Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aim... more Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J Â DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings show differential autoreceptor effects on dopamine synthesis between C57BL/6J and DBA/2J mice, and suggest that decreased dopaminergic activity is associated with excessive drinking.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), May 1, 2015
Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens (NAc), which may ... more Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens (NAc), which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors (KORs) have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors, and are known to inhibit dopamine release in the NAc. The effects of chronic ethanol exposure on KOR-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. Five weeks of chronic intermittent ethanol (CIE) exposure in male C57BL/6 mice were used to examine the role of KORs in chronic ethanol-induced increases in ethanol intake and also marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after CIE exposure, with and without KOR blockade by nor-binaltorphimine (norBNI, 10 mg/kg i.p.). Functional alterations in KORs were assessed using fast scan cyclic volta...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 24, 2017
Cocaine abuse disrupts dopamine system function, including reduced cocaine inhibition of the dopa... more Cocaine abuse disrupts dopamine system function, including reduced cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criteria for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were two-fold; we sought to: 1) identify the molecular mechanisms by which cocaine exposure produces tolerance, and 2) determine if amphetamine-induced reductions in cocaine intake is connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed coca...
Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleter... more Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode K7 channels influence alcohol intake and dependence. K7 channels are a class of slowly activating voltage-dependent K channels that regulate neuronal excitability. Studies indicate that the K7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and K7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 express...
Determining neurobiological factors that contribute to individual variance in drug addiction vuln... more Determining neurobiological factors that contribute to individual variance in drug addiction vulnerability allows for identification of at-risk populations, use of preventative measures and personalized medicine in the treatment of substance use disorders. Rodents that exhibit high locomotor activity when exploring an inescapable novel environment (high-responder; HR) are more susceptible to the reinforcing effects of many abused compounds, including nicotine, as compared to animals that exhibit low locomotor activity (low-responder; LR). Given that nicotinic acetylcholine receptor (nAChR) modulation of reward-related dopamine signaling at accumbal dopamine terminals is critical for the acquisition of drug self-administration, we hypothesized that nAChR modulation of dopamine release would be predicted by an animal's novelty response. Using voltammetry in the nucleus accumbens core of rats, we found that nicotine produced opposite effects in HR and LR animals on stimulation frequencies that model phasic dopamine release, whereby release magnitude was either augmented or attenuated, respectively. Further, nicotine suppressed dopamine release elected by stimulation frequencies that model tonic release in LR animals, but had no effect in HR animals. The differential effects of nicotine were likely due to desensitization of nAChRs, since the nAChR antagonists mecamylamine (non-selective, 2 μM), dihydro-beta-erythroidine (β2-selective, 500 nM), and α-conotoxin MII [H9A; L15A] (α6-selective, 100 nM) produced effects similar to nicotine. Moreover, dihydro-beta-erythroidine failed to show differential effects in HR and LR rats when applied after α-conotoxin MII [H9A; L15A], suggesting a critical role of α6β2 compared non α6-containing nAChRs in the differential effects observed in these phenotypes. These results delineate a potential mechanism for individual variability in behavioral sensitivity to nicotine.
Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on s... more Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slowe...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 31, 2017
Although the dopamine transporter is the primary site of action for cocaine, and the dopamine sys... more Although the dopamine transporter is the primary site of action for cocaine, and the dopamine system is known to mediate the reinforcing and rewarding effects of cocaine, the dopaminergic variations underlying individual differences in cocaine self-administration behaviors are not fully understood. Recent advances in the application of economic principles to operant tasks in rodents have allowed for the within-subject, within-session determination of both consummatory and appetitive responding for reinforcers. Here we combined a behavioral economics approach, deemed the 'threshold procedure', with cocaine self-administration and ex vivo voltammetric recording of dopamine signaling in the core of the nucleus accumbens of rats to determine the relationship between dopamine signaling and discrete aspects of cocaine taking and seeking. We found neither dopamine release or uptake tracked individual differences in cocaine consumption or the reinforcing efficacy of cocaine. Cocaine...
