Anti-manic effect of deep brain stimulation of the ventral tegmental area in an animal model of mania induced by methamphetamine.

BACKGROUND: Treatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD. AIM: The present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m-amph). METHODS: Wistar rats were given 14 days of m-amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low-frequency stimulation (LFS) or continuous high-frequency stimulation (HFS). Immediately after DBS, manic-like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open-field tests and fast-scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry. RESULTS: M-amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M-amph increased DA reuptake time post-sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc. CONCLUSION: These results demonstrate that both VTA LFS and HFS DBS exert anti-manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti-manic effects.

Effects of Unilateral High Frequency Stimulation of the Subthalamic Nucleus on Risk-avoidant Behavior in a Partial 6-hydroxydopamine Model of Parkinson's Disease.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a well-established treatment for the motor symptoms of Parkinson's disease (PD). While PD is primarily characterized by motor symptoms such as tremor, rigidity, and bradykinesia, it also involves a range of non-motor symptoms, and anxiety is one of the most common. The relationship between PD and anxiety is complex and can be a result of both pathological neural changes and the psychological and emotional impacts of living with a chronic progressive condition. Managing anxiety in PD is critical for improving the patients' quality of life. However, patients undergoing STN DBS can occasionally experience increased anxiety. METHODS: This study investigates changes in risk-avoidant behavior following STN DBS in a pre-motor animal model of PD under chronic and acute unilateral high frequency stimulation. RESULTS: No significant changes in risk-avoidant behaviors were observed in rats who underwent STN DBS compared with sham stimulation controls. Chronic stimulation prevented sensitization in the elevated zero maze. CONCLUSIONS: These results suggest that unilateral stimulation of the STN may have minimal effects on risk-avoidant behaviors in PD. However, additional research is required to fully understand the mechanisms responsible for changes in anxiety during STN DBS for PD.

Fenofibrate promotes neuroprotection in a model of rotenone-induced Parkinson's disease.

Parkinson's disease is a neurodegenerative disease, the etiology of which remains unknown, but some likely causes include oxidative stress, mitochondrial dysfunction and neuroinflammation. Peroxisome-proliferator-activated receptor (PPAR) agonists have been studied in animal models of Parkinson's disease and have shown neuroprotective effects. In this study, we aimed to (1) confirm the neuroprotective effects of PPAR-alpha agonist fenofibrate. To this end, male rats received fenofibrate (100 mg/kg) orally for 15 days, 5 days before the intraperitoneal injections of rotenone (2.5 mg/kg for 10 days). After finishing the treatment with rotenone and fenofibrate, animals were subjected to the open field, the forced swim test and the two-way active avoidance task. Subsequently, rats were euthanized for measurement of dopamine and metabolites levels in the striatum and quantification of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta (SNpc). In addition, we aimed to (2) evaluate the neuroprotective effects of fenofibrate on the accumulation of α-synuclein aggregates. Here, rats were treated for 5 days with fenofibrate continuing for over 28 days with rotenone. Then, animals were perfused for immunohistochemistry analysis of α-synuclein. The results showed that fenofibrate reduced depressive-like behavior and memory impairment induced by rotenone. Moreover, fenofibrate diminished the depletion of striatal dopamine and protected against dopaminergic neuronal death in the SNpc. Likewise, the administration of fenofibrate attenuated the aggregation of α-synuclein in the SNpc and striatum in the rotenone-lesioned rats. Our study confirmed that fenofibrate exerted neuroprotective effects because parkinsonian rats exhibited reduced behavioral, neurochemical and immunohistochemical changes, and importantly, a lower number of α-synuclein aggregates.

Stimulation of the subparafascicular thalamic nucleus modulates dopamine release in the inferior colliculus of rats.

