Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
-
Neuropsychopharmacology · Jul 2013
Nabilone decreases marijuana withdrawal and a laboratory measure of marijuana relapse.
Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Δ(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. ⋯ Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment.
-
Neuropsychopharmacology · Jul 2013
Pain after discontinuation of morphine treatment is associated with synaptic increase of GluA4-containing AMPAR in the dorsal horn of the spinal cord.
Withdrawal from prescribed opioids results in increased pain sensitivity, which prolongs the treatment. This pain sensitivity is attributed to neuroplastic changes that converge at the spinal cord dorsal horn. We have recently reported that repeated morphine administration triggers an insertion of GluA2-lacking (Ca(2+)-permeable) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) in the hippocampus. ⋯ Furthermore, current-voltage relationships of AMPAR-mediated EPSCs showed that rectification index (an indicator of Ca(2+)-permeable AMPAR contribution) is increased in morphine-treated but not in saline-treated mice. These effects could be reversed by infusion of GluA4 antibody through patch pipette. This is the first direct evidence for a role of GluA4-containing AMPAR in morphine-induced pain and highlights spinal GluA4-containing AMPAR as targets to prevent the morphine-induced pain sensitivity.
-
Neuropsychopharmacology · Jul 2013
Small-molecule inhibitors at the PSD-95/nNOS interface have antidepressant-like properties in mice.
Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca(2+), which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. ⋯ The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.
-
Neuropsychopharmacology · Jun 2013
Randomized Controlled TrialNaloxone-reversible modulation of pain circuitry by left prefrontal rTMS.
A 20-minute session of 10 Hz repetitive transcranial magnetic stimulation (rTMS) of Brodmann Area (BA) nine of the left dorsolateral prefrontal cortex (DLPFC) can produce analgesic effects on postoperative and laboratory-induced pain. This analgesia is blocked by pretreatment with naloxone, a μ-opioid antagonist. The purpose of this sham-controlled, double-blind, crossover study was to identify the neural circuitry that underlies the analgesic effects of left DLPFC rTMS, and to examine how the function of this circuit, including midbrain and medulla, changes during opioid blockade. ⋯ This analgesia was associated with elevated blood oxygenation-level dependent (BOLD) signal in BAs 9 and 10, and diminished BOLD signal in the anterior cingulate, thalamus, midbrain, and medulla during pain. Naloxone pretreatment largely abolished rTMS-induced analgesia, as well as rTMS-induced attenuation of BOLD signal response to painful stimuli throughout pain processing regions, including midbrain and medulla. These preliminary results suggest that left DLPFC rTMS drives top-down opioidergic analgesia.
-
Neuropsychopharmacology · Jun 2013
Memory of conditioned taste aversion is erased by inhibition of PI3K in the insular cortex.
The conditioned taste aversion (CTA) paradigm, in which association between a novel taste and visceral malaise is formed, gives a unique experimental setting to examine the mechanisms underlying memory acquisition and extinction processes. AKT is a main kinase of the phosphoinositide 3-kinase cascade (PI3K) and has been implicated in long-term memory. We have recently reported that blockade of PI3K in the basolateral amygdala (BLA) before retrieval of fear memory was associated with long-term reduction in fear responses, suggesting a possible role of PI3K inhibition in fear erasure. ⋯ Inhibition of AKT phosphorylation in the IC before or after the first CTA retrieval test resulted in reduction in the aversion index. This reduction in aversion is due to the erasure of the original CTA trace memory, as re-application of the unconditioned stimulus (lithium chloride) did not induce the recovery of aversion in LY294002-treated animals. Our present data add new evidence to suggest that PI3K is engaged in consolidation of aversive memories, as its inhibition is associated with erasure of CTA memory.