Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

突触传递：调节、可塑性和滥用药物的影响

• 批准号: 9155443
• 负责人: David M Lovinger
• 金额: $ 110.13万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9155443
• 关键词: Acute; Affect; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcohols; Behavior; Behavior Control; Brain; Brain region; CNR1 gene; Catabolism; Chronic; Clinical Research; Cocaine; Cognition; Corpus striatum structure; Coupled; Decision Making; Dependence; Dopamine; Dorsal; Dose; Drug Exposure; Drug effect disorder; Elements; Endocannabinoids; Ethanol; Exposure to; G-Protein-Coupled Receptors; GTP-Binding Proteins; Glutamates; Goals; Green Fluorescent Proteins; Habits; Interneurons; Intoxication; Investigation; Laboratories; Learning; Lobular Neoplasia; Long-Term Depression; Measures; Mediating; Membrane Proteins; Motivation; Mus; National Institute on Alcohol Abuse and Alcoholism; Neurons; Neurophysiology - biologic function; Neurosciences; Opioid Receptor; Oxycodone; Pattern; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Population; Prefrontal Cortex; Probability; Process; Prosencephalon; Psychological reinforcement; Rattus; Receptor Activation; Recruitment Activity; Reporter; Reporting; Research; Research Personnel; Rewards; Role; Scanning; Sensorimotor functions; Signal Transduction; Slice; Synapses; Synaptic Transmission; Synaptic plasticity; Techniques; Thalamic structure; Training; Ventral Striatum; Work; addiction; alcohol and other drug; alcohol behavior; alcohol effect; alcohol exposure; alcohol seeking behavior; base; cholinergic; dopaminergic neuron; drinking; drug of abuse; in vivo; interest; metabotropic glutamate receptor 2; nerve supply; neural circuit; neuroadaptation; neurogenetics; neuronal circuitry; neuroregulation; optogenetics; prescription opiate; prevent; protein expression; psychostimulant; receptor; receptor function; relating to nervous system; research study; response; striosome; synaptic depression; translational study

Research within the Laboratory for Integrative Neuroscience, Section on Synaptic Pharmacology, continues to focus on mechanisms underlying neuromodulation and plasticity and the effects of alcohol and other drugs of abuse on these neuronal functions. Our main interest is the function of the dorsal striatum (DS), a brain region involved in action control and selection, as well as action learning and addiction. Striatal Synaptic Plasticity and Drugs of Abuse We have continued our examination of changes in long-lasting striatal synaptic plasticity following in vivo exposure to drugs of abuse. These studies are carried out with electrophysiological recording in brain slices following the in vivo treatment. Our previous findings indicated that exposure to ethanol for 2-4 weeks in vivo led to a decrease in a form of long-term synaptic depression (LTD) that is initiated by endogenous cannabinoid (endocannabinoid) activation of CB1 receptors on cortical afferents to the dorsolateral striatum (DLS). In addition to CB1 receptors that activate Gi/o-type G-proteins, LTD at corticostriatal synapses can also be induced by activation of other G protein-coupled receptors (GPCRs) that activate Gi/o-dependent intracellular signaling. It appears that these forms of LTD are expressed presynaptically as a decrease in the probability of glutamate release. The mu opiate receptor (MOR) is among the receptors that can trigger LTD, and we recently reported that MOR-LTD is prevented by prior in vivo exposure to even a single dose of the prescription opiate drug oxycodone. The LTD activated by delta-type opiate receptors (DORs) is not affected by this in vivo drug exposure. Interestingly, MOR-LTD is mutually occlusive with endocannabinoid-LTD, while no such interactions between DOR-LTD and either endocannabinoid- or MOR-LTD are observed. Thus, it appears that DOR-LTD occurs at a separate synaptic population or has a mechanism distinct from MOR- and endocannabinoid-LTD. Preliminary experiments indicate that chronic intermittent ethanol exposure prevents MOR-LTD, while DOR-LTD is unaffected by this exposure. Our current working hypothesis is that chronic exposure to several drugs of abuse results in loss of some forms of Gi/o-mediated LTD in DLS. Loss of this synaptic depression would result in stronger cortical drive onto the projection neurons of the DLS. Given the role of the DLS in habit formation, the net effect of these drug actions on LTD could be the promotion of habitual drug seeking and taking. We have worked with the Laboratory of Neurogenetics and the Laboratory of Clinical and Translational Studies here at NIAAA to examine another form of corticostriatal LTD initiated by activation of the Gi/o-coupled metabotropic glutamate receptor 2 (mGluR2 or GRIM2). This receptor and the LTD resulting from its activation are missing in the alcohol preferring P rats. Mice lacking the receptor show increased alcohol intake, implicating GRIM2 in control of drinking. We are currently examining if the function of this receptor is altered following chronic alcohol exposure, and how the receptor might contribute to excess drinking. We are also using optogenetic techniques to examine synapses in the striatum made by afferents from identified cortical and thalamic regions. This analysis will allow us to determine what forms of Gi/o-mediated LTD occur at which synapses both under control conditions and following in vivo drug exposure. Dopamine Release and Modulation Thereof in Different Striatal Subcompartments The striatum can be separated into striosome and matrix subcompartments based on protein expression patterns, afferent innervation and efferent projection targets. Within the dorsal striatum, and especially in DLS, the striosome compartments/continuum generally processes associative and/or limbic information, while the larger matrix handles sensorimotor functions. We have used a mouse that expresses green fluorescent protein preferentially in the striosome compartment, as characterized in LIN (the Nr4a1-GFP mouse) to examine subcompartmental differences in control of dopamine. Dopamine has key roles in controlling striatal circuitry, and as such has been implicated in action control, decision making, motivation, reward and reinforcement. We used fast-scan cyclic voltammetry to measure dopamine release in the different subcompartments in striatal slices from these reporter mice. In the dorsal striatum, dopamine release was stronger in matrix than in striosomes, while the opposite was true in more ventral striatal regions. Cocaine enhanced dopamine release to a greater extent in striosomes than in matrix in the dorsal striatum. These findings indicate that dopaminergic influence may initially be weaker in striosomes, perhaps due to high levels of expression of the dopamine clearing transporter. Psychostimulant drugs that act through this transporter appear to equalize release in the two subcompartments, perhaps leading to increased associative/limbic circuitry influences on the dorsal striatum. We have also examined modulation of dopamine release by CB1 agonists and endocannabinoids in the ventral striatum. We find that CB1 receptor activation inhibits dopamine release when release is driven by optogenetic activation of striatal cholinergic interneurons (CINs). This modulation was observed either with synthetic CB1 agonists or when endocannabinoid levels were enhanced by blocking catabolism or by short trains of CIN activation. The release driven by CINs is also inhibited when glutamatergic synaptic transmission is inhibited, and the effects of CB1 activation and glutamatergic antagonism are mutually occlusive. Dopaminergic neurons and CINs do not express CB1, and this CB1 modulation was prevented when receptors were removed from prefrontal cortex afferents to ventral striatum. Thus, our evidence supports the idea that CIN activation recruits cortical glutamatergic afferents that help to drive dopamine release. This cortical glutamatergic drive is itself modulated by endocannabinoids acting through CB1 receptors. These findings provide evidence of a new mechanism for control of dopamine and its many neural functions.

综合神经科学实验室突触药理学部分的研究继续关注神经调节和可塑性的潜在机制，以及酒精和其他滥用药物对这些神经元功能的影响。我们的主要兴趣是背纹状体（DS）的功能，这是一个涉及动作控制和选择，以及动作学习和成瘾的大脑区域。