Although dopamine is commonly studied for its role in incentive motivation, cognition, and various neuropsychiatric disorders, evidence from Parkinson's disease (PD) patients that present auditory deficits suggest that dopamine is also involved in central auditory processing. It has been recently discovered that the subparafascicular thalamic nucleus (SPF) sends dopaminergic projections to the inferior colliculus (IC), an important convergence hub for the ascending and descending auditory pathways. In the present study, our aim was to provide neurochemical evidence that activation of SPF neurons evokes dopamine release in the IC of anesthetized rats using fast-scan cyclic and paired pulse voltammetry in combination with carbon fiber microelectrodes. Electrical stimulation of the SPF (60 and 90 Hz) evoked dopamine release in the IC in a frequency-dependent manner, with higher frequencies evoking greater amplitude dopamine responses. Optogenetic-evoked dopamine responses were similar to the effects of electrical stimulation suggesting that electrical stimulation-evoked dopamine release was not due to nonspecific activation of fibers of passage, but rather to activation of SPF cells projecting to the IC. Selective dopamine reuptake blockade enhanced the evoked dopamine response, while selective blockade of serotonin did not, confirming the selectivity of the neurochemical recordings to dopamine. Therefore, the SPF neuronal pathway functionally mediates dopamine release in the IC and thus may be involved in auditory processing deficits associated with PD.

Effects of environmentally relevant concentrations of the anti-inflammatory drug diclofenac in freshwater fish Rhamdia quelen.

The presence of pharmaceuticals in the aquatic environment and its impact on humans and the ecosystem are emerging issues in environmental health. This study evaluated the potential biochemical, genetic and reproductive effects of the diclofenac by waterborne exposure, in a semi-static bioassay for 21 days. The fish Rhamdia quelen were exposed to environmental concentrations of diclofenac (0, 0.2, 2 and 20µg/L). The results showed that in the liver, diclofenac reduced the catalase and ethoxyresorufin- O- deethylase activities in fish exposed to 2µg/L, and superoxide dismutase in all exposed groups. The levels of reduced glutathione and glutathione S-transferase (GST) activity increased at all tested concentrations. Lipid peroxidation (LPO) was reduced in the groups exposed to 0.2 and 20µg/L of diclofenac, but there was no protein oxidation. In the testis, the concentration of 0.2µg/L caused major changes as inhibition of SOD, glutathione peroxidase and GST activities and also LPO decrease. Diclofenac was not genotoxic and not altered plasma testosterone and estradiol levels and testicular morphology. In brain, there was a reduction of dopamine and its metabolite DOPAC (3, 4-dihydroxyphenylacetic acid) in exposure to diclofenac, but this not disrupted the hypothalamic-pituitary-gonadal axis.

Antidepressant-like effect of celecoxib piroxicam in rat models of depression.

Beyond the current hypothesis of depression, several new biological substrates have been proposed for this disorder. The present study investigated whether the anti-inflammatory drugs celecoxib and piroxicam have antidepressant activity in animal models of depression. After acute administration, we observed antidepressant-like effects of celecoxib (10 mg/kg) and piroxicam (10 mg/kg) in the modified forced swim test in rats. Piroxicam increased serotonin and norepinephrine levels in the hippocampus. Prolonged (21-day) treatment with celecoxib (10 mg/kg) and piroxicam (10 mg/kg) rescued sucrose preference in a chronic mild stress model of depression. Additionally, the chronic mild stress-induced reduction of hippocampal glutathione was prevented by treatment with celecoxib and piroxicam. Superoxide dismutase in the hippocampus was increased after chronic mild stress compared with the non-stressed saline group. The non-stressed celecoxib and piroxicam groups and stressed piroxicam group exhibited an increase in hippocampal superoxide dismutase activity compared with the stressed saline group. Lipid hydroperoxide was increased in the stressed group treated with vehicle and non-stressed group treated with imipramine but not in the stressed groups treated with celecoxib and piroxicam. These results suggest that the antidepressant-like effects of anti-inflammatory drugs might be attributable to enhanced antioxidant defenses and attenuated oxidative stress in the hippocampus.

Optimizing SH-SY5Y cell culture: exploring the beneficial effects of an alternative media supplement on cell proliferation and viability.