The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporte... more The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DATs occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximate...
Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates bec... more Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2. We evaluated a newly developed G protein signaling-biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it pro...
The hypocretin/orexin (HCRT) system is implicated in reward and reinforcement processes through a... more The hypocretin/orexin (HCRT) system is implicated in reward and reinforcement processes through actions on the mesolimbic dopamine (DA) system. Here we provide evidence for the relationship between HCRT and DA in vivo in anesthetized and freely moving mice. The ability of cocaine to elicit reward-related behaviors in mice lacking the HCRT prepro-peptide (HCRT knock-out; KO) and wild-type controls was determined using conditioned place preference. Using a combination of microdialysis and in vivo fast scan cyclic voltammetry in anesthetized and freely moving mice, we investigated the underlying role of HCRT in the regulation of DA release and uptake. We show that, unlike wild-type mice, HCRT KO mice fail to develop characteristic conditioned place preference for cocaine. These mice also demonstrated reduced DA release and uptake under baseline conditions in both anesthetized and freely moving experiments. Further, diminished DA signaling in HCRT KO mice persists following administration of cocaine. These findings indicate that HCRT is essential for the expression of behaviors associated with the rewarding effects of cocaine, and suggest that HCRT regulation of reward and reinforcement may be related to disruptions to DA neurotransmission.
b-Phenylethylamine (b-PEA) is an endogenous amine that is found in trace amounts in the brain. It... more b-Phenylethylamine (b-PEA) is an endogenous amine that is found in trace amounts in the brain. It is believed that the locomotor-stimulating action of b-PEA, much like amphetamine, depends on its ability to increase extracellular dopamine (DA) concentrations owing to reversal of the direction of dopamine transporter (DAT)-mediated DA transport. b-PEA can also bind directly to the recently identified G protein-coupled receptors, but the physiological significance of this interaction is unclear. To assess the mechanism by which b-PEA mediates its effects, we compared the neurochemical and behavioral effects of this amine in wild type (WT), heterozygous and 'null' DAT mutant mice. In microdialysis studies, b-PEA, administered either systemically or locally via intrastriatal infusion, produced a pronounced outflow of striatal DA in WT mice whereas no increase was detected in mice lacking the DAT (DAT-KO mice). Similarly, in fast-scan voltammetry studies b-PEA did not alter DA release and clearance rate in striatal slices from DAT-KO mice. In behavioral studies b-PEA produced a robust but transient increase in locomotor activity in WT and heterozygous mice. In DAT-KO mice, whose locomotor activity and stereotypy are increased in a novel environment, b-PEA (10-100 mg/kg) exerted a potent inhibitory action. At high doses, b-PEA induced stereotypies in WT and heterozygous mice; some manifestations of stereotypy were also observed in the DAT-KO mice. These data demonstrate that the DAT is required for the striatal DA-releasing and hyperlocomotor actions of b-PEA. The inhibitory action on hyperactivity and certain stereotypies induced by b-PEA in DAT-KO mice indicate that targets other than the DAT are responsible for these effects.
The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly ... more The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of...
Regional differences in the kinetics and pharmacological inhibition of dopamine uptake were inves... more Regional differences in the kinetics and pharmacological inhibition of dopamine uptake were investigated with fast-scan cyclic voltammetry in both the intact rat brain and a brain slice preparation. The regions compared were the basolateral amygdaloid nucleus, caudate-putamen, and nucleus accumbens. The frequency dependence of dopamine efflux evoked in vivo by electrical stimulation of the medial forebrain bundle was evaluated by nonlinear curve fitting with a Michaelis-Menten-based kinetic model. The Km for dopamine uptake was found to be significantly higher in the basolateral amygdala (0.6 microM) than in the other two regions (0.2 microM), whereas the Vmax value for dopamine uptake in the basolateral amygdala was significantly lower (0.49 microM/s vs. 3.8 and 2.4 microM/s in the caudate and accumbens, respectively). Similar kinetics were also obtained in brain slices. Addition of a dopamine uptake inhibitor, cocaine or nomifensine (10 microM), to the perfusion buffer increased the apparent Km value > 25-fold in slices of both the caudate-putamen and nucleus accumbens. In contrast, neither uptake inhibitor had an observable effect in the basolateral amygdaloid nucleus. Thus, dopamine uptake in the rat brain is regionally distinct with regard to rate, affinity, and sensitivity to competitive inhibition.
