Serotonergic Regulation of Synaptic Dopamine Levels Mitigates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

Background: The serotonin (5-HT) system can manipulate the processing of exogenous L-DOPA in the DA-denervated striatum, resulting in the modulation of L-DOPA-induced dyskinesia (LID).

Objective: To characterize the effects of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) or the serotonin transporter (SERT) inhibitor, Citalopram on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease.

Methods: MitoPark (MP) mice at 20 weeks of age, subjected to a 14-day administration of L-DOPA/Carbidopa, displayed dyskinesia, referred to as LID.

Attenuating mitochondrial dysfunction and morphological disruption with PT320 delays dopamine degeneration in MitoPark mice.

Background: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases.

PT320, a Sustained-Release GLP-1 Receptor Agonist, Ameliorates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks.

Tetrabenazine Mitigates Aberrant Release and Clearance of Dopamine in the Nigrostriatal System, and Alleviates L-DOPA-Induced Dyskinesia in a Mouse Model of Parkinson's Disease.

Background: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson's disease.

Objective: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease.

Methods: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days.

Post-stroke Delivery of Valproic Acid Promotes Functional Recovery and Differentially Modifies Responses of Peri-Infarct Microglia.

The specific role of peri-infarct microglia and the timing of its morphological changes following ischemic stroke are not well understood. Valproic acid (VPA) can protect against ischemic damage and promote recovery. In this study, we first determined whether a single dose of VPA after stroke could decrease infarction area or improve functional recovery.

Sustained Release GLP-1 Agonist PT320 Delays Disease Progression in a Mouse Model of Parkinson's Disease.

GLP-1 agonists have become increasingly interesting as a new Parkinson's disease (PD) clinical treatment strategy. Additional preclinical studies are important to validate this approach and define the disease stage when they are most effective. We hence characterized the efficacy of PT320, a sustained release formulation of the long acting GLP-1 agonist, exenatide, in a progressive PD (MitoPark) mouse model.

Delayed Dopamine Dysfunction and Motor Deficits in Female Parkinson Model Mice.

This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson's disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior.

Release parameters during progressive degeneration of dopamine neurons in a mouse model reveal earlier impairment of spontaneous than forced behaviors.

To determine the role of reduced dopaminergic transmission for declines of forced versus spontaneous behavior, we used a model of Parkinson's disease with progressive degeneration of dopamine (DA) neurons, the MitoPark mouse. Mice were subjected to rotarod tests of motor coordination, and open field and cylinder tests for spontaneous locomotor activity and postural axial support. To measure DA release in dorsal striatum and the shell of Nucleus Accumbens (NAc), we used ex vivo fast-scan cyclic voltammetry in 6- to 24-week-old mice.

Nicotine-Induced Conditional Place Preference Is Affected by Head Injury: Correlation with Dopamine Release in the Nucleus Accumbens Shell.

Background: Traumatic brain injury is known to impact dopamine-mediated reward pathways, but the underlying mechanisms have not been fully established.

Methods: Nicotine-induced conditional place preference was used to study rats exposed to a 6-psi fluid percussion injury with and without prior exposure to nicotine. Preference was quantified as a score defined as (C1 - C2) / (C1 + C2), where C1 is time in the nicotine-paired compartment and C2 is time in the saline-paired compartment.

Differences in Nicotine Encoding Dopamine Release between the Striatum and Shell Portion of the Nucleus Accumbens.

The aim of this work was to determine the effect of nicotine desensitization on dopamine (DA) release in the dorsal striatum and shell of the nucleus accumbens (NAc) from brain slices. In vitro fast-scan cyclic voltammetry analysis was used to evaluate dopamine release in the dorsal striatum and the NAc shell of Sprague-Dawley rats after infusion of nicotine, a nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (Mec), and an α4β2 cholinergic receptor antagonist (DHβe). DA release related to nicotine desensitization in the striatum and NAc shell was compared.

Profound deficits in hippocampal synaptic plasticity after traumatic brain injury and seizure is ameliorated by prophylactic levetiracetam.

Aim: To determine the precise effects of post-traumatic seizure activity on hippocampal processes, we induced seizures at various intervals after traumatic brain injury (TBI) and analyzed plasticity at CA1 Schaffer collateral synapses.

Material And Methods: Rats were initially separated into two groups; one exposed solely to fluid percussion injury (FPI) at 2 Psi and the other only receiving kainic acid (KA)-induced seizures without FPI. Electrophysiological (ePhys) studies including paired-pulse stimulation for short-term presynaptic plasticity and long-term potentiation (LTP) of CA1 Schaffer collateral synapses of the hippocampus for post-synaptic function survey were followed at post-event 1 hour, 3 and 7 days respectively.

Effect of traumatic brain injury on nicotine-induced modulation of dopamine release in the striatum and nucleus accumbens shell.

Background: Traumatic brain injury is associated with substantial alterations in reward processing, but underlying mechanisms are controversial.

Objective: A better understanding of alterations in dopamine (DA) release patterns from the dorsal striatum and nucleus accumbens shell (NAc) may provide insights into posttraumatic reward pathology.

Materials And Methods: The patterns of DA release with or without exposure to nicotine in brain slices with striatum and NAc, isolated from Sprague-Dawley rats with 6 psi fluid percussion (FPI) or sham injury were analysis by using fast-scan cyclic voltammetry.