In the quest to unravel the mysteries of neurological diseases, comprehending the underlying mechanisms is supreme. The SH-SY5Y human neuroblastoma cell line serves as a crucial tool in this endeavor; however, the cells are known for its sensitivity and slow proliferation rates. Typically, this cell line is cultured with 10% Fetal Bovine Serum (FBS) supplement. Nu-Serum (NuS), a low-protein alternative to FBS, is promising to advance cell culture practices. Herein, we evaluated the substitution of NuS for FBS to test the hypothesis that an alternative serum supplement can aid and promote SH-SY5Y cell proliferation and differentiation. Our findings revealed that the NuS-supplemented group exhibited a notable increase in adhered cells compared to both the FBS and serum-free (SF) groups. Importantly, cell viability remained high in both sera treated groups, with the NuS-supplemented cells displaying significantly larger cell sizes compared to the SF-treated group. Furthermore, cell proliferation rates were higher in the NuS-treated group, and neuroblast-like morphology was observed earlier than FBS group. Notably, both FBS and NuS supported the differentiation of these cells into mature neurons. Our data supports NuS as an alternative for SH-SY5Y cell culture, with the potential to elevate the quality of research in the neuroscience field.

Midbrain dopaminergic degeneration differentially modulates primary motor cortex activity and motor behavior in hemi-parkinsonian rats.

Parkinson's disease (PD) is marked by degeneration in the nigrostriatal dopaminergic pathway, affecting motor control via complex changes in the cortico-basal ganglia-thalamic motor network, including the primary motor cortex (M1). The modulation of M1 neuronal activity by dopaminergic inputs, particularly from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc), plays a crucial role in PD pathophysiology. This study investigates how nigrostriatal dopaminergic degeneration influences M1 neuronal activity in rats using in vivo calcium imaging. Histological analysis confirmed dopaminergic lesion severity, with high lesion level rats showing significant motor deficits. Levodopa treatment improved fine motor abilities, particularly in high lesion level rats. Analysis of M1 calcium signals based on dopaminergic lesion severity revealed distinct M1 activity patterns. Animals with low dopaminergic lesion showed increased calcium events, while high lesion level rats exhibited decreased activity, partially restored by levodopa. These findings suggest that M1 activity is more sensitive to transient fluctuations in dopaminergic transmission, rather than to chronic high or low dopaminergic signaling. This study underscores the complex interplay between dopaminergic signaling and M1 neuronal activity in PD symptoms development. Further research integrating behavioral and calcium imaging data can elucidate mechanisms underlying motor deficits and therapeutic responses in PD.

A Special Issue on the Roles of Dopamine in Neural Circuits, Genetics, and Behavior.

Over the past 80 years, research on dopamine has undergone significant evolution, reshaping our understanding of its roles in the brain and the body [...].

Investigating the Pathogenic Interplay of Alpha-Synuclein, Tau, and Amyloid Beta in Lewy Body Dementia: Insights from Viral-Mediated Overexpression in Transgenic Mouse Models.

Lewy body dementia (LBD) is an often misdiagnosed and mistreated neurodegenerative disorder clinically characterized by the emergence of neuropsychiatric symptoms followed by motor impairment. LBD falls within an undefined range between Alzheimer's disease (AD) and Parkinson's disease (PD) due to the potential pathogenic synergistic effects of tau, beta-amyloid (Aß), and alpha-synuclein (αsyn). A lack of reliable and relevant animal models hinders the elucidation of the molecular characteristics and phenotypic consequences of these interactions. Here, the goal was to evaluate whether the viral-mediated overexpression of αsyn in adult hTau and APP/PS1 mice or the overexpression of tau in Line 61 hThy1-αsyn mice resulted in pathology and behavior resembling LBD. The transgenes were injected intravenously via the tail vein using AAV-PHP.eB in 3-month-old hThy1-αsyn, hTau, or APP/PS1 mice that were then aged to 6-, 9-, and 12-months-old for subsequent phenotypic and histological characterization. Although we achieved the widespread expression of αsyn in hTau and tau in hThy1-αsyn mice, no αsyn pathology in hTau mice and only mild tau pathology in hThy1-αsyn mice was observed. Additionally, cognitive, motor, and limbic behavior phenotypes were not affected by overexpression of the transgenes. Furthermore, our APP/PS1 mice experienced premature deaths starting at 3 months post-injection (MPI), therefore precluding further analyses at later time points. An evaluation of the remaining 3-MPI indicated no αsyn pathology or cognitive and motor behavioral changes. Taken together, we conclude that the overexpression of αsyn in hTau and APP/PS1 mice and tau in hThy1-αsyn mice does not recapitulate the behavioral and neuropathological phenotypes observed in LBD.

