Interoceptive Cues Research Articles

Stimulant-induced adaptations in neostriatal matrix and striosome systems: Transiting from instrumental responding to habitual behavior in drug addiction

Converging evidence indicates that repeated exposure to motor stimulants such as cocaine and amphetamine produces marked alterations in network responsiveness of striatal neurons to subsequent challenge with the same stimulant drug. Such alterations, which correlate with persistent patterns of repetitive behavior, associate with distinct compartmental changes in the neostriatum. Striatal matrix system neurons undergo “silencing” following repeated drug challenges, allowing striosome system neurons to exhibit preferential activation. Matrix neurons are innervated by sensory and motor areas of neocortex and are activated in the course of on-going, adaptive behavior. Inactivation of matrix neurons by chronic stimulant exposure may therefore constrain sensorimotor and cognitive processing. In turn, the striosomes are anatomically connected through re-entrant loops with limbic prefrontal and allocortical structures, such as anterior cingulate cortex, orbital frontal cortex, and basolateral amygdala, all of which play a part in stimulant-induced reinforcement and relapse to drug-taking. Moreover, functional evidence links striosome system neurons, which are responsible for providing inhibitory regulatory feedback to midbrain dopamine neurons, with reinforcement-based processes. In considering such evidence, we postulate that recurrent matrix inactivation and recruitment of striosome-based pathways by chronic stimulant exposure represent neural end-points of the transit from action–outcome associative behavior to conditioned habitual responding. Within this theoretical framework, habitual behavior can be elicited by both interoceptive cues and exteroceptive conditioned stimuli to promote the automatic execution of learned responses.

Associative Mechanisms and Drug-Related Behavior

Associative Mechanisms and Drug-Related Behavior

The influence of sex on extracellular dopamine and locomotor activity in C57BL/6J mice before and after acute cocaine challenge

C57BL6/J (C57) mice serve as a useful animal model of cocaine abuse because they self-administer cocaine, exhibit place conditioning to cocaine, discriminate the interoceptive cues of cocaine, and are used for backcrossing strains of genetically modified mice. The present study was to examine the influence of sex on extracellular DA and locomotor activity in C57 mice in response to acute cocaine challenge. In the first experiment, male and female mice were implanted with guide cannulae aimed at the dorsal striatum. Microdialysates were collected in three consecutive phases: baseline, post-saline injection, and post-cocaine injection. Sex did not influence DA measurements during baseline or after intraperitoneal (i.p.) saline injection. Cocaine (20 mg/kg) injections increased peak extracellular DA of both sexes, and the increase was greater for males (278%+/-14.0%) than females (182.5%+/-10.8%) (P<0.05). In the second experiment, under conditions similar to the microdialysis experiment, locomotor activity of male and female mice was assessed during baseline, after saline injection, and after cocaine injection (5, 10, 20, or 40 mg/kg). Cocaine dose-dependently increased activity; however, sex did not influence locomotor activity during baseline, after saline, or after any cocaine dose. Results of the experiments established that cocaine (20 mg/kg) increased extracellular DA in the dorsal striatum to a greater extent in male than in female mice; however, when cocaine was administered under similar experimental conditions, sex did not influence cocaine stimulation of locomotor activity over a wide range of doses.

Contribution of tactile and interoceptive cues to the perception of the direction of gravity

