The hyperalgesic properties of the emetic drug lithium chloride (LiCl) were examined in eight exp... more The hyperalgesic properties of the emetic drug lithium chloride (LiCl) were examined in eight experiments. At a dose of 63.6 mg/kg, LiCl produced hyperalgesia in the radiant-heat (Experiment 1a) and immersion (Experiment 1b) tail-flick tests.
Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by... more Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed signiĒcant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal).
A flavor paired with morphine shifted to the right the function relating morphine dose to tail-fl... more A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms.
Abstract—We used an ABA renewal design to study the neural correlates, and role of D1 dopamine re... more Abstract—We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished alcohol-seeking. Rats were trained to respond for 4% beer in one context (A), extinguished in a different (B) context, and then tested for responding in the original training context (A) or the extinction context (B). ABA renewal was mediated by D1 dopamine receptors because it was prevented by SCH23390.
Abstract. Rationale: Pavlovian conditioning processes have been accorded an important role in mai... more Abstract. Rationale: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal.
Abstract—Contexts play an important role in controlling the expression of extinguished behaviors.... more Abstract—Contexts play an important role in controlling the expression of extinguished behaviors. We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished instrumental responding. Rats were trained to respond for a sucrose reward in one context (A). Responding was then extinguished in the same (A) or different (B) context. Rats were tested for responding in the original training context (A).
Abstract—Rats were trained to self-administer cocaine in a distinctive context (context A). They ... more Abstract—Rats were trained to self-administer cocaine in a distinctive context (context A). They were then extinguished in a second context (context B) prior to test for cocaineseeking in the original training context, context A (group ABA), context B (group ABB) or no test (group AB0). Group ABA showed renewal of extinguished cocaine-seeking associated with c-Fos induction in basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex.
Sensitivity to noxious stimulation is not invariant; rather, it is modulated by discrete pain inh... more Sensitivity to noxious stimulation is not invariant; rather, it is modulated by discrete pain inhibitory and facilitatory circuits. This paper reviews the neural circuits for pain facilitation, describes the conditions governing their environmental activation, and examines their role in an animal's behavioral repertoire. Mechanisms for pain facilitation are contrasted at both the neural and behavioral level with mechanisms for pain inhibition.
Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear condit... more Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB 3 CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl-D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error.
Extinction is the reduction in drug seeking when the contingency between drug seeking behavior an... more Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B). Rats were subsequently tested in the training context, A (ABA), or the extinction context, B (ABB). Pre-test injections of the glutamate AMPA receptor antagonist, NBQX (1 µg) into AcbSh had no effect on renewal of alcoholic beer seeking when rats were returned to the training context (ABA). However, NBQX increased responding when rats were tested in the extinction context (ABB). In a second experiment, rats received training, extinction, and test in the same context. Pre-test injections of NBQX (0, 0.3, and 1 µg) into the AcbSh dose-dependently attenuated expression of extinction. We also found that NBQX in the AcbSh had no effect on initial acquisition of extinction or the motivation to respond for reward as measured by break point on a progressive ratio schedule. Finally, we show that pharmacological disconnection of a basolateral amygdala (BLA) → AcbSh pathway via NBQX in AcbSh combined with reversible inactivation of the contralateral BLA attenuates expression of extinction. Together, these results suggest that AcbSh AMPA receptors mediate expression of extinguished reward seeking through glutamatergic inputs from the BLA.
Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review r... more Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review recent electrophysiological, molecular and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray region, can be linked to prediction error and expectation modulation of fear learning, as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signaling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit might represent a conserved mechanism for regulating fear learning in mammals.
The hypothalamus is a neural structure critical for expression of motivated behaviours that ensur... more The hypothalamus is a neural structure critical for expression of motivated behaviours that ensure survival of the individual and the species. It is a heterogeneous structure, generally recognised to have four distinct regions in the rostrocaudal axis (preoptic, supraoptic, tuberal and mammillary). The tuberal hypothalamus in particular has been implicated in the neural control of appetitive motivation, including feeding and drug seeking. Here we review the role of the tuberal hypothalamus in appetitive motivation. First, we review evidence that different regions of the hypothalamus exert opposing control over feeding. We then review evidence that a similar bi-directional regulation characterises hypothalamic contributions to drug seeking and reward seeking. Lateral regions of the dorsal tuberal hypothalamus are important for promoting reinstatement of drug seeking, whereas medial regions of the dorsal tuberal hypothalamus are important for inhibiting this drug seeking after extinction training. Finally, we review evidence that these different roles for medial versus lateral dorsal tuberal hypothalamus in promoting or preventing reinstatement of drug seeking are mediated, at least in part, by different populations of hypothalamic neurons as well as the neural circuits in which they are located.
