The functional dilatory response in the streptozotocin-induced diabetic rat was investigated usin... more The functional dilatory response in the streptozotocin-induced diabetic rat was investigated using thoracic aortas and coronary microcirculation. The aortas were cut in 4 mm intact or denuded rings and mounted into 20-ml organ baths. Coronary microcirculation was evaluated with isolated hearts perfused under constant flow conditions. Firstly, vasodilation to iloprost (Ilo) was examined. Dose-response curves to Ilo (10 pM-10 microM) on phenylephrine (PE, 30 nM for endothelium-denuded, and 0.3 microM for intact) preconstricted rings of diabetics and age-matched controls were comparable (n = 6). Decreased vasodilation in diabetic group was observed when dose-response curves to Ilo (1 nM-0.1 microM) were realized in isolated hearts (-22 +/- 3.3% vs -46 +/- 3.9%, n = 6, p < 0.05). Secondly, dose-response curves to forskolin (FSK), an adenylate-cyclase activator, performed in hearts (1 nM-3 microM), and on PE preconstricted rings (10 pM-10 microM) of diabetics and age-matched controls were comparable. Finally, the effect of an activator of ATP sensitive potassium channels (KATP), cromakalim (CMK), was evaluated in coronary circulation (0.3 nM-3 microM) and in aortas (10 pM-10 microM). Decreased vasodilation to CMK was observed in diabetic hearts (-10.5 +/- 4.3 vs -30.1 +/- 2.8%, n = 6, p < 0.05). In conclusion, under our experimental conditions, diabetes affects selectively the coronary vasodilation to iloprost. This modification of vascular reactivity may be due to a decrease of KATP channels sensitivity but not to a decreased activity of adenylate-cyclase.
Inverse incentive learning is the loss by stimuli of their ability to elicit approach and other r... more Inverse incentive learning is the loss by stimuli of their ability to elicit approach and other responses. We used c-Fos immunohistochemistry to identify brain regions associated with inverse incentive learning. Rats that had daily treatments with haloperidol (0.25mg/kg) paired with placing their forepaws on a horizontal bar elevated 10cm above the floor initially descended almost immediately but over days descent latencies grew longer, revealing inverse incentive learning. Control rats that were tested daily and received haloperidol (Unpaired group) or saline later in their home cage showed no evidence of increased descent latencies. On the final test day, all groups were tested after haloperidol and only the Paired group showed increased descent latencies. c-Fos levels in the nucleus accumbens core and ventral pallidum were lower in the Paired group than in the Unpaired and Saline groups even though all groups received haloperidol on the test day. Compared to the Saline group both the Paired and Unpaired groups showed evidence of lower c-Fos levels in the dorsal striatum and nucleus accumbens shell, possibly a result of daily haloperidol injections. No group differences in c-Fos were found in the piriform cortex, ventral hippocampus, ventral tegmental area or lateral habenula. Results reveal, by means of different patterns of c-Fos expression, brain region-specific changes in neuronal activity associated with inverse incentive learning. Results support possible underlying neuroplastic changes for learned decreases in responsivity to environmental stimuli.