Without relevant visual cues, the Subjective Visual Vertical (SVV) is biased in roll tilted subjects toward the body axis (Aubert or A-effect). This effect is generally ascribed to changes in the vestibular and somatosensory inputs following a body tilt. This study focused on the contribution of interoception and tactile cues in the SVV. The body-cast technology and gastric fullness were used to obtain a diffuse tactile stimulation and an overload stomach stimulation, respectively. Fifteen subjects placed in a tilt-chair were rolled sideways from 0° to 90°. They were asked to adjust a luminous line to the vertical under two body restriction conditions (strapped vs. body-cast) and two stomach load conditions (empty vs. full). Results showed (1) an improvement in the SVV judgment when somaesthetic cues were available in the full stomach condition ( p<0.001), (2) an increased A-effect for the higher body tilt values in the body-cast condition (beyond 45°, p<0.001), and (3) a smaller disrupting effect of the body-cast in the SVV judgment in the full stomach condition ( p<0.05). Since the vestibular system produced the same gravity response in all conditions, it can be stated that somaesthetic cues are involved in the SVV. Tactile mechanoreceptors may have contributed by detecting the changing pattern of pressures generated on the skin that results from changes in body orientation. The stomach load may act through the inertial forces exerted against the gravity load when the stomach is full by the mechanoreceptors in the fundus. Thus, the somaesthetic system can indicate the direction of gravity via patterns of pressure within and at the surface of the body.

Contribution of tactile and interoceptive cues to the perception of the direction of gravity

Without relevant visual cues, the Subjective Visual Vertical (SVV) is biased in roll tilted subjects toward the body axis (Aubert or A-effect). This effect is generally ascribed to changes in the vestibular and somatosensory inputs following a body tilt. This study focused on the contribution of interoception and tactile cues in the SVV. The body-cast technology and gastric fullness were used to obtain a diffuse tactile stimulation and an overload stomach stimulation, respectively. Fifteen subjects placed in a tilt-chair were rolled sideways from 0° to 90°. They were asked to adjust a luminous line to the vertical under two body restriction conditions (strapped vs. body-cast) and two stomach load conditions (empty vs. full). Results showed (1) an improvement in the SVV judgment when somaesthetic cues were available in the full stomach condition (p<0.001), (2) an increased A-effect for the higher body tilt values in the body-cast condition (beyond 45°, p<0.001), and (3) a smaller disrupting effect of the body-cast in the SVV judgment in the full stomach condition (p<0.05). Since the vestibular system produced the same gravity response in all conditions, it can be stated that somaesthetic cues are involved in the SVV. Tactile mechanoreceptors may have contributed by detecting the changing pattern of pressures generated on the skin that results from changes in body orientation. The stomach load may act through the inertial forces exerted against the gravity load when the stomach is full by the mechanoreceptors in the fundus. Thus, the somaesthetic system can indicate the direction of gravity via patterns of pressure within and at the surface of the body.

Environmental modulation of the interoceptive effects of amphetamine in the rat

The aim of the present study was to investigate the effect of environmental novelty on amphetamine discrimination. Two groups of rats (home group and novelty group) were trained to perform water-reinforced operant behavior in cages equipped with two levers and a retractable liquid dipper (0.1 cc cup). The experimental procedures for the two groups were identical except for the fact that home rats were housed and tested in the operant cages whereas novelty rats were transferred daily to these cages for the testing sessions (25 min). The rats were trained to discriminate one of two doses of amphetamine (0.25 and 0.5 mg/kg) from saline. Saline and amphetamine were administered intraperitoneally immediately before each daily session according to a semi-random schedule for a total of 50 sessions. Reinforcements were delivered according to a fixed ratio that was increased daily from 2 to 30. Successful drug discrimination was achieved when activity on the appropriate lever before the first reinforcement was greater than 80% of total activity, on at least seven out of eight consecutive sessions. When training was conducted with 0.25 mg/kg of amphetamine, no home rat acquired drug discrimination whereas 56% of novelty rats reached criterion. When training was conducted with 0.5 mg/kg of amphetamine, drug discrimination was achieved by 50% of home rat versus 86% of novelty rats. These findings indicate that environmental novelty can alter the ability of amphetamine to produce interoceptive cues.

