Browsing by Subject "Reward"
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Item Affective responses in cocaine-experienced rats reveal cue-induced drug craving and cocaine reward magnitude(2011-08) Maier, Esther Yvonne; Duvauchelle, Christine L.; Schallert, Timothy; Gonzales, Rueben A.; Gore, Andrea C.; Monfils, Marie H.The development and persistence of cocaine dependence are greatly influenced by emotional affect and cocaine associative learning. Cocaine is known to enhance nucleus accumbens (NAcc) dopamine, serve as a positive reinforcer and produce negative effects, such as anxiety that may influence cocaine intake behavior. In the first study, I investigated the effects of the anxiolytic, diazepam on NAcc dopamine levels and cocaine self-administration behavior. These are two factors associated with cocaine rewarding effects. Diazepam has no effect on NAcc dopamine, but affects cocaine self-administration. This supports the notion that decreasing the anxiogenic effects of cocaine increases the rewarding value in a dopamine independent manner. Therefore, increasing the aversive effects of cocaine might be a novel approach to fight cocaine dependence. In the second study, I studied cocaine-induced associative learning and changes in affect during cocaine conditioning and extinction. 50-kHz ultrasonic vocalizations (USVs) in rats are thought to reflect positive affect and occur upon appetitive stimuli and with cocaine delivery. First, I explored whether USVs might be elicited in anticipation of impending drug delivery. Shortly into conditioning, rats elicited USVs when placed in the cocaine-associated environment. USVs progressively increased, indicating a growing learned association between cocaine intake and cocaine-associated cues. This suggests that USVs may be a useful model for investigating cocaine craving and serve as a pharmacological target for interventions aimed to reduce cocaine craving and relapse. I then examined the effects of short-term deprivation of cocaine and cocaine cues on cocaine-conditioned USVs, which were both exaggerated after abstinence. The results may have clinical implications, in that intermittently avoiding cues or context may enhance drug cue salience and increase the probability of relapse. Motivational aspects of cocaine were assessed comparing commonly measured lever response rate and locomotion with cocaine-induced USVs during cocaine administration and extinction. In agreement with prevailing findings, lever responding for cocaine and cocaine-induced locomotor activity increased across conditioning sessions. However, the number of USVs evoked in response to cocaine infusion decreased with cocaine experience. These findings suggest growing tolerance to the rewarding properties of cocaine. These studies underscore the value of USV assessment during drug dependence studies.Item Mechanisms in ethanol modulation of GABA release onto dopaminergic neurons of the ventral tegmental area(2009-12) Theile, Jonathan William; Morrisett, Richard A.; Gonzales, Rueben A.; Morikawa, Hitoshi; Mayfield, Roy D.; Mihic, S. J.Activation of ventral tegmental area (VTA) dopaminergic (DA) neurons by ethanol has been implicated in the rewarding and reinforcing actions of ethanol. GABAergic transmission is thought to play an important role in regulating the activity of DA neurons. While at most central synapses ethanol generally increases inhibitory synaptic transmission, no studies have explored the effect of acute ethanol on GABAergic transmission in the VTA. Here we investigated how ethanol modulates GABAergic transmission in the VTA in relation to the overall action of ethanol on VTA-DA neuron activity. We demonstrated that ethanol dose-dependently enhances action potential-dependent and -independent GABA release onto VTA-DA neurons. Utilizing whole-cell voltage clamp recording techniques, ethanol increased both spontaneous and miniature inhibitory postsynaptic current (s/mIPSC) frequency while having minimal effect on s/mIPSC amplitude. The ethanol enhancement in GABA release was independent of GABAB auto-receptor inhibition of release. Intra-terminal calcium levels regulate neurotransmitter release, thus we investigated how modulation of calcium levels would affect the ethanol-enhancement in GABA release. Ethanol enhanced mIPSC frequency in the presence of the voltage-gated calcium channel blockers, cadmium chloride and nicardipine. However, blockade of intracellular calcium stores with 2-APB and cyclopiazonic acid eliminated the ethanol-enhancement of mIPSC frequency. Intracellular calcium stores are regulated via Gq protein-coupled receptors such as the 5-HT2C receptor. 5-HT2C receptor activation robustly enhanced mIPSC frequency whereas blockade inhibited the ethanol-enhancement in mIPSC frequency. These observations suggest that increased calcium release from intracellular stores via 5-HT2C receptor activation is involved in the ethanol-enhancement of GABA release onto VTA-DA neurons. Utilizing cell-attached current-clamp recordings, we demonstrated that the ethanol-enhancement of VTA-DA neuron activity is modulated by the concurrent enhancement in GABA release. Blockade and activation of GABAA receptors enhanced and reversed, respectively, the stimulatory effect of ethanol on VTA-DA neurons. Mu-opioid receptors (MORs) on GABAergic interneurons have been demonstrated to modulate both basal and ethanol-enhanced VTA-DA activity in vivo, though we failed to demonstrate such an effect in vitro. Overall, the results of this