The contribution of ATP-sensitive potassium channel (KATP channel) blockade in the vasoconstricti... more The contribution of ATP-sensitive potassium channel (KATP channel) blockade in the vasoconstriction produced by vasopressin was studied. All experiments were performed using rat thoracic aorta cut in 4-mm rings, denuded from their endothelium and mounted into 20-ml organ baths. Glibenclamide (0.01-10 microM), a KATP channel antagonist, did not induce any measurable contraction, nor did it reduce the maximum contraction induced by vasopressin and phenylephrine. The specific inhibition of lemakalim-induced (a KATP channel activator) relaxation by vasopressin was investigated. Lemakalim (0.01-0.3 microM) relaxed both vasopressin (0.1 microM) and phenylephrine (0.3 microM) preconstricted vessels. However, in contrast to what would be expected from KATP blockade by vasopressin, rings preconstricted with vasopressin were more sensitive to the relaxant action of lemakalim, compared to phenylephrine preconstricted vessels (log[EC50] of -7.82 +/- 0.01 and -7.10 +/- 0.02, respectively, p < 0.05). Dose-response curves to papaverine (3-30 microM) in rings preconstricted with vasopressin and phenylephrine were comparable. When aortic rings were pretreated with lemakalim (0.1 microM), the maximum active tension induced by vasopressin was reduced (2.68 +/- 0.23 in control conditions vs. 0.62 +/- 0.08 g on pretreated vessels, p < 0.001), whereas that by phenylephrine was slightly increased. In order to explain the stronger relaxant action of lemakalim against vasopressin-induced constriction, the contribution of calcium influx through L-type calcium channels in the constriction of aortic rings to vasopressin and phenylephrine was compared.(ABSTRACT TRUNCATED AT 250 WORDS)
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2011
Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes i... more Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes in the dopamine (DA) system. However, it is not known whether these changes are directly related to drug-driven behaviors or whether they simply are adaptive responses to long-term drug exposure. Here, we combined the rat model of cocaine self-administration with brain slice electrophysiology to identify drug-use related alterations in the neuromodulatory effects of DA in the oval bed nucleus of the stria terminalis (ovBST), a robust DA terminal field. Long-Evans rats self-administered cocaine intravenously (0.75 mg/kg/injection) for an average of 15 d, on reward-lean or -rich schedules of reinforcement. Brain slice recordings conducted 20 h after the last self-administration session revealed a reversal of the neuromodulatory effect of DA on GABA(A)-IPSCs. Specifically, the effect of DA switched from a D2-mediated decrease in drug-naive rats to a D1-receptor-mediated increase in GABA(A)-I...
The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala... more The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala, a forebrain macrostructure with extensive projection to motor nuclei of the hindbrain. The subnuclei of the BST coordinate autonomic, neuroendocrine, and somato-motor functions and receive robust neuromodulatory monoaminergic afferents, including 5-HT-, noradrenaline (NA)-, and dopamine (DA)-containing terminals. In contrast to 5-HT and NA, little is known about how DA modulates neuronal activity or synaptic transmission in the BST. DA-containing afferents to the BST originate in the ventral tegmental area, the periaqueducal gray, and the retrorubral field. They form a fairly diffuse input to the dorsolateral BST with dense terminal fields in the oval (ovBST) and juxtacapsular (jxBST) nuclei. The efferent-afferent connectivity of the BST suggests that it may play a key role in motivated behaviors, consistent with recent evidence that the dorsolateral BST is a target for drugs of abuse. This study describes the effects of DA on synaptic transmission in the ovBST. Whole cell voltage clamp recordings were performed on ovBST neurons in brain slices from adult rats in the presence or absence of exogenous DA and receptor-targeted agonists and antagonists. The results showed that DA selectively and exclusively reduced inhibitory synaptic transmission in the ovBST in a dose-dependent and D2-like dopamine receptor-dependent manner. DA also modulated excitatory synaptic transmission in a dose-dependent dependent manner. However, this effect was mediated by α2-noradrenergic receptors. Thus these data reveal a double dissociation in catecholaminergic regulation of excitatory and inhibitory synaptic transmission in the ovBST and may shed light on the mechanisms involved in neuropathological behaviors such as stress-induced relapse to consumption of drugs of abuse.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
The lateral amygdaloid (LA) nucleus is the main input station of the amygdala for sensory afferen... more The lateral amygdaloid (LA) nucleus is the main input station of the amygdala for sensory afferents. However, it is unclear how the lateral nucleus transforms these inputs, because its intrinsic connectivity is poorly understood. Here, we took advantage of the fact that glutamatergic neurons of the lateral nucleus send a primarily unidirectional projection to the basomedial nucleus. Consequently, it was possible to infer the targets of their intranuclear axons (projection cells vs inhibitory interneurons) by backfiring some projection neurons from the basomedial nucleus and analyzing evoked responses in other LA projection cells. Basomedial stimuli evoked markedly different synaptic responses depending on the orientation of the slices. In coronal slices (intact and decorticated), the prevalent response of LA neurons was an inhibition, regardless of the stimulation intensity. This inhibition was sensitive to GABA(A) and non-NMDA receptor antagonists, suggesting that it was mediated b...