Toward a unified treatment for emotional disorders

Over 40 years of development of cognitive behavioral approaches to treating anxiety and related emotional disorders have left us with highly efficacious treatments that are increasingly widely accepted. Nevertheless, these manualized protocols have become numerous and somewhat complex, restricting effective training and dissemination. Deepening understanding of the nature of emotional disorders reveals that commonalities in etiology and latent structure among these disorders supercedes differences. This suggests the possibility of distilling a set of psychological procedures that would comprise a unified intervention for emotional disorders. Based on theory and data emerging from the fields of learning, emotional development and regulation, and cognitive science, we identify three fundamental therapeutic components relevant to the treatment of emotional disorders generally. These three components include (a) altering antecedent cognitive reappraisals; (b) preventing emotional avoidance; and (c) facilitating action tendencies not associated with the emotion that is dysregulated. This treatment takes place in the context of provoking emotional expression (emotional exposure) through situational, internal, and somatic (interoceptive cues), as well as through standard mood-induction exercises, and differs from patient to patient only in the situational cues and exercises utilized. Theory and rationale supporting this new approach are described along with some preliminary experience with the protocol. This unified treatment may represent a more efficient and possibly a more effective strategy in treating emotional disorders, pending further evaluation.

Addiction motivation reformulated: an affective processing model of negative reinforcement.

This article offers a reformulation of the negative reinforcement model of drug addiction and proposes that the escape and avoidance of negative affect is the prepotent motive for addictive drug use. The authors posit that negative affect is the motivational core of the withdrawal syndrome and argue that, through repeated cycles of drug use and withdrawal, addicted organisms learn to detect interoceptive cues of negative affect preconsciously. Thus, the motivational basis of much drug use is opaque and tends not to reflect cognitive control. When either stressors or abstinence causes negative affect to grow and enter consciousness, increasing negative affect biases information processing in ways that promote renewed drug administration. After explicating their model, the authors address previous critiques of negative reinforcement models in light of their reformulation and review predictions generated by their model.

Pleasure and displeasure from the body: Perspectives from exercise

The affective changes associated with acute exercise have been studied extensively in exercise and health psychology, but not in affective psychology. This paper presents a summary of the relevant findings and a tentative theoretical model. According to this model, affective responses to exercise are jointly influenced by cognitive factors, such as physical self-efficacy, and interoceptive (e.g., muscular or respiratory) cues that reach the affective centres of the brain via subcortical routes. Furthermore, the balance between these two determinants is hypothesised to shift as a function of exercise intensity, with cognitive factors being dominant at low intensities and interoceptive cues gaining salience as intensity approaches the individual's functional limits and the maintenance of a physiological steady-state becomes impossible.

A novel cognitive-behavioral approach for treatment-resistant drug dependence

Despite the application of treatments that combine methadone administration, weekly counseling, and contingency reinforcement strategies, many opiate-dependent patients continue illicit drug use. In this controlled study we piloted a novel cognitive-behavioral treatment (CBT) designed to reduce illicit drug use among patients receiving methadone treatment. The treatment targeted the reduction of sensitivity to interoceptive cues associated with drug craving, and trained alternative responses to these cues. Patients (N = 23) were randomly assigned to either this novel CBT program or a program of increased counseling, such that the two programs of treatment were equated for therapist contact, assessment time, and contingency-reinforcement strategies. We found that, compared to a doubling of contact with their outpatient counselor, the new program was associated with significantly greater reductions in illicit drug use for women, but not for men. Reasons for differential performance by women and men and future directions for this new treatment are discussed.

Anatomical substrates of orexin–dopamine interactions: lateral hypothalamic projections to the ventral tegmental area

