Browsing by Subject "VTA"

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Chronic Forced and Free Exercise on Cocaine Place Conditioning and Glutamatergic Synaptic Plasticity in the VTA
(2018) Do, Minh; Morikawa, Hitoshi
Exercise may be useful in preventing substance use disorders and addiction. It is well known that chronic exercise, both forced and voluntary, decreases addiction vulnerability in rodent models and likely in humans. However, the mechanism by which chronic exercise accomplishes this has not been fully evaluated. Here, a conditioned place preference (CPP) paradigm was used to measure the learning of cocaine-associated environmental cues in two groups of rats following a period of both forced and free running. It is shown that rats subjected to chronic forced running displayed no significant deviation in learning of contextual cues paired with cocaine through CPP. On the other hand, rats subjected to chronic free running displayed a notable decrease in acquisition of cocaine-CPP. To investigate the mechanism by which chronic exercise affects cocaine-CPP, we will conduct future electrophysiological studies in the ventral tegmental area (VTA), an area that has been widely implicated in the natural reward circuitry of the brain. The VTA and its role in addiction has been studied extensively by the Morikawa Lab, with one previous study finding that repeated social defeat stress enhances glutamatergic synaptic plasticity in the VTA and cocaine-CPP. Essentially, we expect to observe a decrease in long-term potentiation (LTP) of NMDA-mediated glutamatergic synaptic plasticity in the VTA and consequently, a decrease in cocaine-CPP following both chronic forced and free exercise. If observed, our findings will suggest that decreased plasticity of glutamatergic transmission may be responsible for decreased addiction vulnerability through chronic exercise.
Effects of opioid antagonism on operant ethanol self-administration in adolescence and characterization of extracellular GABA in the ventral tegmental area
(2016-12) Zandy, Shannon Laine; Gonzales, Rueben Anthony; Harris, Robert A; Marinelli, Michela; Morikawa, Hitoshi; Morrisett, Richard A
The endogenous opioid peptide system is hypothesized to be involved in ethanol self-administration and relapse behaviors. Naltrexone, a nonselective opioid antagonist, is an approved medication for alcohol use disorder which has been shown to decrease drinking in adult animal models and select clinical populations, but little is known about the efficacy of naltrexone in animal models that begin drinking ethanol in adolescence. Therefore, we investigated the effects of systemic naltrexone administration in an adolescent rat model of operant ethanol self-administration. We found that naltrexone significantly reduced ethanol intake and motivation to obtain ethanol in adolescent and adult rats. Following a period of abstinence, naltrexone also significantly reduced “relapse” to alcohol seeking in both age groups. These results extend findings that naltrexone is effective at reducing ethanol intake to an adolescent animal model and support opioid antagonism as a treatment strategy for decreasing problem drinking in late adolescents and young adults. One potential mechanism underlying the effects of opioid receptor blockade on ethanol self-administration implicates γ-aminobutyric acid (GABA) neurons within the ventral tegmental area (VTA). Inhibitory signaling in the VTA is involved in the mechanism of action of many drugs of abuse yet there are few studies measuring extracellular GABA concentration in this region. Therefore, the remaining experiments focused on developing methods to quantify extracellular GABA in the VTA. We first describe a novel, sensitive fluorescence method to quantify GABA concentration using high performance liquid chromatography (HPLC) of an ophthalaldehyde/sulfite derivative, previously reported to produce low fluorescence not suitable for in vivo microdialysis applications. Next, we used quantitative microdialysis under transient conditions to characterize basal extracellular GABA concentration and the influence of uptake mechanisms in the VTA. Our results show that inhibition of GABA uptake significantly increased extracellular GABA concentration and reduced in vivo extraction fraction of the probe. Reduced in vivo extraction fraction caused significant underestimation of the increase in extracellular GABA by conventional microdialysis. Together, these results establish the foundation for future studies to investigate the regulation of extracellular GABA concentration and uptake mechanisms in the VTA in mediating the effects of ethanol, opioid antagonism and associated drug-related behaviors.
