Deranda B. Lester

Adenosine–Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders

Adenosine–dopamine interactions in the central nervous system (CNS) have been studied for many years in view of their relevance for disorders of the CNS and their treatments. The discovery of adenosine and dopamine receptor containing receptor mosaics (RM, higher‐order receptor heteromers) in the striatum opened up a new understanding of these interactions. Initial findings indicated the existence of A2AR‐D2R heterodimers and A1R‐D1R heterodimers in the striatum that were followed by indications for the existence of striatal A2AR‐D3R and A2AR‐D4R heterodimers. Of particular interest was the demonstration that antagonistic allosteric A2A‐D2 and A1‐D1 receptor–receptor interactions take place in striatal A2AR‐D2R and A1R‐D1R heteromers. As a consequence, additional characterization of these heterodimers led to new aspects on the pathophysiology of Parkinsons disease (PD), schizophrenia, drug addiction, and l‐DOPA‐induced dyskinesias relevant for their treatments. In fact, A2AR antagonists were introduced in the symptomatic treatment of PD in view of the discovery of the antagonistic A2AR–D2R interaction in the dorsal striatum that leads to reduced D2R recognition and Gi/o coupling in striato‐pallidal GABAergic neurons. In recent years, indications have been obtained that A2AR‐D2R and A1R‐D1R heteromers do not exist as heterodimers, rather as RM. In fact, A2A‐CB1‐D2 RM and A2A‐D2‐mGlu5 RM have been discovered using a sequential BRET‐FRET technique and by using the BRET technique in combination with bimolecular fluorescence complementation. Thus, other pathogenic mechanisms beside the well‐known alterations in the release and/or decoding of dopamine in the basal ganglia and limbic system are involved in PD, schizophrenia and drug addiction. In fact, alterations in the stoichiometry and/or topology of A2A‐CB1‐D2 and A2A‐D2‐mGlu5 RM may play a role. Thus, the integrative receptor–receptor interactions in these RM give novel aspects on the pathophysiology and treatment strategies, based on combined treatments, for PD, schizophrenia, and drug addiction.

Acetylcholine-Dopamine Interactions in the Pathophysiology and Treatment of CNS Disorders: Dopamine-Acetylcholine Interactions in CNS Disorders

Dopaminergic neurons in the substantia nigra pars compacta and ventral tegmental area of the midbrain form the nigrostriatal and mesocorticolimbic dopaminergic pathways that, respectively, project to dorsal and ventral striatum (including prefrontal cortex). These midbrain dopaminergic nuclei and their respective forebrain and cortical target areas are well established as serving a critical role in mediating voluntary motor control, as evidenced in Parkinsons disease, and incentive‐motivated behaviors and cognitive functions, as exhibited in drug addiction and schizophrenia, respectively. Although it cannot be disputed that excitatory and inhibitory amino acid‐based neurotransmitters, such as glutamate and GABA, play a vital role in modulating activity of midbrain dopaminergic neurons, recent evidence suggests that acetylcholine may be as important in regulating dopaminergic transmission. Midbrain dopaminergic cell tonic and phasic activity is closely dependent upon projections from hindbrain pedunculopontine and the laterodorsal tegmental nuclei, which comprises the only known cholinergic inputs to these neurons. In close coordination with glutamatergic and GABAergic activity, these excitatory cholinergic projections activate nicotinic and muscarinic acetylcholine receptors within the substantia nigra and ventral tegmental area to modulate dopamine transmission in the dorsal/ventral striatum and prefrontal cortex. Additionally, acetylcholine‐containing interneurons in the striatum also constitute an important neural substrate to provide further cholinergic modulation of forebrain striatal dopaminergic transmission. In this review, we examine neurological and psychopathological conditions associated with dysfunctions in the interaction of acetylcholine and dopamine and conventional and new pharmacological approaches to treat these disorders.

Evolution of Deep Brain Stimulation: Human Electrometer and Smart Devices Supporting the Next Generation of Therapy

Deep brain stimulation (DBS) provides therapeutic benefit for several neuropathologies, including Parkinson disease (PD), epilepsy, chronic pain, and depression. Despite well‐established clinical efficacy, the mechanism of DBS remains poorly understood. In this review, we begin by summarizing the current understanding of the DBS mechanism. Using this knowledge as a framework, we then explore a specific hypothesis regarding DBS of the subthalamic nucleus (STN) for the treatment of PD. This hypothesis states that therapeutic benefit is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target cell control by dopamine. While highly controversial, we present preliminary data that are consistent with specific predications testing this hypothesis. We additionally propose that developing new technologies (e.g., human electrometer and closed‐loop smart devices) for monitoring dopaminergic neurotransmission during STN DBS will further advance this treatment approach.

