The Asp40 mu-opioid receptor allele does not predict naltrexone treatment efficacy in heavy drinkers.
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Adult↗
Biomedical subjects
Howard L Fields
Publications and source records attributed to Howard L Fields.
Cholecystokinin is necessary for the expression of morphine conditioned place preference.
There is evidence that the neuropeptide cholecystokinin (CCK) is important for the rewarding effects of drugs of abuse. However, less is known regarding the role of CCK in drug seeking and craving. The present study investigated whether the CCK(B) antagonist L-365, 260 could block morphine-induced drug seeking using the conditioned place preference paradigm and whether the dopaminergic reward pathway contributes to the effect of L-365, 260 on expression of morphine place preference. We found that systemic administration of the CCK(B) antagonist L-365, 260 attenuates the expression of morphine-induced drug seeking as assessed using conditioned place preference (CPP) and shows that this effect is mediated by CCK(B) receptors in the anterior nucleus accumbens (NAcc). Additionally, we demonstrate that this effect is dependent on D(2) receptor activation in the anterior nucleus accumbens (NAcc). These results indicate that endogenous CCK modulates the incentive-salience of morphine-associated cues and suggest that CCK antagonists may be useful in the treatment of drug craving.
Animals↗
How prior reward experience biases exploratory movements: a probabilistic model.
Animals return to rewarded locations. An example of this is conditioned place preference (CPP), which is widely used in studies of drug reward. Although CPP is expressed as increased time spent in a previously rewarded location, the behavioral strategy underlying this change is unknown. We continuously monitored rats (n = 22) in a three-room in-line configuration, before and after morphine conditioning in one end room. Although sequential room visit durations were variable, their probability distribution was exponential, indicating that the processes controlling visit durations can be modeled by instantaneous room exit probabilities. Further analysis of room transitions and computer simulations of probabilistic models revealed that the exploratory bias toward the morphine room is best explained by an increase in the probability of a subset of rapid, direct transitions from the saline- to the morphine-paired room by the central room. This finding sharply delineates and constrains possible neural mechanisms for a class of self-initiated, goal-directed behaviors toward previously rewarded locations.
Analgesics, Opioid↗
Rat nucleus accumbens neurons persistently encode locations associated with morphine reward.
When rats and mice are free to explore a familiar environment they spend more time in a previously rewarded location. This conditioned place preference (CPP) results from an increased probability of initiating transitions from an unrewarded location to one previously paired with reward. We recorded nucleus accumbens (NAc) neurons while rats explored a three-room in-line apparatus. Before place conditioning, approximately equal proportions of NAc neurons show excitations or inhibitions when the rat is in each of the rooms (morphine paired, center or saline paired). Conditioning increased the proportion of neurons inhibited while the rat was in the morphine room and neurons excited in the saline room. Many of the neurons in these two groups responded during room transitions. Furthermore, the postconditioning increase in the population of neurons with room-selective responding persisted for several weeks after the last morphine treatment. This long-lasting change in population responses of NAc neurons to initially neutral locations is a neural correlate of the change in location preference manifest as CPP.
Action Potentials↗
Endogenous opioid blockade and impulsive responding in alcoholics and healthy controls.
The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug's effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX's effect on choice bias across individuals was robustly predictable. NTX's effect on choice bias was significantly correlated with scores on Rotter's Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX's effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.
Adult↗
The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?
The ventral tegmental area (VTA) and in particular VTA dopamine (DA) neurons are postulated to play a central role in reward, motivation and drug addiction. However, most evidence implicating VTA DA neurons in these functions is based on indirect electrophysiological characterization, rather than cytochemical identification. These physiological criteria were first established in the substantia nigra pars compacta (SNc), but their validity in the VTA is uncertain. In the current study we found that while 88 +/- 2% of SNc neurons labelled by the neuronal marker NeuN were co-labelled for the catecholamine enzyme tyrosine hydroxylase (TH), a much smaller percentage (55 +/- 2%) of VTA neurons co-expressed TH. In addition, using in vitro whole-cell recordings we found that widely accepted physiological criteria for VTA DA neurons, including the hyperpolarization-activated inwardly rectifying non-specific cation current (I(h)), spike duration, and inhibition by DA D2 receptor agonists, do not reliably predict the DA content of VTA neurons. We could not distinguish DA neurons from other VTA neurons by size, shape, input resistance, I(h) size, or spontaneous firing rate. Although the absence of an I(h) reliably predicted that a VTA neuron was non-dopaminergic, and I(h)(-) neurons differ from I(h)(+) neurons in firing rate, interspike interval (ISI) standard deviation, and ISI skew, no physiological property examined here is both sensitive and selective for DA neurons in the VTA. We conclude that reliable physiological criteria for VTA DA neuron identification have yet to be determined, and that the criteria currently being used are unreliable.
