Melissa J. Nirenberg

Compulsive eating and weight gain related to dopamine agonist use

Dopamine agonists have been implicated in causing compulsive behaviors in patients with Parkinsons disease (PD). These have included gambling, hypersexuality, hobbyism, and other repetitive, purposeless behaviors (“punding”). In this report, we describe 7 patients in whom compulsive eating developed in the context of pramipexole use. All of the affected patients had significant, undesired weight gain; 4 had other comorbid compulsive behaviors. In the 5 patients who lowered the dose of pramipexole or discontinued dopamine agonist treatment, the behavior remitted and no further weight gain occurred. Physicians should be aware that compulsive eating resulting in significant weight gain may occur in PD as a side‐effect of dopamine agonist medications such as pramipexole. Given the known risks of the associated weight gain and obesity, further investigation is warranted.

VESICULAR MONOAMINE TRANSPORTER-2 : IMMUNOGOLD LOCALIZATION IN STRIATAL AXONS AND TERMINALS

The vesicular monoamine transporter‐2 (VMAT2) mediates the reserpinesensitive neuronal uptake of monoamines into vesicles and other intracellular organelles. Accordingly, this transporter is expressed at high levels in regions that contain a dense monoamine innervation, such as the rat dorsolateral striatum. We used ultrastructural immunocytochemistry in this region to show that immunogold labeling for VMAT2 is present in varicose axonal processes, many of which also contain the catecholamine‐synthesizing enzyme tyrosine‐hydroxylase. Within these mainly dopaminergic processes, VMAT2 was associated with small synaptic vesicles (SSVs) and more rarely with large dense‐core vesicles or tubulovesicles. These findings suggest that SSVs are the major organelles involved in the storage and release of dopamine in the dorsolateral striatum. Synapse 26:194–198, 1997.

Prospective cohort study of impulse control disorders in Parkinson's disease

Impulse control disorders (ICDs) are potentially serious side effects of dopamine agonist therapy in Parkinsons disease (PD), but prospective data are lacking about their incidence, time course, and risk factors. This work was a 4‐year, prospective cohort study of outpatients with PD and no previous ICDs (N = 164). All subjects treated with a dopamine agonist during the study were followed longitudinally for new‐onset ICDs. Baseline characteristics were compared in groups with (ICD+) and without (ICD−) subsequent ICDs. Forty‐six subjects were treated with a dopamine agonist, including 25 who were newly treated and 21 who received ongoing dopamine agonist therapy. Of these 46 subjects, 18 (39.1%) developed new‐onset ICDs. The timing of ICD onset varied from 3.0 to 114.0 months (median, 23.0) after initiation of dopamine agonist therapy. Baseline demographic characteristics were similar in ICD+ and ICD− groups. At baseline, ICD+ subjects had a greater prevalence of motor complications (61.1% versus 25.0%; P = 0.01) than ICD− subjects, despite comparable total dopaminergic medication usage in both groups (median, 150.0 versus 150.0 levodopa equivalents; P = 0.61). Compared with ICD− subjects, ICD+ subjects had a greater baseline prevalence of caffeine use (100% versus 66.7%; P = 0.007) and higher lifetime prevalence of cigarette smoking (44.4% versus 14.3%; P = 0.04). Peak dopamine agonist doses were higher in ICD+ than ICD− subjects (median 300.0 versus 165.0 L‐dopa equivalents; P = 0.03), but cumulative dopamine agonist exposure was similar in both groups. In summary, the timing of new‐onset ICDs in PD is highly variable. Risk factors include cigarette smoking, caffeine use, motor complications, and higher peak dopamine agonist dosage.