Dopaminergic projections to the forebrain arising from the mesencephalic ventral tegmentum modulate information processing in cortical and limbic sites. The lateral hypothalamus is crucial for the coordination of behavioral responses to interoceptive cues. The presence of a hypothalamic input to the ventral tegmental area has been known for some time, but the organization of this pathway has received little attention. Among the neuropeptides found in the hypothalamus are the orexins, which are selectively expressed in the lateral hypothalamus and adjacent perifornical area and are critically involved in homeostatic regulatory processes, including arousal and feeding. We examined the anatomical relationships between orexin and dopamine neurons in rats, with particular attention to characterizing the lateral hypothalamic projection to midbrain dopamine neurons. Iontophoretic deposits of the retrograde tracer FluoroGold into the ventral tegmental area revealed a large number of retrogradely-labeled cells that formed a band extending from the medial perifornical area arching dorsally over the fornix and then ventrolaterally into the lateral hypothalamus; approximately 20% of these cells expressed orexin A-like immunoreactivity. Moreover, axons that were anterogradely labeled from the lateral hypothalamus were seen throughout the ventral tegmental area, and were often in close proximity to the dendrites and somata of dopamine neurons. Dopamine and orexin fibers were found to codistribute in the medial prefrontal cortex; orexin fibers were present in lower density in the medial shell of the nucleus accumbens, and the central and posterior basolateral nuclei of the amygdala. We conclude that the lateral hypothalamic/perifornical projection represents an anatomical substrate by which interoceptive-related signals may influence forebrain dopamine function.

Mouse Strain Differences in Opiate Reward Learning Are Explained by Differences in Anxiety, Not Reward or Learning

Gene-targeting techniques to produce null mutations provide a powerful method for evaluating the contribution of particular candidate genes involved in motivation. The embryonic stem cell lines in which homologous recombination is undertaken are derived from 129 mice, but because of the impoverished performance of 129 mice on a number of behavioral tasks, mice chimeric for the mutation are often bred with a C57BL/6 mouse strain. Thus, an examination of both parental strains is important in the study of the knock-out mice. Although the C57BL/6 behavioral phenotype is well documented, details of the 129 phenotype have not been the focus of study until recently. We investigated opiate motivation in both 129/SvJ and C57BL/6J mouse strains to determine whether, and under what circumstances, the 129/SvJ mouse exhibited motivated behavior toward opiates. 129/SvJ mice required both drug and contextual cues to demonstrate morphine conditioned place preferences on test day, whereas C57BL/6J mice required only contextual cues to express opiate place conditioning. Pentobarbital and diazepam but not saline, cocaine, or naloxone could substitute for morphine on test day in 129/SvJ mice, demonstrating that morphine indeed has rewarding motivational valence in the 129/SvJ mouse strain. This critical, interoceptive cue in 129/SvJ mice on test day may be the anxiolytic properties of the effective drugs. Therefore, some deficits observed in 129 mice and mice harboring this genetic background may be attributed to high levels of anxiety during the retrieval period rather than to sensory, learning, or motivational deficits.

Long-lasting rebound cue effects following single doses of nicotine and amphetamine: implications for understanding tolerance.

Previous drug-discrimination studies have, with the exception of nicotine (NIC), demonstrated tolerance to the cue effects of a broad range of drugs of abuse. Barrett et al. have shown that tolerance to a drug's cue properties reflects drug-induced rebound shifts in the discrimination baseline and not a weakened or less salient cue. The objective of the present study was to use a discrimination task sensitive to bidirectional cue changes to characterize the interoceptive cues associated with both the primary and rebound cues produced by nicotine in an attempt to understand why a recent study by Shoaib et al. failed to observe tolerance to the nicotine cue. Since dopamine (DA) has been implicated in mediating the NIC cue, rats were trained to discriminate between 0.25 mg/kg amphetamine (AMPH), an indirect DA agonist, and 0.033 mg/kg haloperidol (HAL), a DA antagonist at the D2 receptor site. Training doses were chosen so that rats responded about equally on both levers when tested on saline (SAL) following acquisition. This procedure provided a behavioral baseline to assess NIC-related changes along a presumed continuum of DA-mediated cues. Following acquisition of the discrimination: (i) NIC substitution tests were conducted, (ii) rats were tested for lever choice at intervals from 2 h to 48 h following treatment with single doses of 0.25 mg/kg and 0.50 mg/kg NIC, and (iii) rats were challenged with test doses of NIC during a period of NIC rebound. (i) NIC substituted for AMPH in a dose- dependent manner. (ii) At short intervals after treatment with 0.25 mg/kg and 0.50 mg/kg NIC, rats responded primarily on the AMPH lever followed by a shift to predominant responding on the HAL lever 16-24 h post-treatment, before returning to predrug levels. (iii) No evidence was observed for acute tolerance to NIC. The robust and long-lasting rebound cues associated with training level doses of NIC suggest that maximal tolerance would likely develop to the NIC cue during the acquisition phase of the conventional NIC-saline discrimination study.

