Local control of striatal dopamine release

The mesolimbic and nigrostriatal dopamine (DA) systems play a key role in the physiology of reward seeking, motivation and motor control. Importantly, they are also involved in the pathophysiology of Parkinson’s and Huntington’s disease, schizophrenia and addiction. Control of DA release in the striatum is tightly linked to firing of DA neurons in the ventral tegmental area (VTA) and the substantia nigra (SN). However, local influences in the striatum affect release by exerting their action directly on axon terminals. For example, endogenous glutamatergic and cholinergic activity is sufficient to trigger striatal DA release independently of cell body firing. Recent developments involving genetic manipulation, pharmacological selectivity or selective stimulation have allowed for better characterization of these phenomena. Such termino-terminal forms of control of DA release transform considerably our understanding of the mesolimbic and nigrostriatal systems, and have strong implications as potential mechanisms to modify impaired control of DA release in the diseased brain. Here, we review these and related mechanisms and their implications in the physiology of ascending DA systems

Impaired performance of the Q175 mouse model of Huntington’s disease in the touch screen paired associates learning task

Cognitive disturbances often predate characteristic motor dysfunction in individuals with Huntington’s disease (HD) and place an increasing burden on the HD patients and caregivers with the progression of the disorder. Therefore, application of maximally translational cognitive tests to animal models of HD is imperative for the development of treatments that could alleviate cognitive decline in human patients. Here, we examined the performance of the Q175 mouse knock-in model of HD in the touch screen version of the paired associates learning (PAL) task. We found that 10–11-month-old heterozygous Q175 mice had severely attenuated learning curve in the PAL task, which was conceptually similar to previously documented impaired performance of individuals with HD in the PAL task of the Cambridge Neuropsychological Test Automated Battery (CANTAB). Besides high rate of errors in PAL task, Q175 mice exhibited considerably lower responding rate than age-matched wild-type (WT) animals. Our examination of effortful operant responding during fixed ratio (FR) and progressive ratio (PR) reinforcement schedules in a separate cohort of similar age confirmed slower and unselective performance of mutant animals, as observed during PAL task, but suggested that motivation to work for nutritional reward in the touch screen setting was similar in Q175 and WT mice. We also demonstrated that pronounced sensorimotor disturbances in Q175 mice can be detected at early touch screen testing stages, (e.g., during “Punish Incorrect” phase of operant pretraining), so we propose that shorter test routines may be utilised for more expedient studies of treatments aimed at the rescue of HD-related phenotype

Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by motor as well as nonmotor symptoms for which there is currently no cure. The Q175 mouse model of HD recapitulates many of the symptoms identified in HD patients including disruptions of the sleep/wake cycle. In this study, we sought to determine if the daily administration of the histamine-3 receptor (H3R) antagonist/inverse agonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) would improve nonmotor symptoms in the Q175 line. This class of drugs acts on autoreceptors found at histaminergic synapses and results in increased levels of histamine (HA). HA is a neuromodulator whose levels vary with a daily rhythm with peak release during the active cycle and relatively lower levels during sleep. H3Rs are widely expressed in brain regions involved in cognitive processes and activation of these receptors promotes wakefulness. We administered GSK189254 nightly to homozygote and heterozygote Q175 mice for 4 weeks and confirmed that the plasma levels of the drug were elevated to a therapeutic range. We demonstrate that daily treatment with GSK189254 improved several behavioral measures in the Q175 mice including strengthening activity rhythms, cognitive performance and mood as measured by the tail suspension test. The treatment also reduced inappropriate activity during the normal sleep time. The drug treatment did not alter motor performance and coordination as measured by the challenging beam test. Our findings suggest that drugs targeting the H3R system may show benefits as cognitive enhancers in the management of HD

Possible use of a H3R antagonist for the management of nonmotor symptoms in the Q175 mouse model of Huntington's disease.

Huntington's disease (HD) is an autosomal dominant, neurodegenerative disorder characterized by motor as well as nonmotor symptoms for which there is currently no cure. The Q175 mouse model of HD recapitulates many of the symptoms identified in HD patients including disruptions of the sleep/wake cycle. In this study, we sought to determine if the daily administration of the histamine-3 receptor (H3R) antagonist/inverse agonist 6-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-3-pyridinecarboxamide hydrochloride (GSK189254) would improve nonmotor symptoms in the Q175 line. This class of drugs acts on autoreceptors found at histaminergic synapses and results in increased levels of histamine (HA). HA is a neuromodulator whose levels vary with a daily rhythm with peak release during the active cycle and relatively lower levels during sleep. H3Rs are widely expressed in brain regions involved in cognitive processes and activation of these receptors promotes wakefulness. We administered GSK189254 nightly to homozygote and heterozygote Q175 mice for 4 weeks and confirmed that the plasma levels of the drug were elevated to a therapeutic range. We demonstrate that daily treatment with GSK189254 improved several behavioral measures in the Q175 mice including strengthening activity rhythms, cognitive performance and mood as measured by the tail suspension test. The treatment also reduced inappropriate activity during the normal sleep time. The drug treatment did not alter motor performance and coordination as measured by the challenging beam test. Our findings suggest that drugs targeting the H3R system may show benefits as cognitive enhancers in the management of HD

Unravelling and Exploiting Astrocyte Dysfunction in Huntington's Disease

Astrocytes are abundant within mature neural circuits and are involved in brain disorders. Here, we summarize our current understanding of astrocytes and Huntington's disease (HD), with a focus on correlative and causative dysfunctions of ion homeostasis, calcium signaling, and neurotransmitter clearance, as well as on the use of transplanted astrocytes to produce therapeutic benefit in mouse models of HD. Overall, the data suggest that astrocyte dysfunction is an important contributor to the onset and progression of some HD symptoms in mice. Additional exploration of astrocytes in HD mouse models and humans is needed and may provide new therapeutic opportunities to explore in conjunction with neuronal rescue and repair strategies

Unravelling and Exploiting Astrocyte Dysfunction in Huntington’s Disease

Astrocytes are abundant within mature neural circuits and are involved in brain disorders. Here, we summarize our current understanding of astrocytes and Huntington's disease (HD), with a focus on correlative and causative dysfunctions of ion homeostasis, calcium signaling, and neurotransmitter clearance, as well as on the use of transplanted astrocytes to produce therapeutic benefit in mouse models of HD. Overall, the data suggest that astrocyte dysfunction is an important contributor to the onset and progression of some HD symptoms in mice. Additional exploration of astrocytes in HD mouse models and humans is needed and may provide new therapeutic opportunities to explore in conjunction with neuronal rescue and repair strategies

Selective Activation of Cholinergic Interneurons Enhances Accumbal Phasic Dopamine Release: Setting the Tone for Reward Processing

SummaryDopamine plays a critical role in motor control, addiction, and reward-seeking behaviors, and its release dynamics have traditionally been linked to changes in midbrain dopamine neuron activity. Here, we report that selective endogenous cholinergic activation achieved via in vitro optogenetic stimulation of nucleus accumbens, a terminal field of dopaminergic neurons, elicits real-time dopamine release. This mechanism occurs via direct actions on dopamine terminals, does not require changes in neuron firing within the midbrain, and is dependent on glutamatergic receptor activity. More importantly, we demonstrate that in vivo selective activation of cholinergic interneurons is sufficient to elicit dopamine release in the nucleus accumbens. Therefore, the control of accumbal extracellular dopamine levels by endogenous cholinergic activity results from a complex convergence of neurotransmitter/neuromodulator systems that may ultimately synergize to drive motivated behavior