study suggest that the 5-HT2C receptor and intra-terminal calcium-dependent ethanol enhancement in GABA release acts to regulate the overall stimulatory effect of ethanol on VTA-DA activity.Item The effect of reward-based motivation on associative memory processing in the medial temporal lobes(2013-05) Wolosin, Sasha Monica; Preston, Alison R.; Beer, Jennifer S; Huk, Alexander C; Poldrack, Russell A; Schnyer, David MWhat determines whether an experience is encoded to memory? One factor is reward-based motivation: we are more likely to remember information if we believe it will lead to future rewards. Memory critically depends on the integrity of the medial temporal lobes (MTL). Notably, the MTL is comprised of subregions that are hypothesized to serve different functions in memory and may be differentially influenced by reward. The present research examines how reward-based motivation influences associative memory processing within MTL subregions of the human brain. In two high-resolution functional magnetic resonance imaging (fMRI) studies, a high-value or low-value monetary cue preceded a pair of objects indicating potential reward for successful retrieval of the association on a later memory test. Memory was enhanced for pairs preceded by high-value compared to low-value reward cues, however participants differed in the degree to which reward value influenced memory. In fMRI Study 1, the behavioral effect of reward on memory was associated with reward-related activation changes in hippocampal subregions dentate gyrus/CA₂,₃ and enhanced connectivity between dentate gyrus/CA₂,₃ and reward-related midbrain regions during encoding and retrieval. In fMRI Study 2, patterns of MTL activations represented reward context, showing greater consistency among events of the same reward value than among events of different reward values. Successful memory formation was associated with enhanced hippocampal reward representations during the anticipatory cue phase prior to object pair encoding. During object pair encoding, the degree of reward representation in hippocampus and more specifically dentate gyrus/CA₂,₃ was associated with individual differences in the behavioral effect of reward on memory. Finally, a series of behavioral studies demonstrate that during motivated learning, associative memory accuracy increases monotonically with increasing reward value, and may be enhanced when participants must maintain information about reward cues in short-term memory prior to encoding. These findings indicate that reward-based motivation enhances associative memory processing specifically within dentate gyrus/CA₂,₃ through interactions with reward-related midbrain regions. Furthermore, these results suggest that associative memory may be facilitated when information about reward context is incorporated into stored memory representations. Collectively, these findings shed light on fundamental mechanisms through which reward impacts associative memory.Item Ultrasonic vocalization reveals individual differences in the rewarding and motivational effects of amphetamine in rats(2012-08) Ahrens, Allison Melinda; Schallert, Timothy; Duvauchelle, Christine L.; Gonzales, Rueben; Jones, Theresa; Cormack, LawrenceThe pleasurable and euphoric effects of drugs play an important role in drug abuse; however, there are no established preclinical models for directly assessing the hedonic effects of drugs in rodents. The purpose of this dissertation was to investigate rat ultrasonic vocalizations (USVs) as a potential method for measuring positive affective states associated with amphetamine reinforcement. USVs are high-frequency social signals that rats use to communicate with one another. Calls in the 50-kHz range are thought to be a sign of positive affect, since they are elicited by naturally rewarding stimuli, and are modulated by mesolimbic dopamine activity. At the time this dissertation was begun, the majority of USV research focused on natural rewards, such as sex and social interactions, and the USVs associated with repeated exposure to a drug or appetitive desire for a drug had not been studied. Therefore, the objective of this dissertation was to characterize the production of 50-kHz USVs during repeated administration of amphetamine within different paradigms commonly used to study the behavioral and motivational effects of stimulants in rats. First, I found that the 50-kHz USVs elicited by amphetamine were sensitized by repeated exposure, showing that USV expression parallels the sensitization of mesolimbic circuitry that is involved in the development of addiction. Second, I found that rats produce conditioned anticipatory 50-kHz USVs during exposure to cues that predicted amphetamine, with the magnitude of anticipatory calling increasing as drug-cue associations were learned and strengthened. Third, I found that the number of unconditioned 50-kHz USVs produced during the initial amphetamine exposure predicted the subsequent expression of anticipatory 50-kHz USVs, the development of conditioned place preference for an amphetamine-paired environment, and corticosterone responses to the drug. Overall, these findings suggest that 50-kHz USVs are an expression of behavioral arousal associated with both the positive effects of amphetamine itself, and the incentive-motivational states elicited by drug-paired cues. In addition, they show that the intensity of the initial 50-kHz USV response to amphetamine reflects individual differences in sensitivity to drug reinforcement.