Estradiol affects how ethanol influences dopamine neuron activity in the ventral tegmental area
(2021-04-16) Lambeth, Philip Stanhope; Gonzales, Rueben Anthony; Mangieri, Regina Anne; Harris, R. Adron; Morikawa, Hitoshi; Lasek, Amy W
Females can progress to alcohol and other substance use disorders more quickly than males. The ovarian hormone 17β-estradiol (E2) contributes to sex differences observed in drug use and abuse and may be a principal driver of these differences. However, it is not entirely clear how E2 acts to affect processing of ethanol reward, and several brain regions and mechanisms are implicated. We sought to clarify the role of E2 in modulating the response of ventral tegmental area dopamine neurons to ethanol. To this end, I recorded spontaneous action potentials and inhibitory postsynaptic currents from dopaminergic neurons in acute horizontal brain slices from ovariectomized (OVX) dopamine neuron reporter mice (Pitx3-eGFP) treated with either vehicle (VEH) or E2. My data confirmed that ethanol stimulation of the firing rate of dopamine neurons from OVX+E2 mice was greater than that of OVX+VEH animals. Further, we hypothesized that the firing rate increase would be accompanied by a concomitant decrease in ethanol stimulated inhibition onto those same neurons. I found that although ethanol caused the expected increase in the frequency of GABA [subscript A] receptor-mediated synaptic inhibition in both groups, there was no difference in this response between OVX+E2 and OVX+VEH animals. I also observed a small effect of ethanol to increase the amplitude of these currents in both groups. These findings lend additional support for the ability of E2 to enhance ventral tegmental area dopamine neuron responses to ethanol and suggest that this effect is not mediated by an E2-elicited suppression of synaptic inhibition, although future studies are needed to conclusively determine the mechanism. The experiments and research surveyed in this document help to strengthen the field of addiction generally, as well as alcohol research specifically. As although alcohol has some very specific effects, the information that we learn about dopaminergic transmission as it relates to drug use can be used well outside of the alcohol field. Furthermore, this research has led to new insights into the underlying causes and subsequent consequences of sex differences, both physiological and behavioral.
Social isolation enhances calcium signaling and synaptic plasticity in dopamine neurons of the ventral tegmental area
(2012-08) Ramsey, Leslie Anne; Morikawa, Hitoshi; Mauk, Michael; Jones, Theresa; Harris, Adron; Johnston, Daniel
Environmental experiences play a critical role in an individualʼs risk of becoming addicted. Positive experiences may mitigate addiction vulnerability, whereas adverse experiences, particularly during adolescence, have been shown to increase addiction risk. Social isolation in rodents is a model system used to study the effects of such experiences, yet its impact on the learning and memory processes that underlie addiction remains elusive. Although social isolation is known to alter the functioning of the dopaminergic system, as well as reward processing and learning, its effect on dopamine (DA) neurons of the ventral tegmental area (VTA) is unknown. The data presented in this dissertation demonstrate that social isolation of rats during a critical period in adolescence (postnatal days 21-42) enhances long-term potentiation (LTP) of N-methyl D-aspartate receptor (NMDAR)-mediated glutamatergic transmission in the VTA. Activation of NMDARs is critical to the generation of DA neuron bursts that encode rewards and reward-predictive cues, and NMDARs are necessary for associative reward learning. The isolation-induced enhancement of NMDAR LTP results from augmentation of metabotropic glutamate receptor (mGluR)-dependent calcium (Ca²⁺) signaling via an increase in inositol 1,4,5-trisphosphate(IP3) sensitivity. Isolation-mediated effects on Ca²⁺ signaling and NMDAR plasticity were not reversed by a subsequent period of resocialization. Furthermore, social isolation during this critical period occludes the effect of repeated amphetamine exposure on mGluR/IP₃-mediated Ca²⁺ signaling and synaptic plasticity. Although corticotropin releasing factor (CRF) further facilitates mGluR/IP3-mediated Ca²⁺ signaling in DA neurons, alterations in CRF receptors are not responsible for the effects of isolation on Ca²⁺ signaling and synaptic plasticity. In addition, the learning of associations between environmental stimuli and drug rewards is acquired more quickly and is more resistant to extinction in isolated animals. Data presented in this dissertation lend support to the theory that enhanced mGluR/IP₃-mediated Ca²⁺ signaling and NMDAR plasticity facilitate the learning and memory of drug-associated stimuli. This dissertation provides the first demonstration of a cellular basis for the critical time window of social isolation during adolescence. NMDAR plasticity in the VTA may thus represent a neural substrate by which early life experiences regulate addiction vulnerability. (Note: Behavioral data were acquired by Mickael Degoulet)