Honokiol decreases alpha-synuclein mRNA levels and reveals novel targets for modulating alpha-synuclein expression.

Background: Intracytoplasmic inclusions comprised of aggregated alpha-synuclein (αsyn) represent a key histopathological feature of neurological disorders collectively termed "synucleinopathies," which includes Parkinson's disease (PD). Mutations and multiplications in the SNCA gene encoding αsyn cause familial forms of PD and a large body of evidence indicate a correlation between αsyn accumulation and disease. Decreasing αsyn expression is recognized as a valid target for PD therapeutics, with down-regulation of SNCA expression potentially attenuating downstream cascades of pathologic events. Here, we evaluated if Honokiol (HKL), a polyphenolic compound derived from magnolia tree bark with demonstrated neuroprotective properties, can modulate αsyn levels in multiple experimental models. Methods: Human neuroglioma cells stably overexpressing αsyn, mouse primary neurons, and human iPSC-derived neurons were exposed to HKL and αsyn protein and SNCA messenger RNA levels were assessed. The effect of HKL on rotenone-induced overexpression of αsyn levels was further assessed and transcriptional profiling of mouse cortical neurons treated with HKL was performed to identify potential targets of HKL. Results: We demonstrate that HKL can successfully reduce αsyn protein levels and SNCA expression in multiple in vitro models of PD with our data supporting a mechanism whereby HKL acts by post-transcriptional modulation of SNCA rather than modulating αsyn protein degradation. Transcriptional profiling of mouse cortical neurons treated with HKL identifies several differentially expressed genes (DEG) as potential targets to modulate SNCA expression. Conclusion: This study supports a HKL-mediated downregulation of SNCA as a viable strategy to modify disease progression in PD and other synucleinopathies. HKL has potential as a powerful tool for investigating SNCA gene modulation and its downstream effects.

The role of nucleus accumbens and dorsolateral striatal D2 receptors in active avoidance conditioning.

The role of dopamine (DA) in rewarding motivated actions is well established but its role in learning how to avoid aversive events is still controversial. Here we tested the role of D2-like DA receptors in the nucleus accumbens (NAc) and the dorsolateral striatum (DLS) of rats in the learning and performance of conditioned avoidance responses (CAR). Adult male Wistar rats received systemic, intra-NAc or intra-DLS (pre- or post-training) administration of a D2-like receptor agonist (quinpirole) or antagonist ((-)sulpiride) and were given two sessions in the two-way active avoidance task. The main effects observed were: (i) sulpiride and lower (likely pre-synaptic) doses of quinpirole decreased the number of CARs and increased the number of escape failures; (ii) higher doses of quinpirole (likely post-synaptic) increased inter-trial crossings and failures; (iii) pre-training administration of sulpiride decreased the number of CARs in both training and test sessions when infused into the NAc, but this effect was observed only in the test session when it was infused into the DLS; (iv) post-training administration of sulpiride decreased CARs in the test session when infused into the NAc but not DLS. These findings suggest that activation of D2 receptors in the NAc is critical for fast adaptation to responding to unconditioned and conditioned aversive stimuli while activation of these receptors in the DLS is needed for a slower learning of how to respond to the same stimuli based on previous experiences.

