Parkinson's disease is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. We now report that minocycline, a semisynthetic tetracycline, recently shown to have neuroprotective effects in animal models of stroke͞ischemic injury and Huntington's disease, prevents nigrostriatal dopaminergic neurodegeneration in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (

Amongst the SSRIs examined, only fluoxetine acutely increases extracellular concentrations of norepinephrine and dopamine as well as serotonin in prefrontal cortex, suggesting that fluoxetine is an atypical SSRI.

The objectives of this study were to examine the relationship between somatodendritic and terminal field dopamine (DA) release following manipulation of DA D2 receptors in the ventral tegmental area (VTA), systemic administration of ethanol, and inhibition of DA uptake in the nucleus accumbens (ACB). Perfusion of 5, 25 and 100 microM quinpirole (a D2 agonist), or sulpiride (a D2 antagonist) through the microdialysis probe in the VTA produced dose-related decreases or increases, respectively, in the extracellular levels of DA in both the VTA and ACB of adult Wistar rats. The IP administration of 2-3 g/kg ethanol produced a sustained increase in the extracellular levels of DA (150-200% of baseline) in the ACB for at least 2 h after injection, whereas only a transient increase was observed in the VTA. Local perfusion of the ACB with 100 microM GBR12909, a DA uptake inhibitor, elevated the extracellular levels of DA in the ACB to approximately 400% of baseline, but decreased the extracellular levels of DA in the VTA to approximately 50% of baseline. Overall, the results suggest that (a) there is an association between somatodendritic and terminal field DA release when D2 cell body autoreceptors in the VTA are manipulated, (b) elevating synaptic levels of DA in the terminal field activates a long-loop negative feedback system to the VTA, and (c) different mechanisms may be mediating the actions of ethanol on DA neuronal activity and terminal DA release.

The cannabinoid CB 1 receptor is one of the most abundant G protein-coupled receptors in the brain and is a promising target of therapeutic drug development. Success of drug development for neuropsychiatric indications is significantly enhanced with the ability to directly measure spatial and temporal binding of compounds to receptors in central compartments. We assessed the utility of a new positron emission tomography (PET) radioligand to image CB 1 receptors in monkey brain. showed that the majority (489%) of brain uptake in regions with high receptor densities was specific and reversibly bound to CB 1 receptors in the high binding regions. [ 11 C]MePPEP was rapidly removed from arterial plasma. Regional brain uptake could be quantified as distribution volume relative to the concentration of parent radiotracer in plasma. The P-glycoprotein (P-gp) inhibitor DCPQ ((R)-4- [(1a,6,10b)-1,1-dichloro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c]cyclohepten-6-yl]-[(5-quinolinyloxy)methyl]-1-piperazineethanol) did not significantly increase brain uptake of [ 11 C]MePPEP, suggesting it is not a substrate for this efflux transporter at the blood-brain barrier.[ 11 C]MePPEP is a radioligand with high brain uptake, high specific signal to CB 1 receptors, and adequately fast washout from brain that allows quantification with 11 C (half-life ¼ 20 min). These promising results in monkey justify studying this radioligand in human subjects.