Progress in neuro-psychopharmacology & biological psychiatry, Jan 27, 2015
Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phe... more Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phenotypic learning traits representative of neural circuitry that underlies SIP and hypothesized that rats that are response-learners will be more susceptible in developing compulsive water drinking. Using the Y-maze, the rats were characterized as either place- or response-learners. They were exposed to the SIP protocol for a period of 21days. Subsequent histological staining for FosB/ΔFosB examined neuronal activation associated with SIP in several brain regions. The rats with a preference for a response-learning strategy were more likely to develop SIP than the rats using a place-learning strategy. Furthermore amphetamine sensitization, observed to increase SIP, also shifted learning strategy to a response-learning strategy. No differences were observed in FosB/ΔFosB expression between SIP and non-SIP rats in the dorsolateral striatum (DLS) and CA1 region of the hippocampus. However, SI...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational br... more Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) ...
Impulse control is an executive process that allows animals to inhibit their actions until an app... more Impulse control is an executive process that allows animals to inhibit their actions until an appropriate time. Previously, we reported that learning a simple response inhibition task increases AMPA currents at excitatory synapses in the prelimbic region of the medial prefrontal cortex (mPFC). Here, we examined whether modifications to intrinsic excitability occurred alongside the synaptic changes. To that end, we trained rats to obtain a food reward in a response inhibition task by withhold responding on a lever until they were signaled to respond. We then measured excitability, using whole-cell patch clamp recordings in brain slices, by quantifying action potentials generated by the injection of depolarizing current steps. Training in this task depressed the excitability of layer V pyramidal neurons of the prelimbic, but not infralimbic, region of the mPFC relative to behavioral controls. This decrease in maximum spiking frequency was significantly correlated with performance on the final session of the task. This change in intrinsic excitability may represent a homeostatic mechanism counterbalancing increased excitatory synaptic inputs onto those neurons in trained rats. Interestingly, subjects trained with a cue that predicted imminent reward availability had increased excitability in infralimbic, but not the prelimbic, pyramidal neurons. This dissociation suggests that both prelimbic and infralimbic neurons are involved in directing action, but specialized for different types of information, inhibitory or anticipatory, respectively.
The functional dilatory response in the streptozotocin-induced diabetic rat was investigated usin... more The functional dilatory response in the streptozotocin-induced diabetic rat was investigated using thoracic aortas and coronary microcirculation. The aortas were cut in 4 mm intact or denuded rings and mounted into 20-ml organ baths. Coronary microcirculation was evaluated with isolated hearts perfused under constant flow conditions. Firstly, vasodilation to iloprost (Ilo) was examined. Dose-response curves to Ilo (10 pM-10 microM) on phenylephrine (PE, 30 nM for endothelium-denuded, and 0.3 microM for intact) preconstricted rings of diabetics and age-matched controls were comparable (n = 6). Decreased vasodilation in diabetic group was observed when dose-response curves to Ilo (1 nM-0.1 microM) were realized in isolated hearts (-22 +/- 3.3% vs -46 +/- 3.9%, n = 6, p < 0.05). Secondly, dose-response curves to forskolin (FSK), an adenylate-cyclase activator, performed in hearts (1 nM-3 microM), and on PE preconstricted rings (10 pM-10 microM) of diabetics and age-matched controls were comparable. Finally, the effect of an activator of ATP sensitive potassium channels (KATP), cromakalim (CMK), was evaluated in coronary circulation (0.3 nM-3 microM) and in aortas (10 pM-10 microM). Decreased vasodilation to CMK was observed in diabetic hearts (-10.5 +/- 4.3 vs -30.1 +/- 2.8%, n = 6, p < 0.05). In conclusion, under our experimental conditions, diabetes affects selectively the coronary vasodilation to iloprost. This modification of vascular reactivity may be due to a decrease of KATP channels sensitivity but not to a decreased activity of adenylate-cyclase.