Multinuclear Magnetic Resonance Spectroscopy for in Vivo Assessment of Mitochondrial Dysfunction in Parkinson's Disease

Parkinsons disease (PD) is a common and often devastating neurodegenerative disease affecting up to one million individuals in the United States alone. Multiple lines of evidence support mitochondrial dysfunction as a primary or secondary event in PD pathogenesis; a better understanding, therefore, of how mitochondrial function is altered in vivo in brain tissue in PD is a critical step toward developing potential PD biomarkers. In vivo study of mitochondrial metabolism in human subjects has previously been technically challenging. However, proton and phosphorus magnetic resonance spectroscopy (1H and 31P MRS) are powerful noninvasive techniques that allow evaluation in vivo of lactate, a marker of anaerobic glycolysis, and high energy phosphates, such as adenosine triphosphate and phosphocreatine, directly reflecting mitochondrial function. This article reviews previous 1H and 31P MRS studies in PD, which demonstrate metabolic abnormalities consistent with mitochondrial dysfunction, and then presents recent 1H MRS data revealing abnormally elevated lactate levels in PD subjects.

Multiple system atrophy in a patient with the spinocerebellar ataxia 3 gene mutation.

The cerebellar variant of multiple system atrophy (MSA‐C) has overlapping clinical features with the hereditary spinocerebellar ataxias (SCAs), but can usually be distinguished on a clinical basis. We describe a patient who developed a sporadic, late‐onset, rapidly progressive neurodegenerative disorder consistent with MSA‐C. Genetic testing, however, showed an abnormal expansion of one allele of the spinocerebellar ataxia 3 (SCA3) gene. The clinical impression of MSA‐C was confirmed by identification of numerous α‐synuclein–containing glial cytoplasmic inclusions on autopsy. These findings suggest that abnormal expansion of the SCA3 gene may be a risk factor for the development of MSA‐C.

Regional and subcellular distribution of a neutral and basic amino acid transporter in forebrain neurons containing nitric oxide synthase.

The neutral and basic amino acid transporter (NBAT) facilitates sodium‐independent transport of L‐amino acids in renal and intestinal epithelial cells and has been postulated to play a similar role in neurons. In previous studies, NBAT has been detected within enteric and brainstem autonomic neurons in a distribution similar to that of constitutive nitric oxide synthase (cNOS). Furthermore, L‐arginine, the required precursor for nitric oxide synthesis, is an excellent NBAT substrate. Together, these findings suggest that NBAT may play a role in the regulation of nitric oxide synthesis, through the control of precursor availability. To gain insight into the potential physiological role of NBAT in central neurons, we used an antipeptide antiserum to examine the light and electron microscopic immunocytochemical localization of NBAT in the rat forebrain and to compare this distribution with that of cNOS. Immunolabeling for NBAT was detected within perikarya and dendrite‐like processes that were most numerous in the frontal and cingulate cortex, the ventral striatum, the central amygdala, and the bed nucleus of the stria terminalis. Labeled varicose axonal processes were distributed most densely in the agranular insular cortex and the paraventricular nuclei of the thalamus and hypothalamus (PVH). Electron microscopy showed that immunogold labeling for NBAT was distributed along plasmalemmal and vacuolar membranes within somata, dendrites, and axonal profiles. Many of the NBAT‐containing somata and dendrites contained detectable cNOS. Our results suggest that expression of NBAT may provide specific populations of cNOS‐containing forebrain neurons with a unique mechanism for regulating somatodendritic synthesis of nitric oxide. J. Comp. Neurol. 404:459–472, 1999.

Dopamine agonist withdrawal syndrome and non-motor symptoms after Parkinson’s disease surgery

ARTICLEnnSir, I read with interest the manuscript by Dr Thobois and colleagues (Thobois et al. , 2010), in which the authors report the occurrence of depression and apathy after deep brain stimulation surgery for Parkinson’s disease and correlate these symptoms with mesolimbic dopaminergic denervation on neuroimaging studies. I agree with the authors’ interpretation of post-surgical apathy as a drug withdrawal state precipitated by the rapid tapering of dopaminergic medications (Rabinak and Nirenberg, 2010). My strong suspicion, however, is that severe non-motor symptoms that occur after deep brain stimulation are largely attributable to dopamine agonist withdrawal syndrome (DAWS) rather than a non-specific dopamine withdrawal state (Rabinak and Nirenberg, 2010). Furthermore, I have significant safety concerns about the use of piribedil as a treatment for these withdrawal symptoms.nnRecognition of DAWS is critical because it: (i) exclusively occurs in patients with baseline dopamine agonist-related impulse control disorders; (ii) responds only to dopamine agonist repletion and not to levodopa or other Parkinson’s disease medications; and (iii) includes not only apathy and depression, but also a broad …