Action Potentials↗
Endogenous opioids encode relative taste preference.
Endogenous opioid signaling contributes to the neural control of food intake. Opioid signaling is thought to regulate palatability, the reward value of a food item as determined by orosensory cues such as taste and texture. The reward value of a food reflects not only these sensory properties but also the relative value of competing food choices. In the present experiment, we used a consummatory contrast paradigm to manipulate the relative value of a sucrose solution for two groups of rats. Systemic injection of the nonspecific opioid antagonist naltrexone suppressed sucrose intake; for both groups, however, this suppression was selective, occurring only for the relatively more valuable sucrose solution. Our results indicate that endogenous opioid signaling contributes to the encoding of relative reward value.
Animals↗
Isolating the modulatory effect of expectation on pain transmission: a functional magnetic resonance imaging study.
We use a novel balanced experimental design to specifically investigate brain mechanisms underlying the modulating effect of expected pain intensity on afferent nociceptive processing and pain perception. We used two visual cues, each conditioned to one of two noxious thermal stimuli [ approximately 48 degrees C (high) or 47 degrees C (low)]. The visual cues were presented just before and during application of the noxious thermal stimulus. Subjects reported significantly higher pain when the noxious stimulus was preceded by the high-intensity visual cue. To control for expectancy effects, for one-half of the runs, the noxious thermal stimuli were accompanied by the cue conditioned to the other stimulus. Comparing functional magnetic resonance imaging blood oxygenation level-dependent activations produced by the high and low thermal stimulus intensities presented with the high-intensity visual cue showed significant activations in nociceptive regions of the thalamus, second somatosensory cortex, and insular cortex. To isolate the effect of expectancy, we compared activations produced by the two visual cues presented with the high-intensity noxious thermal stimulus; this showed significant differences in the ipsilateral caudal anterior cingulate cortex, the head of the caudate, cerebellum, and the contralateral nucleus cuneiformis (nCF). We propose that pain intensity expectancy modulates activations produced by noxious stimuli through a distinct modulatory network that converges with afferent nociceptive input in the nCF.
Adult↗
Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine.
Dopamine neurons in the ventral tegmental area (VTA) represent a critical site of synaptic plasticity induced by addictive drugs. Orexin/hypocretin-containing neurons in the lateral hypothalamus project to the VTA, and behavioral studies have suggested that orexin neurons play an important role in motivation, feeding, and adaptive behaviors. However, the role of orexin signaling in neural plasticity is poorly understood. The present study shows that in vitro application of orexin A induces potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission via a PLC/PKC-dependent insertion of NMDARs in VTA dopamine neuron synapses. Furthermore, in vivo administration of an orexin 1 receptor antagonist blocks locomotor sensitization to cocaine and occludes cocaine-induced potentiation of excitatory currents in VTA dopamine neurons. These results provide in vitro and in vivo evidence for a critical role of orexin signaling in the VTA in neural plasticity relevant to addiction.
Analysis of Variance↗
Kappa opioids selectively control dopaminergic neurons projecting to the prefrontal cortex.
Dopaminergic afferents arising from the ventral tegmental area (VTA) are crucial elements in the neural circuits that mediate arousal, motivation, and reinforcement. Two major targets of these afferents are the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAc). Whereas dopamine (DA) in the mPFC has been implicated in working memory and attentional processes, DA in the NAc is required for responding to reward predictive cues. These distinct functions suggest a role for independent firing patterns of dopaminergic neurons projecting to these brain regions. In fact, DA release in mPFC and NAc can be differentially modulated. However, to date, electrophysiological studies have largely overlooked heterogeneity among VTA neurons. Here, we provide direct evidence for differential neurotransmitter control of DA neural activity and corresponding DA release based on projection target. Kappa opioid receptor agonists inhibit VTA DA neurons that project to the mPFC but not those that project to the NAc. Moreover, DA levels in the mPFC, but not the NAc, are reduced after local infusion of kappa opioid receptor agonists into the VTA. These findings demonstrate that DA release in specific brain regions can be independently regulated by opioid targeting of a subpopulation of VTA DA neurons. Selective control of VTA DA neurons projecting to the mPFC has important implications for understanding addiction, attention disorders, and schizophrenia, all of which are associated with DA dysfunction in the mPFC.
Animals↗
Inhibitions of nucleus accumbens neurons encode a gating signal for reward-directed behavior.