Defining a Path Toward the Use of Fast-Scan Cyclic Voltammetry in Human Studies.

Fast Scan Cyclic Voltammetry (FSCV) has been used for decades as a neurochemical tool for in vivo detection of phasic changes in electroactive neurotransmitters in animal models. Recently, multiple research groups have initiated human neurochemical studies using FSCV or demonstrated interest in bringing FSCV into clinical use. However, there remain technical challenges that limit clinical implementation of FSCV by creating barriers to appropriate scientific rigor and patient safety. In order to progress with clinical FSCV, these limitations must be first addressed through (1) appropriate pre-clinical studies to ensure accurate measurement of neurotransmitters and (2) the application of a risk management framework to assess patient safety. The intent of this work is to bring awareness of the current issues associated with FSCV to the scientific, engineering, and clinical communities and encourage them to seek solutions or alternatives that ensure data accuracy, rigor and reproducibility, and patient safety.

Functional disconnection of the substantia nigra pars compacta from the pedunculopontine nucleus impairs learning of a conditioned avoidance task.

The pedunculopontine tegmental nucleus (PPTg) targets nuclei in the basal ganglia, including the substantia nigra pars compacta (SNc), in which neuronal loss occurs in Parkinson's disease, a condition in which patients show cognitive as well as motor disturbances. Partial loss and functional abnormalities of neurons in the PPTg are also associated with Parkinson's disease. We hypothesized that the interaction of PPTg and SNc might be important for cognitive impairments and so investigated whether disrupting the connections between the PPTg and SNc impaired learning of a conditioned avoidance response (CAR) by male Wistar rats. The following groups were tested: PPTg unilateral; SNc unilateral; PPTg-SNc ipsilateral (ipsilateral lesions in PPTg and SNc); PPTg-SNc contralateral (contralateral lesions in PPTg and SNc); sham lesions (of each type). SNc lesions were made with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine HCl (MPTP, 0.6micromol); PPTg lesions with ibotenate (24nmol). After recovery, all rats underwent 50-trial sessions of 2-way active avoidance conditioning for 3 consecutive days. Rats with unilateral lesions in PPTg or SNc learnt this, however rats with contralateral (but not ipsilateral) combined lesions in both structures presented no sign of learning. This effect was not likely to be due to sensorimotor impairment because lesions did not affect reaction time to the tone or footshock during conditioning. However, an increased number of non-responses were observed in the rats with contralateral lesions. The results support the hypothesis that a functional interaction between PPTg and SNc is needed for CAR learning and performance.

Non-motor function of the midbrain dopaminergic neurons.

The roles of the nigrostriatal pathway are far beyond the simple control of motor functions. The tonic release of dopamine in the dorsal and ventral striatum controls the choice of proper actions toward a given environmental situation. In the striatum, a specific action is triggered by a specific stimulus associated with it. When the subject faces a novel and salient stimulus, the phasic release of dopamine allows synaptic plasticity in the cortico-striatal synapses. Neurons of different regions of cortical areas make synapses that converge to the same medium spine neurons of the striatum. The convergent associations form functional units encoding body parts, objects, locations, and symbolic representations of the subject's world. Such units emerge in the striatum in a repetitive manner, like a mosaic of broken mirrors. The phasic release of dopamine allows the association of units to encode an action of the subject directed to an object or location with the outcome of this action. Reinforced stimulus-action-outcome associations will affect future decision making when the same stimulus (object, location, idea) is presented to the subject in the future. In the absence of a minimal amount of striatal dopamine, no action is initiated as seen in Parkinson's disease subjects. The abnormal and improper association of these units leads to the initiation of unpurposeful and sometimes repetitive actions, as those observed in dyskinetic patients. The association of an excessive reinforcement of some actions, like drug consumption, leads to drug addiction. Improper associations of ideas and unpleasant outcomes may be related to traumatic and depressive symptoms common in many diseases, including Parkinson's disease. The same can be said about the learning and memory impairments observed in demented and nondemented Parkinson's disease patients.

