptor antagonist (-)-pindolol (8 micromol kg(-1) s.c.), did not antagonize the inhibition produced by anpirtoline. 4. The present results demonstrate opposite effects, facilitation and inhibition, of male rat ejaculatory behaviour by stimulation of 5-HT1A and 5-HT1B receptors, respectively, suggesting that the SSRI-induced inhibition of male ejaculatory dysfunction is due to 5-HT1B receptor stimulation.

Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic beta-Antagonists; Animals; Benzopyrans; Ejaculation; Female; Male; Morpholines; Pindolol; Piperidines; Propanolamines; Pyridines; Rats; Rats, Wistar; Receptor, Serotonin, 5-HT1B; Receptors, Serotonin; Receptors, Serotonin, 5-HT1; Serotonin Agents; Serotonin Antagonists; Serotonin Receptor Agonists; Sexual Behavior, Animal; Time Factors