The nucleus accumbens (NAcc) is critical in the control of goal-directed behavior. Pharmacological studies suggest that the NAcc may act in both instructive and permissive modes; however, previous electrophysiological studies in behaving rats have reported firing patterns consistent with an instructive, but not permissive, role for NAcc neurons. We now report that a subset of NAcc neurons shows a long-lasting inhibition in firing rate whose onset precedes initiation of goal-directed sequences of behavior and terminates at the conclusion of the sequence. Together with data from previous behavioral studies, this firing pattern suggests that, when active, these neurons tonically inhibit appetitive and consummatory behaviors and that, when inhibited, these neurons permissively gate those behaviors.
Animals↗
A single injection of the kappa opioid antagonist norbinaltorphimine increases ethanol consumption in rats.
RATIONALE: Kappa opioid receptor (KOR) agonists interfere with the reinforcing effects of drugs of abuse. KOR agonists decrease heroin, cocaine, and ethanol self-administration, and block heroin and cocaine conditioned place preference (CPP) in rats. However, KOR agonists also produce emesis and dysphoria, making it difficult to determine if their effects on self-administration are due to an action on reward mechanisms or are secondary to the drug's direct aversive effects. Assuming that endogenous KOR ligands modulate circuits involved in drug and alcohol reward, selective KOR antagonists can be used to clarify these issues. If KOR antagonists increase drug self-administration then it is likely that endogenous KOR agonists directly modulate drug intake. OBJECTIVES: To determine the effects of nor-BNI, the highly selective KOR antagonist, on ethanol consumption and CPP. METHODS: Thirty-eight male Lewis rats were given free access to ethanol until stable self-administration was achieved. Animals were then administered a single injection of nor-BNI (10 mg kg(-1)) while ethanol intake was monitored. RESULTS: A single injection of nor-BNI induces a long-lasting increase in ethanol consumption, but does not induce a CPP. A high/low split revealed that this effect was primarily due to an increase in drinking in nor-BNI-treated high drinkers, which drank significantly more than saline-treated high drinkers and also drank significantly more when compared to their own pretreatment baseline. CONCLUSIONS: Blocking the KOR system increases ethanol self-administration, suggesting that the decrease in self-administration seen with KOR agonists is due to a direct modulation of reward circuitry.
Alcohol Drinking↗
Encoding of palatability and appetitive behaviors by distinct neuronal populations in the nucleus accumbens.
Obesity is a major public health problem. Palatability (i.e., the reinforcing value of food, derived from orosensory cues) is a significant factor in determining food intake and contributes to increased consumption leading to obesity. The nucleus accumbens is a ventral striatal region that is important for both appetitive and consummatory behaviors and has been implicated in modulating palatability. In this study, we investigated palatability encoding in the firing of nucleus accumbens neurons in rats. Nucleus accumbens neurons with significant changes in firing rate during consummatory behavior displayed one of two principal firing patterns. Firing in one class of nucleus accumbens neurons was correlated with the palatability of sucrose reinforcers; changes in neural activity in this class consisted primarily of excitations. Within this group of neurons, a subset was sensitive to the relative value of sucrose reinforcers, as assessed by a behavioral contrast paradigm. A second and distinct population of nucleus accumbens neurons, with changes in firing that were pre-dominantly inhibitions, was not sensitive to reinforcer palatability; rather, these inhibitions were present even during unreinforced bouts of licking. In addition, the onset of these inhibitions typically occurred before the initiation of the licking behavior itself. We propose that two primary classes of nucleus accumbens neurons contribute to neural processing immediately before and during reinforcer consumption: inhibitions related to initiation and maintenance of consummatory behaviors and excitations that encode reinforcer palatability.
Animals↗
Treatment response in antidepressant-naïve postherpetic neuralgia patients: double-blind, randomized trial.
UNLABELLED: In 47 patients with postherpetic neuralgia (PHN) who had never had an adequate trial of any antidepressant, we performed a randomized, double-blind, parallel design trial comparing desipramine, amitriptyline, and fluoxetine. Patients were titrated to a maximum of 150 mg/day for desipramine and amitriptyline and 60 mg/day for fluoxetine over a 3-week period and then treated for an additional 3 weeks before tapering off study medication. A total of 38 subjects (81%) completed the entire trial. The modified intent-to-treat analysis of percent change in daily diary pain intensity scores showed no significant differences among the 3 drugs (ANOVA P = .120). Desipramine produced the greatest reduction in pain intensity (47%), followed by amitriptyline (38%) and fluoxetine (35%). Clinically meaningful pain relief (moderate or better) was significantly more likely with desipramine (12/15 patients) than with amitriptyline (9/17) or fluoxetine (5/15); chi(2)P = 0.036). The 11 subjects using opioids at study entry had smaller reductions in pain than those not using concomitant opioids. The fluoxetine group had the highest noncompletion rate (33%), with 1 subject hospitalized for hyponatremia. Although the magnitude of pain reduction and the category pain relief rating was not significantly different among the 3 drugs, the tricyclics desipramine and amitriptyline were well tolerated and provided clinically meaningful pain relief in 53% to 80% of subjects. PERSPECTIVE: Few clinical trials focus on patients who are naïve to an entire class of medication. In this randomized blinded trial, the tricyclic antidepressants desipramine and amitriptyline were compared to the serotonin-selective antidepressant fluoxetine. All 3 drugs reduced PHN pain, with desipramine providing satisfactory relief in 80% of those treated.