Extinction promotes abstinence from drug seeking. Extinction expression is an active process, dep... more Extinction promotes abstinence from drug seeking. Extinction expression is an active process, dependent on infralimbic prefrontal cortex (ilPFC). However, the neurocircuitry mediating extinction expression is unknown. Here we studied the neural mechanisms for expression of extinction of alcoholic beer seeking in rats. We first examined the pattern of activation in prefrontal cortex projections to medial dorsal hypothalamus (MDH) (i.e., perifornical and dorsomedial nuclei) during extinction expression. Double labeling for retrograde tracer cholera toxin B subunit (CTb) and the neuronal activity marker c-Fos revealed significant recruitment of MDH projecting ilPFC neurons during extinction expression. We then studied the causal role of MDH in inhibiting alcoholic beer seeking during extinction expression. MDH infusion of the inhibitory neuropeptide cocaine-and amphetamine-regulated transcript prevented extinction expression, showing that MDH is necessary for extinction expression. Next we examined the pattern of activation in MDH projections to paraventricular thalamus (PVT) during extinction expression. Double labeling for CTb and c-Fos revealed significant recruitment of PVT projecting MDH neurons during extinction expression. We also showed, using triple-label immunofluorescence, that the majority of PVT projecting extinction neurons express prodynorphin, suggesting that actions at opioid receptors (KORs) in PVT may be critical for inhibiting alcoholic beer seeking. Consistent with this, infusions of a KOR agonist into PVT prevented reinstatement of alcoholic beer seeking showing that PVT KOR activation is sufficient to inhibit alcoholic beer seeking. Together, these findings identify a role for MDH and its ilPFC afferents and PVT efferents in inhibiting alcoholic beer seeking during extinction expression.
Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinc... more Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinction of drug seeking are poorly understood but are of significant interest because of their potential to identify novel approaches that promote abstinence from drug taking. Here we review recent literature on the neural mechanisms for extinction in drug self-administration paradigms. First, we consider the brain regions important for extinction of drug seeking. Functional inactivation studies have identified infralimbic prefrontal cortex, nucleus accumbens shell, as well as medial dorsal hypothalamus in the expression of extinction of drug seeking. These structures have been implicated in extinction expression across several reinforcers including cocaine, heroin, and alcohol. Second, we consider molecular studies which show that extinction training is associated with plasticity in glutamatergic signaling in both nucleus accumbens shell and core, and that this training may reverse or ameliorate the neuroadaptations produced by chronic drug exposure and spontaneous withdrawal. Finally, we consider the neural circuitry for extinction of drug seeking. Functional disconnection and neuroanatomical tracing studies show that extinction expression depends, at least in part, on cortico-striatal-hypothalamic and cortico-hypothalalmic-thalamic pathways. Moreover, they indicate that the expression of extinction and reinstatement of drug seeking may depend on parallel pathways that converge within lateral hypothalamus and paraventricular thalamus. (G.P. McNally).
... Friday, May 27 (Ballroom D): Alliston Reid Wofford College President&am... more ... Friday, May 27 (Ballroom D): Alliston Reid Wofford College President's Introduction. Special Section on Extinction K. Matthew Lattal Oregon Health & Science University - Extinction and behavior: What are we modeling and how do we do it? ...
The hyperalgesic properties of the emetic drug lithium chloride (LiCl) were examined in eight exp... more The hyperalgesic properties of the emetic drug lithium chloride (LiCl) were examined in eight experiments. At a dose of 63.6 mg/kg, LiCl produced hyperalgesia in the radiant-heat (Experiment 1a) and immersion (Experiment 1b) tail-flick tests.
Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by... more Rats undergoing opiate withdrawal displayed clear behavioral and autonomic changes accompanied by hyperalgesia and increased plasma corticosterone. In situ hybridization of CRH mRNA revealed signiĒcant increases in the central nucleus of the amygdala but not in the bed nucleus of the stria terminalis among rats either chronically pre-treated with morphine, given an injection of naloxone, or both (precipitated withdrawal).
A flavor paired with morphine shifted to the right the function relating morphine dose to tail-fl... more A flavor paired with morphine shifted to the right the function relating morphine dose to tail-flick latencies and provoked hyperalgesic responses when rats were tested in the absence of morphine. These learned increases in nociceptive sensitivity were not mediated by alterations in tail-skin temperature. Microinjection of the competitive N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphonopentanoic acid (AP-5) into the lateral ventricle reversed the hyperalgesic responses but spared the tolerance to morphine analgesia. By contrast, systemic administration of the noncompetitive NMDA receptor antagonist MK-801 or intrathecal infusion of AP-5 reversed the hyperalgesic responses as well as the tolerance to morphine analgesia. The results demonstrate that associatively mediated tolerance to morphine analgesia can co-occur with hyperalgesic responses and are discussed relative to learned activation of endogenous pronociceptive mechanisms.
