Melatonin synergizes with low doses of L-DOPA to improve dendritic spine density in the mouse striatum in experimental Parkinsonism.

The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the preferred drug for Parkinson's disease, but long-term treatment results in the drug-induced dyskinesias and other side effects. This study was undertaken to examine whether melatonin could potentiate low dose L-DOPA effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced experimental parkinsonism. Mice were treated with the parkinsonian neurotoxin, MPTP, and different doses of melatonin and low doses of L-DOPA. Behavior, striatal histology, and dopamine metabolism were evaluated on the 7th day. MPTP-induced striatal dopamine loss was not modified by melatonin administration (10-30 mg/kg; i.p. at 10-hr intervals, 6 times; or at 2-hr intervals, by day). However, low doses of L-DOPA (5 mg/kg, by oral gavage) administered alone or along with melatonin (10 mg/kg, i.p.) twice everyday for 2 days, 10 hr apart, after two doses of MPTP significantly attenuated striatal dopamine loss and provided improvements in both catalepsy and akinesia. Additionally, Golgi-impregnated striatal sections showed preservation of the medium spiny neurons, which have been damaged in MPTP-treated mouse. The results demonstrated that melatonin, but not L-DOPA, restored spine density and spine morphology of medium spiny neurons in the striatum and suggest that melatonin could be an ideal adjuvant to L-DOPA therapy in Parkinson's disease, and by the use of this neurohormone, it is possible to bring down the therapeutic doses of L-DOPA.

[Pineal hormone melatonin in low doses potentiates psychotropic and chronotropic activity of tofisopam in rats].

Combination with a low dose of pineal hormone melatonin increased the anxiolytic effect of tofisopam (subthreshold dose) in open-field and cross-maze tests, as well as its chronotropic activity in time-course of forced swimming test in rats.

Correlates of alcohol use in adults with ADHD and comorbid alcohol use disorders: exploratory analysis of a placebo-controlled trial of atomoxetine.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) and substance use disorder are often comorbid in adults. The effects of ADHD treatment on comorbid alcohol use disorder have not been extensively studied. OBJECTIVE: To assess correlates of ADHD and alcohol use outcomes in ADHD with comorbid alcohol use disorders, via a post-hoc exploratory subgroup analysis of a previously conducted, randomized, double-blind, placebo-controlled study of recently abstinent adults. METHODS: Adults who had ADHD and alcohol use disorders and were abstinent for 4-30 days were randomized to daily atomoxetine 25-100 mg (mean final dose = 89.9 mg) or placebo for 12 weeks. Changes in ADHD symptoms from baseline to endpoint were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) total score, alcohol use by the timeline followback method, and alcohol cravings by the Obsessive Compulsive Drinking Scale. RESULTS: Of 147 subjects receiving atomoxetine (n = 72) or placebo (n = 75) in the primary study, 80 (54%) completed 12 weeks (n = 32 atomoxetine; n = 48 placebo). Improvements in ADHD symptoms on the AISRS correlated significantly with decreases in alcohol cravings (Pearson's r = 0.28; 95% confidence interval [CI] = 0.11-0.43; p = 0.002), and the correlation was most notable with atomoxetine (r = 0.29; CI [0.04 - 0.51]; p = 0.023) rather than with placebo (r = 0.24; CI [0.00-0.46]; p = 0.055). On-treatment drinking levels correlated with AISRS scores (r = 0.12; CI [0.05 -0.19]; p = 0.001). Relapse to alcohol abuse significantly correlated with worse ADHD symptoms on 15 of 18 items of the AISRS in the placebo group (p < 0.05 for each). CONCLUSIONS: No baseline predictor (other than degree of sobriety) of alcohol use or ADHD outcomes emerged. ADHD symptom improvements correlated significantly with reductions in alcohol cravings, and relapse to alcohol abuse correlated significantly with worsening of most ADHD symptoms in the placebo group, but not in the atomoxetine group. This post-hoc subgroup analysis is of a hypothesis-generating nature, and the generalizability of the findings may be limited by exclusion of adults with common ADHD comorbidities from the base study. Further, prospective clinical trials in larger and more heterogeneous patient populations are warranted to confirm or reject these preliminary associations. TRIAL REGISTRATION (BASE STUDY): ClinicalTrials.gov identifier: NCT00190957.

Cannabinoids enhance susceptibility of immature brain to ethanol neurotoxicity.

OBJECTIVE: Marijuana and alcohol are most widely abused drugs among women of reproductive age. Neurocognitive deficits have been reported in children whose mothers used marijuana during pregnancy. Maternal consumption of ethanol is known to cause serious developmental deficits METHODS: Infant rats and mice received systemic injections of Delta(9)-tetrahydrocannabinol (THC; 1-10mg/kg) or the synthetic cannabinoid WIN 55,212-2 (1-10mg/kg), alone or in combination with subtoxic and toxic ethanol doses, and apoptotic neurodegeneration was studied in the brains RESULTS: Acute administration of THC (1-10mg/kg), the principal psychoactive cannabinoid of marijuana, markedly enhanced proapoptotic properties of ethanol in the neonatal rat brain. THC did not induce neurodegeneration when administered alone. Neuronal degeneration became disseminated and severe when THC was combined with a mildly intoxicating ethanol dose (3gm/kg), with the effect of this drug combination resembling the massive apoptotic death observed when administering ethanol alone at much higher doses. The detrimental effect of THC was mimicked by the synthetic cannabinoid WIN 55,212-2 (1-10mg/kg) and counteracted by the CB(1) receptor antagonist SR141716A (0.4mg/kg). THC enhanced the proapoptotic effect of the GABA(A) agonist phenobarbital and the N-methyl-D-aspartate receptor antagonist dizocilpine. Interestingly, infant CB(1) receptor knock-out mice were less susceptible to the neurotoxic effect of ethanol. Furthermore, the CB(1) receptor antagonist SR141716A ameliorated neurotoxicity of ethanol INTERPRETATION: These observations indicate that CB(1) receptor activation modulates GABAergic and glutamatergic neurotransmission and primes the developing brain to suffer apoptotic neuronal death.