Rationale Existing data strongly suggest that alcohol affects dopamine (DA) neurotransmission in ... more Rationale Existing data strongly suggest that alcohol affects dopamine (DA) neurotransmission in the brain. However, many questions remain about the effects of alcohol on the delicate equilibrium between such neurochemical processes as DA release and uptake. Dysregulation of these processes in the mesolimbic and nigrostriatal systems after chronic alcohol ingestion could be a neuroadaptation contributing to dependence. Objectives In the present study, we have employed an alcohol vapor inhalation model to characterize the effects of chronic alcohol exposure on DA dynamics in rat nucleus accumbens (NAc) and caudate putamen (CP) using fast-scan cyclic voltammetry (FSCV) in brain slices. This method provides a unique view of real-time, spatially resolved changes in DA concentration.
Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aim... more Alcoholism is a prevalent and debilitating neuropsychiatric disease, and much effort has been aimed at elucidating the neurobiological mechanisms underlying maladaptive alcohol drinking in an effort to design rational treatment strategies. In preclinical literature, the use of inbred mouse lines has allowed for the examination of ethanol effects across vulnerable and resistant phenotypes. C57BL/6J mice consistently show higher rates of ethanol drinking compared to most mouse strains. Conversely, DBA/2J mice display low rates of ethanol consumption. Given that the reinforcing and rewarding effects of ethanol are thought to be in part mediated by its actions on dopamine neurotransmission, we hypothesized that alcohol-preferring C57BL/6J and alcohol-avoiding DBA/2J mice would display basal differences in dopamine system function. By administering an L-aromatic acid decarboxylase inhibitor and measuring L-Dopa accumulation via high-performance liquid chromatography as a measure of tyrosine hydroxylase activity, we found no difference in dopamine synthesis between mouse strains in the midbrain, dorsal striatum, or ventral striatum. However, we did find that quinpirole-induced inhibition of dopamine synthesis was greater in the ventral striatum of C57BL/6J mice, suggesting increased presynaptic D2-type dopamine autoreceptor sensitivity. To determine whether dopamine synthesis or autoreceptor sensitivity was altered by a history of ethanol, we exposed C57BL/6J mice to one or two weekly cycles of chronic intermittent ethanol (CIE) exposure and withdrawal. We found that there was an attenuation of baseline dopamine synthesis in the ventral striatum after two cycles of CIE. Finally, we examined tissue content of dopamine and dopamine metabolites across recombinant inbred mice bred from a C57BL/6J Â DBA/2J cross (BXD). We found that low dopaminergic activity, as indicated by high dopamine/metabolite ratios, was positively correlated with drinking. Together, these findings show differential autoreceptor effects on dopamine synthesis between C57BL/6J and DBA/2J mice, and suggest that decreased dopaminergic activity is associated with excessive drinking.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), May 1, 2015
Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens (NAc), which may ... more Chronic ethanol exposure reduces dopamine transmission in the nucleus accumbens (NAc), which may contribute to the negative affective symptoms associated with ethanol withdrawal. Kappa opioid receptors (KORs) have been implicated in withdrawal-induced excessive drinking and anxiety-like behaviors, and are known to inhibit dopamine release in the NAc. The effects of chronic ethanol exposure on KOR-mediated changes in dopamine transmission at the level of the dopamine terminal and withdrawal-related behaviors were examined. Five weeks of chronic intermittent ethanol (CIE) exposure in male C57BL/6 mice were used to examine the role of KORs in chronic ethanol-induced increases in ethanol intake and also marble burying, a measure of anxiety/compulsive-like behavior. Drinking and marble burying were evaluated before and after CIE exposure, with and without KOR blockade by nor-binaltorphimine (norBNI, 10 mg/kg i.p.). Functional alterations in KORs were assessed using fast scan cyclic volta...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 24, 2017
