Cannabinoids exert their psychomotor actions through the CB1 cannabinoid receptor in the brain. Genetic deletion of CB1 in mice causes various symptoms, including changes in locomotor activity, increased ring catalepsy, supraspinal hypoalgesia, and impaired memory extinction. Although the cerebellar cortex contains the highest level of CB1, severe cerebellum-related functional deficits have not been reported in CB1 knock-out mice. To clarify the roles of CB1 in cerebellar function, we subjected CB1 knock-out mice to a delay version of classical eyeblink conditioning. This paradigm is a test for cerebellum-dependent discrete motor learning, in which conditioned stimulus (CS) (352 ms tone) and unconditioned stimulus (US) (100 ms periorbital electrical shock) are coterminated. We found that delay eyeblink conditioning performance was severely impaired in CB1 knock-out mice. In contrast, they exhibited normal performance in a trace version of eyeblink conditioning with 500 ms stimulus-free interval intervened ...

Altered functional connectivity has been reported in infants with prenatal exposure to opioids, which significantly interrupts and influences endogenous neurotransmitter/receptor signaling during fetal programming. Better birth outcomes and long-term developmental outcomes are associated with medication for opioid use disorder (MOUD) during pregnancy, but the neural mechanisms underlying these benefits are largely unknown. We aimed to characterize effects of prenatal opioid/other drug exposure (PODE) and the neural basis for the reported beneficial effects of MOUD by examining neonatal brain functional organization. A cohort of 109 human newborns, 42 PODE, 39 with prenatal exposure to drugs excluding opioids (PDE), 28 drug-free controls (males and females) underwent resting-state fMRI at 2 weeks of age. To examine neural effects of MOUD, PODE infants were separated into subgroups based on whether mothers received MOUD ( n = 31) or no treatment ( n = 11). A novel heatmap analysis was designed to characteriz...

Methylenedioxymethamphetamine (MDMA; “Ecstasy”) is a popular recreational drug and brain serotonin (5-HT) neurotoxin. Neuroimaging data indicate that some human MDMA users develop persistent deficits in brain 5-HT neuronal markers. Although the consequences of MDMA-induced 5-HT neurotoxicity are not fully understood, abstinent MDMA users have been found to have subtle cognitive deficits and altered sleep architecture. The present study sought to test the hypothesis that sleep disturbance plays a role in cognitive deficits in MDMA users. Nineteen abstinent MDMA users and 21 control subjects participated in a 5 d inpatient study in a clinical research unit. Baseline sleep quality was measured using the Pittsburgh Sleep Quality Inventory. Cognitive performance was tested three times daily using a computerized cognitive battery. On the third day of admission, subjects began a 40 h sleep deprivation period and continued cognitive testing using the same daily schedule. At baseline, MDMA users performed less accu...

Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule-binding repeat encoded by exon 10 of the TAU gene. TAU gene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation de...

Although many people drink alcohol regularly, only some become addicted. Several studies have shown that genetic and environmental factors contribute to individual differences in the vulnerability to the effects of alcohol ([Nestler, 2000][1]; [Kreek, 2001][2]; [Crabbe, 2002][3]). Among the environmental factors, stress is perhaps the most important trigger for relapse after a period of abstinence ([Koob and Nestler, 1997][4]; [Piazza and Le Moal, 1998][5]; [Koob and Le Moal, 2001][6]; [Weiss et al., 2001][7]). Here we show that ethanol withdrawal symptoms were completely absent in cannabinoid CB1 receptor-deficient mice, although acute effects of ethanol and ethanol tolerance and preference were basically normal. Furthermore, foot-shock stress had no affect on alcohol preference in Cnr1−/− mice, although it induced a dramatic increase in Cnr1+/+ animals. These results reveal a critical role for the CB1 receptor in clinically important aspects of alcohol dependence and provide a rationale for the use of CB...