Inverse incentive learning is the loss by stimuli of their ability to elicit approach and other r... more Inverse incentive learning is the loss by stimuli of their ability to elicit approach and other responses. We used c-Fos immunohistochemistry to identify brain regions associated with inverse incentive learning. Rats that had daily treatments with haloperidol (0.25mg/kg) paired with placing their forepaws on a horizontal bar elevated 10cm above the floor initially descended almost immediately but over days descent latencies grew longer, revealing inverse incentive learning. Control rats that were tested daily and received haloperidol (Unpaired group) or saline later in their home cage showed no evidence of increased descent latencies. On the final test day, all groups were tested after haloperidol and only the Paired group showed increased descent latencies. c-Fos levels in the nucleus accumbens core and ventral pallidum were lower in the Paired group than in the Unpaired and Saline groups even though all groups received haloperidol on the test day. Compared to the Saline group both the Paired and Unpaired groups showed evidence of lower c-Fos levels in the dorsal striatum and nucleus accumbens shell, possibly a result of daily haloperidol injections. No group differences in c-Fos were found in the piriform cortex, ventral hippocampus, ventral tegmental area or lateral habenula. Results reveal, by means of different patterns of c-Fos expression, brain region-specific changes in neuronal activity associated with inverse incentive learning. Results support possible underlying neuroplastic changes for learned decreases in responsivity to environmental stimuli.
The contribution of ATP-sensitive potassium channel (KATP channel) blockade in the vasoconstricti... more The contribution of ATP-sensitive potassium channel (KATP channel) blockade in the vasoconstriction produced by vasopressin was studied. All experiments were performed using rat thoracic aorta cut in 4-mm rings, denuded from their endothelium and mounted into 20-ml organ baths. Glibenclamide (0.01-10 microM), a KATP channel antagonist, did not induce any measurable contraction, nor did it reduce the maximum contraction induced by vasopressin and phenylephrine. The specific inhibition of lemakalim-induced (a KATP channel activator) relaxation by vasopressin was investigated. Lemakalim (0.01-0.3 microM) relaxed both vasopressin (0.1 microM) and phenylephrine (0.3 microM) preconstricted vessels. However, in contrast to what would be expected from KATP blockade by vasopressin, rings preconstricted with vasopressin were more sensitive to the relaxant action of lemakalim, compared to phenylephrine preconstricted vessels (log[EC50] of -7.82 +/- 0.01 and -7.10 +/- 0.02, respectively, p < 0.05). Dose-response curves to papaverine (3-30 microM) in rings preconstricted with vasopressin and phenylephrine were comparable. When aortic rings were pretreated with lemakalim (0.1 microM), the maximum active tension induced by vasopressin was reduced (2.68 +/- 0.23 in control conditions vs. 0.62 +/- 0.08 g on pretreated vessels, p < 0.001), whereas that by phenylephrine was slightly increased. In order to explain the stronger relaxant action of lemakalim against vasopressin-induced constriction, the contribution of calcium influx through L-type calcium channels in the constriction of aortic rings to vasopressin and phenylephrine was compared.(ABSTRACT TRUNCATED AT 250 WORDS)
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 15, 2011
Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes i... more Chronic exposure to drugs of abuse alters brain reward circuits and produces functional changes in the dopamine (DA) system. However, it is not known whether these changes are directly related to drug-driven behaviors or whether they simply are adaptive responses to long-term drug exposure. Here, we combined the rat model of cocaine self-administration with brain slice electrophysiology to identify drug-use related alterations in the neuromodulatory effects of DA in the oval bed nucleus of the stria terminalis (ovBST), a robust DA terminal field. Long-Evans rats self-administered cocaine intravenously (0.75 mg/kg/injection) for an average of 15 d, on reward-lean or -rich schedules of reinforcement. Brain slice recordings conducted 20 h after the last self-administration session revealed a reversal of the neuromodulatory effect of DA on GABA(A)-IPSCs. Specifically, the effect of DA switched from a D2-mediated decrease in drug-naive rats to a D1-receptor-mediated increase in GABA(A)-I...