Multifactorial motor behavior assessment for real-time evaluation of emerging therapeutics to treat neurologic impairments.

Integrating multiple assessment parameters of motor behavior is critical for understanding neural activity dynamics during motor control in both intact and dysfunctional nervous systems. Here, we described a novel approach (termed Multifactorial Behavioral Assessment (MfBA)) to integrate, in real-time, electrophysiological and biomechanical properties of rodent spinal sensorimotor network activity with behavioral aspects of motor task performance. Specifically, the MfBA simultaneously records limb kinematics, multi-directional forces and electrophysiological metrics, such as high-fidelity chronic intramuscular electromyography synchronized in time to spinal stimulation in order to characterize spinal cord functional motor evoked potentials (fMEPs). Additionally, we designed the MfBA to incorporate a body weight support system to allow bipedal and quadrupedal stepping on a treadmill and in an open field environment to assess function in rodent models of neurologic disorders that impact motor activity. This novel approach was validated using, a neurologically intact cohort, a cohort with unilateral Parkinsonian motor deficits due to midbrain lesioning, and a cohort with complete hind limb paralysis due to T8 spinal cord transection. In the SCI cohort, lumbosacral epidural electrical stimulation (EES) was applied, with and without administration of the serotonergic agonist Quipazine, to enable hind limb motor functions following paralysis. The results presented herein demonstrate the MfBA is capable of integrating multiple metrics of motor activity in order to characterize relationships between EES inputs that modulate mono- and polysynaptic outputs from spinal circuitry which in turn, can be used to elucidate underlying electrophysiologic mechanisms of motor behavior. These results also demonstrate that proposed MfBA is an effective tool to integrate biomechanical and electrophysiology metrics, synchronized to therapeutic inputs such as EES or pharmacology, during body weight supported treadmill or open field motor activities, to target a high range of variations in motor behavior as a result of neurological deficit at the different levels of CNS.

Tracking tonic dopamine levels in vivo using multiple cyclic square wave voltammetry.

For over two decades, fast-scan cyclic voltammetry (FSCV) has served as a reliable analytical method for monitoring dopamine release in near real-time in vivo. However, contemporary FSCV techniques have been limited to measure only rapid (on the order of seconds, i.e. phasic) changes in dopamine release evoked by either electrical stimulation or elicited by presentation of behaviorally salient stimuli, and not slower changes in the tonic extracellular levels of dopamine (i.e. basal concentrations). This is because FSCV is inherently a differential method that requires subtraction of prestimulation tonic levels of dopamine to measure phasic changes relative to a zeroed baseline. Here, we describe the development and application of a novel voltammetric technique, multiple cyclic square wave voltammetry (M-CSWV), for analytical quantification of tonic dopamine concentrations in vivo with relatively high temporal resolution (10 s). M-CSWV enriches the electrochemical information by generating two dimensional voltammograms which enable high sensitivity (limit of detection, 0.17 nM) and selectivity against ascorbic acid, and 3,4-dihydroxyphenylacetic acid (DOPAC), including changes in pH. Using M-CSWV, a tonic dopamine concentration of 120 ±â€¯18 nM (n = 7 rats, ±â€¯SEM) was determined in the striatum of urethane anethetized rats. Pharmacological treatments to elevate dopamine by selectively inhibiting dopamine reuptake and to reduce DOPAC by inhibition of monoamine oxidase supported the selective detection of dopamine in vivo. Overall, M-CSWV offers a novel voltammetric technique to quantify levels and monitor changes in tonic dopamine concentrations in the brain to further our understanding of the role of dopamine in normal behavior and neuropsychiatric disorders.

Mechanism for optimization of signal-to-noise ratio of dopamine release based on short-term bidirectional plasticity.