Cocaine abuse disrupts dopamine system function, including reduced cocaine inhibition of the dopa... more Cocaine abuse disrupts dopamine system function, including reduced cocaine inhibition of the dopamine transporter (DAT), which results in tolerance. Although tolerance is a hallmark of cocaine addiction and a DSM-V criteria for substance abuse disorders, the molecular adaptations producing tolerance are unknown, and testing the impact of DAT changes on drug taking behaviors has proven difficult. In regard to treatment, amphetamine has shown efficacy in reducing cocaine intake; however, the mechanisms underlying these effects have not been explored. The goals of this study were two-fold; we sought to: 1) identify the molecular mechanisms by which cocaine exposure produces tolerance, and 2) determine if amphetamine-induced reductions in cocaine intake is connected to these mechanisms. Using cocaine self-administration and fast-scan cyclic voltammetry in male rats we show that low-dose, continuous amphetamine treatment, during self-administration or abstinence, completely reversed coca...
Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleter... more Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode K7 channels influence alcohol intake and dependence. K7 channels are a class of slowly activating voltage-dependent K channels that regulate neuronal excitability. Studies indicate that the K7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and K7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 express...
Determining neurobiological factors that contribute to individual variance in drug addiction vuln... more Determining neurobiological factors that contribute to individual variance in drug addiction vulnerability allows for identification of at-risk populations, use of preventative measures and personalized medicine in the treatment of substance use disorders. Rodents that exhibit high locomotor activity when exploring an inescapable novel environment (high-responder; HR) are more susceptible to the reinforcing effects of many abused compounds, including nicotine, as compared to animals that exhibit low locomotor activity (low-responder; LR). Given that nicotinic acetylcholine receptor (nAChR) modulation of reward-related dopamine signaling at accumbal dopamine terminals is critical for the acquisition of drug self-administration, we hypothesized that nAChR modulation of dopamine release would be predicted by an animal's novelty response. Using voltammetry in the nucleus accumbens core of rats, we found that nicotine produced opposite effects in HR and LR animals on stimulation frequencies that model phasic dopamine release, whereby release magnitude was either augmented or attenuated, respectively. Further, nicotine suppressed dopamine release elected by stimulation frequencies that model tonic release in LR animals, but had no effect in HR animals. The differential effects of nicotine were likely due to desensitization of nAChRs, since the nAChR antagonists mecamylamine (non-selective, 2 μM), dihydro-beta-erythroidine (β2-selective, 500 nM), and α-conotoxin MII [H9A; L15A] (α6-selective, 100 nM) produced effects similar to nicotine. Moreover, dihydro-beta-erythroidine failed to show differential effects in HR and LR rats when applied after α-conotoxin MII [H9A; L15A], suggesting a critical role of α6β2 compared non α6-containing nAChRs in the differential effects observed in these phenotypes. These results delineate a potential mechanism for individual variability in behavioral sensitivity to nicotine.
Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on s... more Systemically released insulin crosses the blood-brain barrier and binds to insulin receptors on several neural cell types, including dopaminergic neurons. Insulin has been shown to decrease dopamine neuron firing in the ventral tegmental area (VTA), but potentiate release and reuptake at dopamine terminals in the nucleus accumbens (NAc). Here we show that prolonged consumption of a high fat diet blocks insulin's effects in the NAc, but insulin's effects are restored by inhibiting protein tyrosine phosphatase 1B, which supports insulin receptor signaling. Mice fed a high fat diet (60% kcals from fat) displayed significantly higher fasting blood glucose 160 mg/dL, compared to 101 mg/dL for control-diet-fed mice, and high-fat-diet-fed mice showed reduced blood glucose clearance after an intraperitoneal glucose tolerance test. Using fast scan cyclic voltammetry to measure electrically evoked dopamine in brain slices containing the NAc core, high-fat-diet-fed mice exhibited slowe...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 31, 2017
Although the dopamine transporter is the primary site of action for cocaine, and the dopamine sys... more Although the dopamine transporter is the primary site of action for cocaine, and the dopamine system is known to mediate the reinforcing and rewarding effects of cocaine, the dopaminergic variations underlying individual differences in cocaine self-administration behaviors are not fully understood. Recent advances in the application of economic principles to operant tasks in rodents have allowed for the within-subject, within-session determination of both consummatory and appetitive responding for reinforcers. Here we combined a behavioral economics approach, deemed the 'threshold procedure', with cocaine self-administration and ex vivo voltammetric recording of dopamine signaling in the core of the nucleus accumbens of rats to determine the relationship between dopamine signaling and discrete aspects of cocaine taking and seeking. We found neither dopamine release or uptake tracked individual differences in cocaine consumption or the reinforcing efficacy of cocaine. Cocaine...
The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporte... more The reinforcing efficacy of cocaine is thought to stem from inhibition of the dopamine transporter (DAT) and subsequent increases in extracellular dopamine concentrations in the brain. In humans, this hypothesis has generally been supported by positron emission tomography imaging studies where the percent of DATs occupied by cocaine is used as a measure of cocaine activity in the brain. Interpretation of these studies, however, often relies on the assumption that measures of DAT occupancy directly correspond with functional DAT blockade. In the current studies, we used in vivo and in vitro fast scan cyclic voltammetry in mice to measure dopamine uptake inhibition following varying doses of cocaine as well as two high affinity DAT inhibitors. We then compared dopamine clearance rates following these drug treatments to dopamine clearance obtained from DAT knockout mice as a proxy for complete DAT blockade. We found that administration of abused doses of cocaine resulted in approximate...
Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates bec... more Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2. We evaluated a newly developed G protein signaling-biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it pro...
The hypocretin/orexin (HCRT) system is implicated in reward and reinforcement processes through a... more The hypocretin/orexin (HCRT) system is implicated in reward and reinforcement processes through actions on the mesolimbic dopamine (DA) system. Here we provide evidence for the relationship between HCRT and DA in vivo in anesthetized and freely moving mice. The ability of cocaine to elicit reward-related behaviors in mice lacking the HCRT prepro-peptide (HCRT knock-out; KO) and wild-type controls was determined using conditioned place preference. Using a combination of microdialysis and in vivo fast scan cyclic voltammetry in anesthetized and freely moving mice, we investigated the underlying role of HCRT in the regulation of DA release and uptake. We show that, unlike wild-type mice, HCRT KO mice fail to develop characteristic conditioned place preference for cocaine. These mice also demonstrated reduced DA release and uptake under baseline conditions in both anesthetized and freely moving experiments. Further, diminished DA signaling in HCRT KO mice persists following administration of cocaine. These findings indicate that HCRT is essential for the expression of behaviors associated with the rewarding effects of cocaine, and suggest that HCRT regulation of reward and reinforcement may be related to disruptions to DA neurotransmission.