Muscarinic receptor blockade in the ventral tegmental area attenuates cocaine enhancement of laterodorsal tegmentum stimulation-evoked accumbens dopamine efflux in the mouse

The reinforcing properties of cocaine have been related to increased extracellular concentrations of dopamine in the nucleus accumbens (NAc). M5 muscarinic acetylcholine receptors (mAChRs) on dopamine cells in the ventral tegmental area (VTA) facilitate mesoaccumbens dopamine transmission and are critically involved in mediating natural and drug reinforcement. We investigated the effects of pharmacological blockade of mAChRs in the VTA on cocaines ability to enhance electrically evoked NAc dopamine efflux. Using fixed potential amperometry together with carbon fiber recording microelectrodes positioned in the NAc core, we quantified dopamine oxidation currents (dopamine efflux) evoked by brief stimulation (15 monophasic pulses at 50 Hz every 30 s) of the laterodorsal tegmentum (LDT) in urethane (1.5 g/kg, i.p.) anesthetized mice. Compared to predrug baseline responses, cocaine (5 or 10 mg/kg, i.p.) dose‐dependently enhanced LDT stimulation‐evoked NAc dopamine efflux, whereas the nonsubtype selective mAChR antagonist scopolamine (10 μg/0.5 μl) microinfused into the VTA diminished LDT‐evoked NAc dopamine efflux. Preinfusion of scopolamine into the VTA diminished the facilitatory actions of cocaine on LDT stimulation‐evoked NAc dopamine efflux, and when infused at the peak effect of cocaine attenuated LDT‐evoked dopamine efflux to below predrug baseline levels. These findings suggest that LDT cholinergic inputs to dopamine neurons in the VTA, via activation of mAChRs (probably of the M5 subtype), are involved in modulating the facilitatory effects of cocaine on NAc dopamine neurotransmission. They also suggest that the development of antagonists aimed at selectively disrupting M5 receptor function may be valuable in reducing abuse liability of psychostimulants. Synapse 64:216–223, 2010.

Increased amphetamine-induced locomotor activity, sensitization, and accumbal dopamine release in M5 muscarinic receptor knockout mice

IntroductionMuscarinic M5 receptors are the only muscarinic receptor subtype expressed by dopamine-containing neurons of the ventral tegmental area. These cells play an important role for the reinforcing properties of psychostimulants and M5 receptors modulate their activity. Previous studies showed that M5 receptor knockout (M5−/−) mice are less sensitive to the reinforcing properties of addictive drugs.Materials and methodsHere, we investigate the role of M5 receptors in the effects of amphetamine and cocaine on locomotor activity, locomotor sensitization, and dopamine release using M5−/− mice backcrossed to the C57BL/6NTac strain.Statistical analysesSensitization of the locomotor response is considered a model for chronic adaptations to repeated substance exposure, which might be related to drug craving and relapse. The effects of amphetamine on locomotor activity and locomotor sensitization were enhanced in M5−/− mice, while the effects of cocaine were similar in M5−/− and wild-type mice.ResultsConsistent with the behavioral results, amphetamine-, but not cocaine, -elicited dopamine release in nucleus accumbens was enhanced in M5−/− mice.DiscussionThe different effects of amphetamine and cocaine in M5−/− mice may be due to the divergent pharmacological profile of the two drugs, where amphetamine, but not cocaine, is able to release intracellular stores of dopamine. In conclusion, we show here for the first time that amphetamine-induced hyperactivity and dopamine release as well as amphetamine sensitization are enhanced in mice lacking the M5 receptor. These results support the concept that the M5 receptor modulates effects of addictive drugs.

Midbrain acetylcholine and glutamate receptors modulate accumbal dopamine release.