The cannabinoid system has been shown to affect learning and memory in humans and rats, but its effects on attentional performance are less clear. We investigated the role for cannabinoid receptors in the control of visuospatial attention in rats using a self-paced, lateralized reaction time task. Male rats were injected with the selective cannabinoid CB1 receptor agonists delta-9-tetrahydrocannabinol or WIN 55,212-2 or the CB1 receptor antagonist SR 141617A at doses of 0.1, 0.5, and 1.0 mg/kg. Each rat was given all doses of one of the drugs versus vehicle in a Latin Square’s design. For WIN 55,212-2 there was a significant interaction between treatment and target stimulus duration for choice accuracy (p=0.03); this is partly due to increased omissions at the 0.5 sec target stimulus duration. The highest dose of WIN 55,212-2 tended to decrease anticipatory responses, but did not affect pellet retrieval times or reaction times, suggesting that no motor slowing occurred at these doses. The medium dose of WI...

The generation and specification of pyramidal neuron subpopulations during development relies on a complex network of transcription factors. The CB1 cannabinoid receptor is the major molecular target of endocannabinoids and marijuana active compounds. This receptor has been shown to influence neural progenitor proliferation and axonal growth, but its involvement in neuronal differentiation and the functional impact in the adulthood caused by altering its signaling during brain development are not known. Here we show that the CB1 receptor, by preventing Satb2 (special AT-rich binding protein 2)-mediated repression, increased Ctip2 (COUP-TF interacting protein 2) promoter activity, and Ctip2-positive neuron generation. Unbalanced neurogenic fate determination found in complete CB1 −/− mice and in glutamatergic neuron-specific Nex–CB1 −/− mice induced overt alterations in corticospinal motor neuron generation and subcerebral connectivity, thereby resulting in an impairment of skilled motor function in adult m...

Mitochondrial dysfunction is critically involved in Parkinson's disease, characterized by loss of dopaminergic neurons (DaNs) in the substantia nigra (SNc), whereas DaNs in the neighboring ventral tegmental area (VTA) are much less affected. In contrast to VTA, SNc DaNs engage calcium channels to generate action potentials, which lead to oxidant stress by yet unknown pathways. To determine the molecular mechanisms linking calcium load with selective cell death in the presence of mitochondrial deficiency, we analyzed the mitochondrial redox state and the mitochondrial membrane potential in mice of both sexes with genetically induced, severe mitochondrial dysfunction in DaNs (MitoPark mice), at the same time expressing a redox-sensitive GFP targeted to the mitochondrial matrix. Despite mitochondrial insufficiency in all DaNs, exclusively SNc neurons showed an oxidized redox-system, i.e., a low reduced/oxidized glutathione (GSH-GSSG) ratio. This was mimicked by cyanide, but not by rotenone or antimycin A, mak...

Endocannabinoids are endogenous compounds that resemble the active ingredient of marijuana and activate the cannabinoid receptor in the brain. They mediate retrograde signaling from principal cells to interneurons. Endocannabinoid is released from pyramidal cells by Ca2+ influx and suppresses GABAergic transmission (depolarization-induced suppression of inhibition, DSI). Activation of group I metabotropic glutamate receptor stimulates the endocannabinoid release. We predicted that additional neurotransmitters would regulate endocannabinoid release. Inhibitory synapses in CA1 region of acute hippocampal slices from rats were studied using whole-cell patch clamp techniques. We found that low dose (0.2 - 0.5 µM) of carbachol enhanced DSI by activating muscarinic acetylcholine receptors (mAChRs) on postsynaptic cells without affecting basal eIPSC amplitude. Higher dose of carbachol (≧ 1 µM) both enhanced DSI and tonically depressed eIPSCs by releasing endocannabinoids. With AM251, a CB1 receptor antagonist, or...

Environmental stressors activate an endogenous mechanism for suppressing pain that is insensitive to opioid antagonists. The mechanism underlying nonopioid stress-induced analgesia has remained a major gap in the knowledge base. The present studies were conducted to test the hypothesis that nonopioid stress-induced analgesia is mediated by a cannabinoid mechanism. Nonopioid stress-induced analgesia was induced in rats using brief, continuous footshock. SR141716A, a competitive antagonist for cannabinoid CB1 receptors, blocked nonopioid stress-induced analgesia, defined behaviorally in the tail-flick test. By contrast, the opioid antagonist naltrexone and the competitive antagonist for cannabinoid CB2 receptors, SR144528, failed to alter stress analgesia in this paradigm. Blocking reuptake of the endocannabinoid anandamide with AM404 potentiated nonopioid stress-induced analgesia. Acute administration of the prototypic classical cannabinoid delta9-tetrahydrocannabinol similarly enhanced stress analgesia. By...