Abstract—We used an ABA renewal design to study the neural correlates, and role of D1 dopamine re... more Abstract—We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished alcohol-seeking. Rats were trained to respond for 4% beer in one context (A), extinguished in a different (B) context, and then tested for responding in the original training context (A) or the extinction context (B). ABA renewal was mediated by D1 dopamine receptors because it was prevented by SCH23390.
Abstract. Rationale: Pavlovian conditioning processes have been accorded an important role in mai... more Abstract. Rationale: Pavlovian conditioning processes have been accorded an important role in maintaining persistent opiate administration. At least one locus for this contribution is during opiate withdrawal. These experiments studied the contribution of Pavlovian conditioning processes to morphine withdrawal.
Abstract—Contexts play an important role in controlling the expression of extinguished behaviors.... more Abstract—Contexts play an important role in controlling the expression of extinguished behaviors. We used an ABA renewal design to study the neural correlates, and role of D1 dopamine receptors, in contextual control over extinguished instrumental responding. Rats were trained to respond for a sucrose reward in one context (A). Responding was then extinguished in the same (A) or different (B) context. Rats were tested for responding in the original training context (A).
Abstract—Rats were trained to self-administer cocaine in a distinctive context (context A). They ... more Abstract—Rats were trained to self-administer cocaine in a distinctive context (context A). They were then extinguished in a second context (context B) prior to test for cocaineseeking in the original training context, context A (group ABA), context B (group ABB) or no test (group AB0). Group ABA showed renewal of extinguished cocaine-seeking associated with c-Fos induction in basolateral amygdala, lateral hypothalamus, and infralimbic prefrontal cortex.
Sensitivity to noxious stimulation is not invariant; rather, it is modulated by discrete pain inh... more Sensitivity to noxious stimulation is not invariant; rather, it is modulated by discrete pain inhibitory and facilitatory circuits. This paper reviews the neural circuits for pain facilitation, describes the conditions governing their environmental activation, and examines their role in an animal's behavioral repertoire. Mechanisms for pain facilitation are contrasted at both the neural and behavioral level with mechanisms for pain inhibition.
Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear condit... more Three experiments studied temporal-difference (TD) prediction errors during Pavlovian fear conditioning. In Stage I, rats received conditioned stimulus A (CSA) paired with shock. In Stage II, they received pairings of CSA and CSB with shock that blocked learning to CSB. In Stage III, a serial overlapping compound, CSB 3 CSA, was followed by shock. The change in intratrial durations supported fear learning to CSB but reduced fear of CSA, revealing the operation of TD prediction errors. N-methyl-D-aspartate (NMDA) receptor antagonism prior to Stage III prevented learning, whereas opioid receptor antagonism selectively affected predictive learning. These findings support a role for TD prediction errors in fear conditioning. They suggest that NMDA receptors contribute to fear learning by acting on the product of predictive error, whereas opioid receptors contribute to predictive error.
Extinction is the reduction in drug seeking when the contingency between drug seeking behavior an... more Extinction is the reduction in drug seeking when the contingency between drug seeking behavior and the delivery of drug reward is broken. Here, we investigated a role for the nucleus accumbens shell (AcbSh). Rats were trained to respond for 4% (v/v) alcoholic beer in one context (Context A) followed by extinction in a second context (Context B). Rats were subsequently tested in the training context, A (ABA), or the extinction context, B (ABB). Pre-test injections of the glutamate AMPA receptor antagonist, NBQX (1 µg) into AcbSh had no effect on renewal of alcoholic beer seeking when rats were returned to the training context (ABA). However, NBQX increased responding when rats were tested in the extinction context (ABB). In a second experiment, rats received training, extinction, and test in the same context. Pre-test injections of NBQX (0, 0.3, and 1 µg) into the AcbSh dose-dependently attenuated expression of extinction. We also found that NBQX in the AcbSh had no effect on initial acquisition of extinction or the motivation to respond for reward as measured by break point on a progressive ratio schedule. Finally, we show that pharmacological disconnection of a basolateral amygdala (BLA) → AcbSh pathway via NBQX in AcbSh combined with reversible inactivation of the contralateral BLA attenuates expression of extinction. Together, these results suggest that AcbSh AMPA receptors mediate expression of extinguished reward seeking through glutamatergic inputs from the BLA.
Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review r... more Pavlovian fear conditioning depends on synaptic plasticity at amygdala neurons. Here, we review recent electrophysiological, molecular and behavioral evidence suggesting the existence of a distributed neural circuitry regulating amygdala synaptic plasticity during fear learning. This circuitry, which involves projections from the midbrain periaqueductal gray region, can be linked to prediction error and expectation modulation of fear learning, as described by associative and computational learning models. It controls whether, and how much, fear learning occurs by signaling aversive events when they are unexpected. Functional neuroimaging and clinical studies indicate that this prediction circuit is recruited in humans during fear learning and contributes to exposure-based treatments for clinical anxiety. This aversive prediction error circuit might represent a conserved mechanism for regulating fear learning in mammals.