This study determined the role of ventral tegmental area acetylcholine and glutamate receptors in modulating laterodorsal tegmentum stimulation-evoked dopamine efflux in the nucleus accumbens. Rapid changes in dopamine oxidation current were measured at carbon fiber microelectrodes using fixed potential amperometry in urethane anesthetized male mice. Intraventral tegmental area infusions of the muscarinic acetylcholine receptor antagonist scopolamine, the nicotinic acetylcholine receptor antagonist mecamylamine, or the ionotropic glutamate receptor antagonist kynurenate significantly diminished dopamine efflux in the nucleus accumbens evoked by brief electrical stimulation of the laterodorsal tegmentum. These findings suggest that acetylcholine and ionotropic glutamate receptors influence rapid dopaminergic activity and thus the communication of behaviorally relevant information from ventral tegmental area dopamine cells to forebrain areas.

Neuronal pathways involved in deep brain stimulation of the subthalamic nucleus for treatment of parkinson’s disease

In this study, fixed potential amperometry was used to examine several pathways by which Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) or dopamine axons within the dorsal forebrain bundle (DFB) release striatal dopamine, thus potentially providing therapeutic benefits for Parkinson’s Disease patients. In urethane anesthetized mice, electrical stimulations (20 monophasic pulses at 50 Hz every 30 sec) were applied to the STN or DFB while infusing the local anesthetic lidocaine (4%) into the substantia nigra compacta (SNc) or pedunculopontine tegmental nucleus (PPT). Findings suggest that DFB stimulation activates ascending SNc dopamine axons, while STN stimulation evokes striatal dopamine release directly via excitatory glutamatergic inputs to SNc dopamine cells and indirectly via excitatory cholinergic/glutamatergic STN-PPT-SNc pathways.

Comparing Phasic Dopamine Dynamics in the Striatum, Nucleus Accumbens, Amygdala, and Medial Prefrontal Cortex

Midbrain dopaminergic neurons project to and modulate multiple highly interconnected modules of the basal ganglia, limbic system, and frontal cortex. Dopamine regulates behaviors associated with action selection in the striatum, reward in the nucleus accumbens (NAc), emotional processing in the amygdala, and executive functioning in the medial prefrontal cortex (mPFC). The multifunctionality of dopamine likely occurs at the individual synapses, with varied levels of phasic dopamine release acting on different receptor populations. This study aimed to characterize specific aspects of stimulation‐evoked phasic dopamine transmission, beyond simple dopamine release, using in vivo fixed potential amperometry with carbon fiber recording microelectrodes positioned in either the dorsal striatum, NAc, amygdala, or mPFC of anesthetized mice. To summarize results, the present study found that the striatum and NAc had increased stimulation‐evoked phasic dopamine release, faster dopamine uptake (leading to restricted dopamine diffusion), weaker autoreceptor functioning, greater supply levels of available dopamine, and increased dopaminergic responses to DAT blockade compared to the amygdala and mPFC. Overall, these findings indicate that phasic dopamine may have different modes of communication between striatal and corticolimbic regions, with the first being profuse in concentration, rapid, and synaptically confined and the second being more limited in concentration but longer lasting and spatially dispersed. An improved understanding of regional differences in dopamine transmission can lead to more efficient treatments for disorders related to dopamine dysfunction.

Deep brain stimulation enhances movement complexity during gait in individuals with Parkinson’s disease

Deep brain stimulation (DBS) is associated with substantial improvements in motor symptoms of PD. Emerging evidence has suggested that nonlinear measures of complexity may provide greater insight into the efficacy of anti-PD treatments. This study investigated sample entropy and complexity index values in individuals with PD when DBS was OFF compared to ON. Five individuals with PD using DBS performed a four-minute treadmill walking task while 3D kinematics were collected over two periods of 30 s. Participants were tested in the DBS-ON and DBS-OFF conditions. Sample entropy (SE) and complexity index (CI) values were calculated for ankle, knee and hip joint angles. Paired samples t-tests were used to compare mean SE and CI values between the DBS-OFF and DBS-ON conditions, respectively. No differences in SE or CI were observed between the DBS-ON and DBS-OFF conditions at the ankle. At the knee, the DBS-ON was associated with greater SE and CI values than the DBS-OFF condition. At the hip, DBS-ON was associated with greater SE and CI values than the DBS-OFF condition. DBS enhances complexity of movement at the hip and knee joints while complexity at the ankle joint is not significantly altered. Greater complexity of knee and hip joint motion may represent increased adaptability and a greater number of available strategies to complete the gait task.