Repeated electrical stimulation of dopamine (dopamine) fibers can cause variable effects on further dopamine release; sometimes there are short-term decreases while in other cases short-term increases have been reported. Previous studies have failed to discover what factors determine in which way dopamine neurons will respond to repeated stimulation. The aim of the present study was therefore to investigate what determines the direction and magnitude of this particular form of short-term plasticity. Fixed potential amperometry was used to measure dopamine release in the nucleus accumbens in response to two trains of electrical pulses administered to the ventral tegmental area of anesthetized mice. When the pulse trains were of equal magnitude we found that low magnitude stimulation was associated with short-term suppression and high magnitude stimulation with short-term facilitation of dopamine release. Secondly, we found that the magnitude of the second pulse train was critical for determining the sign of the plasticity (suppression or facilitation), while the magnitude of the first pulse train determined the extent to which the response to the second train was suppressed or facilitated. This form of bidirectional plasticity might provide a mechanism to enhance signal-to-noise ratio of dopamine neurotransmission.

Diazepam Inhibits Electrically Evoked and Tonic Dopamine Release in the Nucleus Accumbens and Reverses the Effect of Amphetamine.

Diazepam is a benzodiazepine receptor agonist with anxiolytic and addictive properties. Although most drugs of abuse increase the level of release of dopamine in the nucleus accumbens, here we show that diazepam not only causes the opposite effect but also prevents amphetamine from enhancing dopamine release. We used 20 min sampling in vivo microdialysis and subsecond fast-scan cyclic voltammetry recordings at carbon-fiber microelectrodes to show that diazepam caused a dose-dependent decrease in the level of tonic and electrically evoked dopamine release in the nucleus accumbens of urethane-anesthetized adult male Swiss mice. In fast-scan cyclic voltammetry assays, dopamine release was evoked by electrical stimulation of the ventral tegmental area. We observed that 2 and 3 mg of diazepam/kg reduced the level of electrically evoked dopamine release, and this effect was reversed by administration of the benzodiazepine receptor antagonist flumazenil in doses of 2.5 and 5 mg/kg, respectively. No significant effects on measures of dopamine re-uptake were observed. Cyclic voltammetry experiments further showed that amphetamine (5 mg/kg, intraperitoneally) caused a significant increase in the level of dopamine release and in the half-life for dopamine re-uptake. Diazepam (2 mg/kg) significantly weakened the effect of amphetamine on dopamine release without affecting dopamine re-uptake. These results suggest that the pharmacological effects of benzodiazepines have a dopaminergic component. In addition, our findings challenge the classic view that all drugs of abuse cause dopamine release in the nucleus accumbens and suggest that benzodiazepines could be useful in the treatment of addiction to other drugs that increase the level of dopamine release, such as cocaine, amphetamines, and nicotine.

Paracetamol causes endocrine disruption and hepatotoxicity in male fish Rhamdia quelen after subchronic exposure.

Paracetamol is one of the most widely sold non-prescription drugs. This study aimed to evaluate the effects of the paracetamol on reproductive, biochemical, genetic, histopathological and hematogical biomarkers by waterborne exposure. Male fish of Rhamdia quelen were exposed to environmental concentrations of paracetamol (0, 0.25, 2.5µg/L) in a semi-static bioassay for 21days. Hemoglobin and hematocrit were reduced upon exposure to 0.25µg/L of paracetamol. Leukocytes and thrombocytes increased after paracetamol exposure. Paracetamol reduced testosterone levels in all exposed groups and increased estradiol levels at higher concentration. Serotonin and dopamine levels increased at exposure to 0.25µg/L. Paracetamol also caused protein carbonyls and increased SOD activity in fish exposed to 2.5µg/L and in addition led to an inhibition of EROD and GST activities in both concentrations. Hepatic genotoxicity occurred at the 0.25µg/L concentration. Hepatic tissues of exposed fish showed mild blood congestion and leucocytes infiltration. The results showed that paracetamol disrupted the hypothalamic-pituitary-gonadal axis, changed hematological parameters and caused hepatotoxicity in Rhamdia quelen. The findings suggest that this drug merits attention relative to its potential endocrine disrupter effect and hepatotoxicity, even at concentrations found in the aquatic environment.