b-Phenylethylamine (b-PEA) is an endogenous amine that is found in trace amounts in the brain. It... more b-Phenylethylamine (b-PEA) is an endogenous amine that is found in trace amounts in the brain. It is believed that the locomotor-stimulating action of b-PEA, much like amphetamine, depends on its ability to increase extracellular dopamine (DA) concentrations owing to reversal of the direction of dopamine transporter (DAT)-mediated DA transport. b-PEA can also bind directly to the recently identified G protein-coupled receptors, but the physiological significance of this interaction is unclear. To assess the mechanism by which b-PEA mediates its effects, we compared the neurochemical and behavioral effects of this amine in wild type (WT), heterozygous and 'null' DAT mutant mice. In microdialysis studies, b-PEA, administered either systemically or locally via intrastriatal infusion, produced a pronounced outflow of striatal DA in WT mice whereas no increase was detected in mice lacking the DAT (DAT-KO mice). Similarly, in fast-scan voltammetry studies b-PEA did not alter DA release and clearance rate in striatal slices from DAT-KO mice. In behavioral studies b-PEA produced a robust but transient increase in locomotor activity in WT and heterozygous mice. In DAT-KO mice, whose locomotor activity and stereotypy are increased in a novel environment, b-PEA (10-100 mg/kg) exerted a potent inhibitory action. At high doses, b-PEA induced stereotypies in WT and heterozygous mice; some manifestations of stereotypy were also observed in the DAT-KO mice. These data demonstrate that the DAT is required for the striatal DA-releasing and hyperlocomotor actions of b-PEA. The inhibitory action on hyperactivity and certain stereotypies induced by b-PEA in DAT-KO mice indicate that targets other than the DAT are responsible for these effects.
The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly ... more The US Food and Drug Administration has not approved a treatment for cocaine addiction, possibly due in part to the fact that repeated cocaine use results in dysregulation of multiple neurotransmitter systems, including glutamate and dopamine, and an emergence of increased negative affective states and heightening motivation to take cocaine despite negative consequences. We used a combination therapy approach to assess whether modulation of both glutamate and dopamine transmission would reduce the motivation to self- administer cocaine compared to modulation of either system alone. The metabotropic glutamate 2/3 receptor agonist, LY379268, and the monoamine releaser, phenmetrazine, were used to assess their individual and combined ability to decrease the reinforcing efficacy of cocaine because they modulate glutamate and dopamine levels, respectively. Cocaine breakpoints and cocaine intake was assessed, using a progressive ratio schedule, at baseline in three groups based on dose of...
Regional differences in the kinetics and pharmacological inhibition of dopamine uptake were inves... more Regional differences in the kinetics and pharmacological inhibition of dopamine uptake were investigated with fast-scan cyclic voltammetry in both the intact rat brain and a brain slice preparation. The regions compared were the basolateral amygdaloid nucleus, caudate-putamen, and nucleus accumbens. The frequency dependence of dopamine efflux evoked in vivo by electrical stimulation of the medial forebrain bundle was evaluated by nonlinear curve fitting with a Michaelis-Menten-based kinetic model. The Km for dopamine uptake was found to be significantly higher in the basolateral amygdala (0.6 microM) than in the other two regions (0.2 microM), whereas the Vmax value for dopamine uptake in the basolateral amygdala was significantly lower (0.49 microM/s vs. 3.8 and 2.4 microM/s in the caudate and accumbens, respectively). Similar kinetics were also obtained in brain slices. Addition of a dopamine uptake inhibitor, cocaine or nomifensine (10 microM), to the perfusion buffer increased the apparent Km value > 25-fold in slices of both the caudate-putamen and nucleus accumbens. In contrast, neither uptake inhibitor had an observable effect in the basolateral amygdaloid nucleus. Thus, dopamine uptake in the rat brain is regionally distinct with regard to rate, affinity, and sensitivity to competitive inhibition.
Rationale Existing data strongly suggest that alcohol affects dopamine (DA) neurotransmission in ... more Rationale Existing data strongly suggest that alcohol affects dopamine (DA) neurotransmission in the brain. However, many questions remain about the effects of alcohol on the delicate equilibrium between such neurochemical processes as DA release and uptake. Dysregulation of these processes in the mesolimbic and nigrostriatal systems after chronic alcohol ingestion could be a neuroadaptation contributing to dependence. Objectives In the present study, we have employed an alcohol vapor inhalation model to characterize the effects of chronic alcohol exposure on DA dynamics in rat nucleus accumbens (NAc) and caudate putamen (CP) using fast-scan cyclic voltammetry (FSCV) in brain slices. This method provides a unique view of real-time, spatially resolved changes in DA concentration.
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Papers by Sara Jones