The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala... more The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala, a forebrain macrostructure with extensive projection to motor nuclei of the hindbrain. The subnuclei of the BST coordinate autonomic, neuroendocrine, and somato-motor functions and receive robust neuromodulatory monoaminergic afferents, including 5-HT-, noradrenaline (NA)-, and dopamine (DA)-containing terminals. In contrast to 5-HT and NA, little is known about how DA modulates neuronal activity or synaptic transmission in the BST. DA-containing afferents to the BST originate in the ventral tegmental area, the periaqueducal gray, and the retrorubral field. They form a fairly diffuse input to the dorsolateral BST with dense terminal fields in the oval (ovBST) and juxtacapsular (jxBST) nuclei. The efferent-afferent connectivity of the BST suggests that it may play a key role in motivated behaviors, consistent with recent evidence that the dorsolateral BST is a target for drugs of abuse. This study describes the effects of DA on synaptic transmission in the ovBST. Whole cell voltage clamp recordings were performed on ovBST neurons in brain slices from adult rats in the presence or absence of exogenous DA and receptor-targeted agonists and antagonists. The results showed that DA selectively and exclusively reduced inhibitory synaptic transmission in the ovBST in a dose-dependent and D2-like dopamine receptor-dependent manner. DA also modulated excitatory synaptic transmission in a dose-dependent dependent manner. However, this effect was mediated by α2-noradrenergic receptors. Thus these data reveal a double dissociation in catecholaminergic regulation of excitatory and inhibitory synaptic transmission in the ovBST and may shed light on the mechanisms involved in neuropathological behaviors such as stress-induced relapse to consumption of drugs of abuse.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2003
The lateral amygdaloid (LA) nucleus is the main input station of the amygdala for sensory afferen... more The lateral amygdaloid (LA) nucleus is the main input station of the amygdala for sensory afferents. However, it is unclear how the lateral nucleus transforms these inputs, because its intrinsic connectivity is poorly understood. Here, we took advantage of the fact that glutamatergic neurons of the lateral nucleus send a primarily unidirectional projection to the basomedial nucleus. Consequently, it was possible to infer the targets of their intranuclear axons (projection cells vs inhibitory interneurons) by backfiring some projection neurons from the basomedial nucleus and analyzing evoked responses in other LA projection cells. Basomedial stimuli evoked markedly different synaptic responses depending on the orientation of the slices. In coronal slices (intact and decorticated), the prevalent response of LA neurons was an inhibition, regardless of the stimulation intensity. This inhibition was sensitive to GABA(A) and non-NMDA receptor antagonists, suggesting that it was mediated b...
Progress in neuro-psychopharmacology & biological psychiatry, Jan 27, 2015
Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phe... more Schedule-induced polydipsia (SIP) is excessive, non-regulatory drinking. We aimed to identify phenotypic learning traits representative of neural circuitry that underlies SIP and hypothesized that rats that are response-learners will be more susceptible in developing compulsive water drinking. Using the Y-maze, the rats were characterized as either place- or response-learners. They were exposed to the SIP protocol for a period of 21days. Subsequent histological staining for FosB/ΔFosB examined neuronal activation associated with SIP in several brain regions. The rats with a preference for a response-learning strategy were more likely to develop SIP than the rats using a place-learning strategy. Furthermore amphetamine sensitization, observed to increase SIP, also shifted learning strategy to a response-learning strategy. No differences were observed in FosB/ΔFosB expression between SIP and non-SIP rats in the dorsolateral striatum (DLS) and CA1 region of the hippocampus. However, SI...
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2015
Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational br... more Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) ...
Impulse control is an executive process that allows animals to inhibit their actions until an app... more Impulse control is an executive process that allows animals to inhibit their actions until an appropriate time. Previously, we reported that learning a simple response inhibition task increases AMPA currents at excitatory synapses in the prelimbic region of the medial prefrontal cortex (mPFC). Here, we examined whether modifications to intrinsic excitability occurred alongside the synaptic changes. To that end, we trained rats to obtain a food reward in a response inhibition task by withhold responding on a lever until they were signaled to respond. We then measured excitability, using whole-cell patch clamp recordings in brain slices, by quantifying action potentials generated by the injection of depolarizing current steps. Training in this task depressed the excitability of layer V pyramidal neurons of the prelimbic, but not infralimbic, region of the mPFC relative to behavioral controls. This decrease in maximum spiking frequency was significantly correlated with performance on the final session of the task. This change in intrinsic excitability may represent a homeostatic mechanism counterbalancing increased excitatory synaptic inputs onto those neurons in trained rats. Interestingly, subjects trained with a cue that predicted imminent reward availability had increased excitability in infralimbic, but not the prelimbic, pyramidal neurons. This dissociation suggests that both prelimbic and infralimbic neurons are involved in directing action, but specialized for different types of information, inhibitory or anticipatory, respectively.
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Papers by Eric C Dumont