ULTRASTRUCTURAL LOCALIZATION OF THE VESICULAR MONOAMINE TRANSPORTER 2 IN MESOLIMBIC AND NIGROSTRIATAL DOPAMINERGIC NEURONS

Publisher Summary The ultrastructural localization of vesicular monoamine transporter 2 (VMAT2) have been examined within two distinct populations of midbrain dopaminergic neurons: the mesolimbic dopaminergic neurons, which are relatively resistant to parkinsonism-inducing neurotoxins, and the nigrostriatal dopaminergic neurons, which are selectively vulnerable to both idiopathic and drug-induced Parkinsonism. The neurons in these regions are known to release dopamine from their somata and/or dendrites in the midbrain, as well as from their axonal processes in the striatum. These studies show that VMAT2 is prominently localized to tubulovesicular organelles in midbrain dopaminergic (TH-immunoreactive) perikarya and dendrites. In contrast, VMAT2 is almost exclusively localized to typical small synaptic vesicles (SSVs) and dense core vesicles (DCVs) within catecholaminergic and noncatecholaminergic axonal processes in the midbrain and striatum, as well as within the presumptive dopaminergic terminals in the striatum; whereas in other monoaminergic terminals—discussed in this chapter—VMAT2 is also extensively localized to DCVs. Quantitative comparison of midbrain dopaminergic dendrites showed that there are higher levels of VMAT2 in the ventral tegmental area (VTA) than in the substantia nigra (SN), which may underlie the greater vulnerability of nigrostriatal dopaminergic neurons to neurotoxic insult.

Dopamine agonist withdrawal syndrome in a patient with restless legs syndrome.

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Clinical predictors of frequent patient telephone calls in Parkinson's disease.

– see front matter 2012 Elsevier Ltd. http://dx.doi.org/10.1016/j.parkreldis.2012.06.006 In recent years, there has been increasing recognition of potentially serious side-effects of dopamine agonist (DA) therapy. Impulse control disorders (ICDs) such as pathological gambling, compulsive eating, hypersexuality, and compulsive buying, for example, have been reported in up to 17.1% of patients who use DAs [1–3]. Consequences of ICDs can include serious financial, medical, and/or psychosocial difficulties for patients and their families. Discontinuation of DA therapy is the most effective treatment for ICDs, but is not always tolerated due to motor worsening or dopamine agonist withdrawal syndrome (DAWS), a severe, stereotyped cluster of physical and psychological symptoms that temporally correlate with DA withdrawal and are refractory to levodopa and other neuropsychiatric medications [4]. DAWS can cause marked disability, with symptoms that include anxiety, panic attacks, agoraphobia, irritability, dysphoria, depression, suicidality, insomnia, dizziness, nausea, fatigue, orthostatic hypotension, diaphoresis, generalized pain, and drug cravings. To date, DAWS has only been reported in PD. Thus, it has been unclear whether DAWS is specific to PD, or whether it can also occur in patients treated with DAs for other indications [3]. Herein, we report a case of DAWS in a patient with restless legs syndrome (RLS). A 69-year-old right-handed woman with longstanding obsessive-compulsive traits, childhood-onset essential tremor, occasional marijuana use, and a prior 54 pack-year smoking history presented to our center for ongoing management of childhoodonset idiopathic RLS and periodic limb movement disorder (PLMD). On examination, she had bilateral kinetic tremor with intention, action, and writing, but no Parkinsonism, no cognitive deficits (Mini-Mental State Examination score of 30/30), and no evidence of peripheral neuropathy. She had been taking ropinirole for 7–8 years, with a prescribed dosage of 0.5 mg per night; however, it was subsequently recognized that she had been frequently self-medicating with additional, variable doses of ropinirole due to poorly controlled RLS symptoms. She was also taking clonazepam, 0.25–0.5 mg at bedtime for PLMD. In addition to nocturnal discomfort and restlessness of her legs, she described longstanding restlessness of her arms, as well as frequent awakenings during the night with recurrent RLS symptoms. At her initial visit, the patient reported severe, ropinirolerelated ICDs and punding behaviors that affected her social