Clozapine N-oxide, compound 21, and JHU37160 do not influence effortful reward-seeking behavior in mice.

RATIONALE: Clozapine N-oxide (CNO) has been developed as a ligand to selectively activate designer receptors exclusively activated by designer drugs (DREADDs). However, previous studies have revealed that peripherally injected CNO is reverse-metabolized into clozapine, which, in addition to activating DREADDs, acts as an antagonist at various neurotransmitter receptors, suggesting potential off-target effects of CNO on animal physiology and behaviors. Recently, second-generation DREADD agonists compound 21 (C21) and JHU37160 (J60) have been developed, but their off-target effects are not fully understood. OBJECTIVES: The present studies assessed the effect of novel DREADD ligands on reward-seeking behavior. METHODS: We first tested the possible effect of acute i.p. injection of low-to-moderate (0.1, 0.3, 1, 3 mg/kg) of CNO, C21, and J60 on motivated reward-seeking behavior in wild-type mice. We then examined whether a high dose (10 mg/kg) of these drugs might be able to alter responding. RESULTS: Low-to-moderate doses of all drugs and a high dose of CNO or C21 did not alter operant lick responding for a reward under a progressive ratio schedule of reinforcement, in which the number of operant lick responses to obtain a reward increases after each reward collection. However, high-dose J60 resulted in a total lack of responding that was later observed in an open field arena to be due to a sedative effect. CONCLUSIONS: This study provides definitive evidence that commonly used doses of CNO, C21, and J60 have negligible off-target effects on motivated reward-seeking but urges caution when using high doses of J60 due to sedative effects.

An autopsy case of early-stage amyotrophic lateral sclerosis with TDP-43 immunoreactive neuronal, but not glial, inclusions.

Phosphorylated transactivation response DNA-binding protein 43 kDa (p-TDP-43)-immunoreactive neuronal and glial cytoplasmic inclusions are a histopathological hallmark of sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43. We report an autopsy case of lower motor neuron-predominant ALS in a 47-year-old Japanese man who committed suicide 5 months after onset. Histopathologically, neuronal loss was restricted to the anterior horn of the spinal cord, and no obvious neuronal loss was noted in the motor cortex or brainstem motor nuclei. Bunina bodies were found in the spinal anterior horn cells and the facial and hypoglossal nuclei. Immunohistochemically, p-TDP-43-immunoreactive neuronal, but not glial, cytoplasmic inclusions were frequently found in the spinal anterior horn and facial and hypoglossal nuclei, and rarely in the motor cortex. We considered the present case to be an example of lower motor neuron-predominant ALS. p-TDP-43-immunoreactive aggregates in neurons, but not in glial cells, may be an early-stage pathology of ALS.

[Glucose intolerance in myotonic dystrophy type 1].

Insulin resistance is a characteristic feature of glucose intolerance in myotonic dystrophy type 1 (DM1). DM1 patients with dysglycaemia have liver insulin resistance as well as muscle insulin resistance, and also abnormality of insulin secretion. Insulin resistance in DM1 might result in multiple metabolic defects. Low level of fasting plasma glucose is a characteristic feature in the early stage of glucose intolerance in DM1, Early intervention against insulin resistance in DM1 is suggested because glucose intolerance could deteriorate in a certain degree of cases. Metformin treatment is useful to improve insulin resistance in DM1. Diabetic patients with DM1 usually show mild hyperglycemia. However, poorly controlled patients with hyperglycemic pattern tending to rise from morning to evening exist. Intensive insulin therapy might be necessary in such cases. We should pay attention to hypoglycemia due to hyperinsulinemia, pseudo improvement of glucose control according to exacerbated dysphagia, and acute aggravation caused by infections, at a bedside.

An autopsy case of early ("minimal change") olivopontocerebellar atrophy (multiple system atrophy-cerebellar).

We report a 57-year-old woman with multiple system atrophy (MSA) of 15-month duration. The patient developed dysarthria, followed by impaired balance of gait, mild limb ataxia, and saccadic eye movement. A postmortem examination performed after she was found dead in a bathtub revealed neuronal loss restricted to the olivopontocerebellar system, being more severe in the pontine nucleus. Mild neuronal loss was also found in the anterior vermis and inferior olivary nucleus. Alpha-synuclein immunohistochemistry demonstrated widespread occurrence of glial cytoplasmic inclusions in the central nervous system, which were more numerous in the pontine base and cerebellar white matter. In contrast, neuronal alpha-synuclein accumulation was confined to the pontine and inferior olivary nuclei. The number of neuronal intranuclear inclusions was much higher than that of neuronal cytoplasmic inclusions. Moreover, alpha-synuclein accumulation was more severe in the neurites than in the cytoplasm or nucleus. This case demonstrates the early pattern of brain pathology in MSA-cerebellar (olivopontocerebellar atrophy).

Lewy bodies in Betz cells of the motor cortex in a patient with Parkinson's disease.

Lewy bodies (LBs) were observed in the giant pyramidal cells of Betz in the motor cortex of a patient with Parkinson's disease (PD) of 8-year duration. The patient had shown typical clinical features of PD. No dementia or pyramidal tract signs had been observed. The LBs, found in 8 of 747 Betz cells counted (1.1%), appeared as homogeneous or laminated, spherical inclusions with a clear surrounding halo and were strongly immunoreactive for alpha-synuclein. To our knowledge, this is the first demonstration of LBs in Betz cells. Considering the significant loss of neurons in the predilection sites for LBs, it is possible that in this patient, the motor cortex was also involved in the disease process of PD.