Exercise Ameliorates Motor Deficits and Improves Dopaminergic Functions in the Rat Hemi-Parkinson's Model.

To determine the influences of exercise on motor deficits and dopaminergic transmission in a hemiparkinson animal model, we measured the effects of exercise on the ambulatory system by estimating spatio-temporal parameters during walking, striatal dopamine (DA) release and reuptake and synaptic plasticity in the corticostriatal pathway after unilateral 6-OHDA lesions. 6-OHDA lesioned hemiparkinsonian rats were exercised on a fixed speed treadmill for 30 minutes per day. Controls received the same lesion but no exercise.

Impact of Traumatic Brain Injury on Dopaminergic Transmission.

Brain trauma is often associated with severe morbidity and is a major public health concern. Even when injury is mild and no obvious anatomic disruption is seen, many individuals suffer disabling neuropsychological impairments such as memory loss, mood dysfunction, substance abuse, and adjustment disorder. These changes may be related to subtle disruption of neural circuits as well as functional changes at the neurotransmitter level.

Dopamine release in the nucleus accumbens is altered following traumatic brain injury.

Mild-to-severe traumatic brain injury (TBI) is frequently associated with prolonged dysfunction of reward circuitry, including motivation and salience, which suggests alterations of dopamine (DA) processing within the core and shell of the nucleus accumbens (NAC). Using fast-scan cyclic voltammetry in a rodent model of traumatic brain injury, we found that stimulus-evoked DA release is distinct in the core and shell of the NAC, with the shell being less responsive to tonic stimulation and more sensitive to the number of pulses when phasic stimulation is applied. Exposure to TBI was associated with major changes in both release and reuptake of DA in both the core and shell of NAC, with greater changes seen in the core.

Levetiracetam prophylaxis ameliorates seizure epileptogenesis after fluid percussion injury.

To determine whether post-traumatic seizure severity would be affected by the interval between seizures and head injury, we measured seizures after various times with or without fluid percussion brain injury (2atm fluid percussion injury; FPI). To determine efficacy of anti-seizure medication, we also determined if levetiracetam (LEV) would alter the relationship between injury and subsequent seizures. Early post-traumatic seizures were induced by Kainic acid (KA) at one week after 2atm fluid percussion injury (FPI) in one group (FPI-ES).

Dopamine Release Impairment in Striatum After Different Levels of Cerebral Cortical Fluid Percussion Injury.

To investigate the role of dopamine release in cognitive impairment and motor learning deficits after brain injury, different levels of traumatic brain injury (TBI) were made in rats by using fluid percussion at two different atmospheres (2 Psi and 6 Psi). Tonic and phasic bursting dopamine release and behavior tests followed at several time points. We used in vitro fast-scan cyclic voltammetry to survey dopamine release in the striatum and analyzed the rats' behavior using novel object recognition (NOR) and rotarod tests.

Remote effects on the striatal dopamine system after fluid percussion injury.

Purpose: To investigate the effects of traumatic brain injury (TBI) on the dopamine system in the brain at different distances from the impaction site, we compared the release, reuptake, metabolism, and release probability of dopamine on the sides of the brain ipsilateral and contralateral to the injury at different time points after varying severities of fluid percussion injuries.

Materials And Methods: Tonic (1-pulse evoked) and bursting (10-pulse evoked) dopamine release changes in the ipsilateral and contralateral sides of the striatum resulting from mild (2-Pa) and severe (6-Pa) levels of fluid percussion injury were analyzed at the acute (2h and 24h), subacute (1 and 2 weeks), and chronic stages (4, 6, and 8 weeks) after injury by using fast scan cyclic voltammetry to measure brain slices. The metabolic rate of striatal dopamine was surveyed using high-performance liquid chromatography.

Amantadine ameliorates dopamine-releasing deficits and behavioral deficits in rats after fluid percussion injury.

Aims: To investigate the role of dopamine in cognitive and motor learning skill deficits after a traumatic brain injury (TBI), we investigated dopamine release and behavioral changes at a series of time points after fluid percussion injury, and explored the potential of amantadine hydrochloride as a chronic treatment to provide behavioral recovery.

Materials And Methods: In this study, we sequentially investigated dopamine release at the striatum and behavioral changes at 1, 2, 4, 6, and 8 weeks after fluid percussion injury. Rats subjected to 6-Pa cerebral cortical fluid percussion injury were treated by using subcutaneous infusion pumps filled with either saline (sham group) or amantadine hydrochloride, with a releasing rate of 3.

Postnatal systemic inflammation exacerbates impairment of hippocampal synaptic plasticity in an animal seizure model.

Objective: To investigate the effects of systemic inflammation in the critical postnatal stages on neurophysiological actions of immune processes and neural plasticity in adult rats after kainic acid (KA)-induced seizures.

Methods: To determine changes in hippocampal synaptic plasticity after postnatal central nervous system inflammatory responses and seizure attacks, we performed intraperitoneal injections of lipopolysaccharide (LPS) in postnatal Sprague Dawley rats on day 14 (P14) to induce central nervous system inflammation. We then used a KA tail vein injection on P35 to induce seizure attacks.