Striatal signaling in L-DOPA-induced dyskinesia: common mechanisms with drug abuse and long term memory involving D1 dopamine receptor stimulation

Parkinson’s disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-L-alanine (L-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brain’s response to L-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias. L-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless L-DOPA dosages are reduced to below therapeutic levels. Thus, controlling LID is one of the major challenges in Parkinson’s disease therapy. LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons. Through increased coupling to Gαolf, resulting in greater stimulation of adenylyl-cyclase, D1 receptors phosphorylate DARPP-32 and other protein kinase A targets. Moreover, D1 receptor stimulation activates ERK and triggers a signaling pathway involving mTOR and modifications of histones that results in changes in translation, chromatin modification and gene transcription. In turn, sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID. Importantly, different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation. Here we review evidence implicating D1 receptor signaling in the genesis of LID, analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements, and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinson’s disease brain (Abstract and Full text).

MIGRAINE-LIKE HEADACHE WITH VISUAL DEFICIT AND PERFUSION ABNORMALITY ON MRI

MRI illustrating pertinent findings during the attack of headache and right homonymous hemianopsia (A and B) and at 2-week follow-up (C and D)

The baseline MRI is done at 1.5 T and the follow-up MRI at 3 T. (A) At 150 minutes after symptom onset, axial isotropic diffusion-weighted imaging (b = 1,000 s/mm²) (a) is normal without ischemic injury. The circle of Willis on the time-of-flight magnetic resonance angiogram (MRA) (b) 155 minutes after symptom onset is also normal with symmetric arterial calibers. Axial fluid-attenuated inversion recovery (FLAIR) sequence at 170 minutes (c) is also normal. At 205 minutes, the T1 postcontrast “equilibrium” sequence (d) shows pial vessels dilatation (arrow), overlying the left occipital area. (B) Perfusion images at 210 minutes after symptom onset show symmetric relative cerebral blood volume (rCBV) map (a) and relative cerebral blood flow (rCBF) map (b) through the occipital lobes. The mean transit time (MTT) map (c) and the maximal time to peak of the residue function (Tmax) map (d) show mild delay in contrast arrival time in the left occipital pole. Using the RAPID automated software, the post-processed thresholded and segmented Tmax map (e) highlights 9.5 mL of tissue in blue with Tmax >4 seconds, indicating mild tissue hypoperfusion (benign oligemia). Only scattered and patchy areas within the area of mild hypoperfusion have a Tmax ≥6 seconds (currently accepted threshold^2,7 for significant tissue ischemia) on the Tmax map (d) and these represented less than 3 mL of volume per RAPID (e). This pattern of normal rCBV, rCBF, mildly prolonged MTT and Tmax indicates only mild hypoperfusion without risk of progressing to infarction.^2,7 Similar perfusion changes were seen in 3 additional contiguous slices through the left occipital pole. (C) Follow-up MRI at day 12 shows a normal axial isotropic diffusion-weighted imaging (b = 1,000 s/mm²) (a), normal time-of-flight MRA (b), and normal axial FLAIR (c), without any resultant tissue injury. The improved conspicuity of arteries on this MRA is due to higher magnet strength (3T). The T1 postcontrast sequence (d) shows complete resolution of the prior pial vasodilation. (D) On perfusion imaging, the rCBV (a) and rCBF (b) maps continue to be normal. MTT (c), Tmax (d), and RAPID (e) maps show complete resolution of the left occipital hypoperfusion.

Spongiform degeneration in humans and animals is characterized by vacuolar change in the central nervous system

A. Spongiform degeneration in human diseases. Left to right, CJD prion plaque surrounded by vacuoles¹, counterstained with hematoxylin and eosin; CJD cerebral cortex², counterstained with hematoxylin and eosin; kuru cerebral cortex², counterstained with hematoxylin and eosin; and AD medial temporal lobe³, counterstained with hematoxylin and eosin. B. Spongiform degeneration in rodents. Left to right, brainstem from mouse infected with FrCasE retrovirus⁴, immunostained with anti-FrCasE surface glycoprotein; cortex from Mgrn1 null (Mgrn1^md-nc/Mgrn1^md-nc) mouse⁵, immunostained with anti-glial fibrillary acidic protein; cortex from mahogany (Atrn^mg3J / Atrn^mg3J) mouse⁵, immunostained with anti-glial fibrillary acidic protein; and EM of a brainstem vacuole from mahogany (Atrn^mg3J / Atrn^mg3J) mouse⁵.