Adult↗
Impulsive responding in alcoholics.
BACKGROUND: Impaired decision-making is one diagnostic characteristic of alcoholism. Quantifying decision-making with rapid and robust laboratory-based measures is thus desirable for the testing of novel treatments for alcoholism. Previous research has demonstrated the utility of delay discounting (DD) tasks for quantifying differences in decision-making in substance abusers and normal controls. In DD paradigms subjects choose between a small, immediate reward and a larger, delayed reward. METHODS: We used a novel computerized DD task to demonstrate that abstinent alcoholics (AA, n=14) choose the larger, delayed option significantly less often than control subjects (n=14; p<0.02). This difference in choice tendency was independent of subject age, gender, years of education, or socio-economic status. RESULTS: All subjects discounted as a function of reward delay and amount, with alcoholics demonstrating steeper discounting curves for both variables. This tendency to discount delayed rewards was positively correlated with subjective reports of both alcohol addiction severity (Drug Use Screening Inventory-Revised, Domain 1, p<0.01), and impulsivity (Barratt Impulsivity Scale-11, p<0.004). Novel aspects of this new paradigm include an element of time pressure, an additional experimental condition that evaluated motor impulsivity by assessing the ability to inhibit a pre-potent response, and another control condition to requiring non-subjective choice. CONCLUSIONS: Non-alcoholic controls and alcoholics did not differ on motor impulsivity or non-subjective choice, suggesting that the differing choice behavior of the two groups was due mainly to differences in cognitive impulsivity.
Adult↗
Pain and the placebo: what we have learned.
Despite the recent blossoming of rigorous research into placebo mechanisms and the long-standing use of placebos in clinical trials, there remains widespread and profound misunderstanding of the placebo response among both practicing physicians and clinical researchers. This review identifies and clarifies areas of current confusion about the placebo response (including whether it exists at all), describes its phenomenology, and outlines recent advances in our knowledge of its underlying psychological and neural mechanisms. The focus of the review is the placebo analgesic response rather than placebo responses in general, because much of the best established clinical and experimental work to date has been done on this type of placebo response. In addition, this subfield of placebo research offers a specific neural circuit hypothesis capable of being integrated with equally rigorous experimental work on the psychological (including social psychological) and clinical levels. In this sense, placebo analgesia research bears all the marks of a genuine multilevel interdisciplinary research paradigm in the making, one that could serve as a model for research into other kinds of placebo responses, as well as into other kinds of mind-body responses.
Analgesia↗
Fibromyalgia from the perspective of neuropathic pain.
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Fibromyalgia↗
Both kappa and mu opioid agonists inhibit glutamatergic input to ventral tegmental area neurons.
The ventral tegmental area (VTA) plays a critical role in motivation and reinforcement. Kappa and mu opioid receptor (KOP-R and MOP-R) agonists microinjected into the VTA produce powerful and largely opposing motivational actions. Glutamate transmission within the VTA contributes to these motivational effects. Therefore information about opioid control of glutamate release onto VTA neurons is important. To address this issue, we performed whole cell patch-clamp recordings in VTA slices and measured excitatory postsynaptic currents (EPSCs). There are several classes of neuron in the VTA: principal, secondary, and tertiary. The KOP-R agonist (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide methane-sulfonate hydrate (U69593; 1 microM) produced a small reduction in EPSC amplitude in principal neurons (14%) and a significantly larger inhibition in secondary (47%) and tertiary (33%) neurons. The MOP-R agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO; 3 microM) inhibited glutamate release in principal (42%), secondary (45%), and tertiary neurons (35%). Unlike principal and tertiary neurons, in secondary neurons, the magnitude of the U69593 EPSC inhibition was positively correlated with that produced by DAMGO. Finally, DAMGO did not occlude the U69593 effect in principal neurons, suggesting that some glutamatergic terminals are independently controlled by KOP and MOP receptor activation. These findings show that MOP-R and KOP-R agonists regulate excitatory input onto each VTA cell type.
Analgesics, Opioid↗