The hypothalamus is a neural structure critical for expression of motivated behaviours that ensur... more The hypothalamus is a neural structure critical for expression of motivated behaviours that ensure survival of the individual and the species. It is a heterogeneous structure, generally recognised to have four distinct regions in the rostrocaudal axis (preoptic, supraoptic, tuberal and mammillary). The tuberal hypothalamus in particular has been implicated in the neural control of appetitive motivation, including feeding and drug seeking. Here we review the role of the tuberal hypothalamus in appetitive motivation. First, we review evidence that different regions of the hypothalamus exert opposing control over feeding. We then review evidence that a similar bi-directional regulation characterises hypothalamic contributions to drug seeking and reward seeking. Lateral regions of the dorsal tuberal hypothalamus are important for promoting reinstatement of drug seeking, whereas medial regions of the dorsal tuberal hypothalamus are important for inhibiting this drug seeking after extinction training. Finally, we review evidence that these different roles for medial versus lateral dorsal tuberal hypothalamus in promoting or preventing reinstatement of drug seeking are mediated, at least in part, by different populations of hypothalamic neurons as well as the neural circuits in which they are located.
Extinction promotes abstinence from drug seeking. Extinction expression is an active process, dep... more Extinction promotes abstinence from drug seeking. Extinction expression is an active process, dependent on infralimbic prefrontal cortex (ilPFC). However, the neurocircuitry mediating extinction expression is unknown. Here we studied the neural mechanisms for expression of extinction of alcoholic beer seeking in rats. We first examined the pattern of activation in prefrontal cortex projections to medial dorsal hypothalamus (MDH) (i.e., perifornical and dorsomedial nuclei) during extinction expression. Double labeling for retrograde tracer cholera toxin B subunit (CTb) and the neuronal activity marker c-Fos revealed significant recruitment of MDH projecting ilPFC neurons during extinction expression. We then studied the causal role of MDH in inhibiting alcoholic beer seeking during extinction expression. MDH infusion of the inhibitory neuropeptide cocaine-and amphetamine-regulated transcript prevented extinction expression, showing that MDH is necessary for extinction expression. Next we examined the pattern of activation in MDH projections to paraventricular thalamus (PVT) during extinction expression. Double labeling for CTb and c-Fos revealed significant recruitment of PVT projecting MDH neurons during extinction expression. We also showed, using triple-label immunofluorescence, that the majority of PVT projecting extinction neurons express prodynorphin, suggesting that actions at opioid receptors (KORs) in PVT may be critical for inhibiting alcoholic beer seeking. Consistent with this, infusions of a KOR agonist into PVT prevented reinstatement of alcoholic beer seeking showing that PVT KOR activation is sufficient to inhibit alcoholic beer seeking. Together, these findings identify a role for MDH and its ilPFC afferents and PVT efferents in inhibiting alcoholic beer seeking during extinction expression.
Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinc... more Drug seeking behavior can be reduced or inhibited via extinction. The brain mechanisms for extinction of drug seeking are poorly understood but are of significant interest because of their potential to identify novel approaches that promote abstinence from drug taking. Here we review recent literature on the neural mechanisms for extinction in drug self-administration paradigms. First, we consider the brain regions important for extinction of drug seeking. Functional inactivation studies have identified infralimbic prefrontal cortex, nucleus accumbens shell, as well as medial dorsal hypothalamus in the expression of extinction of drug seeking. These structures have been implicated in extinction expression across several reinforcers including cocaine, heroin, and alcohol. Second, we consider molecular studies which show that extinction training is associated with plasticity in glutamatergic signaling in both nucleus accumbens shell and core, and that this training may reverse or ameliorate the neuroadaptations produced by chronic drug exposure and spontaneous withdrawal. Finally, we consider the neural circuitry for extinction of drug seeking. Functional disconnection and neuroanatomical tracing studies show that extinction expression depends, at least in part, on cortico-striatal-hypothalamic and cortico-hypothalalmic-thalamic pathways. Moreover, they indicate that the expression of extinction and reinstatement of drug seeking may depend on parallel pathways that converge within lateral hypothalamus and paraventricular thalamus. (G.P. McNally).
... Friday, May 27 (Ballroom D): Alliston Reid Wofford College President&am... more ... Friday, May 27 (Ballroom D): Alliston Reid Wofford College President's Introduction. Special Section on Extinction K. Matthew Lattal Oregon Health & Science University - Extinction and behavior: What are we modeling and how do we do it? ...
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