Reactivity to interoceptive cues in nocturnal panic

In this study, patients with panic disorder (PD) who suffered nocturnal panic (NP) attacks were compared with PD patients who never experienced NP attacks and healthy controls. Three tasks were chosen to evaluate attention to cardiac cues, reactivity to induction of respiratory cues, and reactivity to relaxation cues. Relative to healthy controls, PD groups reported more fear of all three tasks and showed more physiological arousal in response to the hyperventilation task. The only task on which the two PD groups differed was the relaxation task, where nocturnal panickers were significantly more distressed. These findings are consistent with the notion that nocturnal panickers are fearful of states involving a diminution of conscious awareness or vigilance.

A modern learning theory perspective on the etiology of panic disorder.

Several theories of the development of panic disorder (PD) with or without agoraphobia have emerged in the last 2 decades. Early theories that proposed a role for classical conditioning were criticized on several grounds. However, each criticism can be met and rejected when one considers current perspectives on conditioning and associative learning. The authors propose that PD develops because exposure to panic attacks causes the conditioning of anxiety (and sometimes panic) to exteroceptive and interoceptive cues. This process is reflected in a variety of cognitive and behavioral phenomena but fundamentally involves emotional learning that is best accounted for by conditioning principles. Anxiety, an anticipatory emotional state that functions to prepare the individual for the next panic, is different from panic, an emotional state designed to deal with a traumatic event that is already in progress. However, the presence of conditioned anxiety potentiates the next panic, which begins the individual's spiral into PD. Several biological and psychological factors create vulnerabilities by influencing the individual's susceptibility to conditioning. The relationship between the present view and other views, particularly those that emphasize the role of catastrophic misinterpretation of somatic sensations, is discussed.

Prefrontal dopamine is directly involved in the anxiogenic interoceptive cue of pentylenetetrazol but not in the interoceptive cue of chlordiazepoxide in the rat.

The prefrontal cortical (PFC) dopamine (DA) system has been implicated in anxiety-related behavioral changes, but direct, unequivocal support for this idea is sparse. The present aim was to study the functional significance of prefrontal DA using the pentylenetetrazol (PTZ) discrimination model of anxiety. A comparison was made with its role in the cue of the anxiolytic drug chlordiazepoxide (CDP). Two groups of rats were trained to discriminate either PTZ (20 mg/kg, s.c.) or CDP (10 mg/kg, i.p.) from saline using an operant drug discrimination procedure. After prolonged training, half of each group was used to assess biochemical changes induced by both drugs in different sub areas of the PFC. For the remaining rats, discrimination training continued and generalization tests with PTZ and CDP were performed. Rats were then provided with bilateral guide cannulae aimed at the ventromedial (vm) PFC, and the effects of local infusions of DAergic drugs on discriminative performance were evaluated. CDP did not affect PFC DA activity, but PTZ increased the DOPAC/DA ratio in the vmPFC selectively. Generalization tests showed that the cues of PTZ and CDP were dose dependent. In PTZ-trained rats, infusions of the DA receptor antagonist cis-flupenthixol into the vmPFC blocked the PTZ cue dose dependently, whereas the agonist apomorphine partially generalized to this cue. In CDP-trained rats, neither drug antagonized or generalized to the CDP cue, showing that PFC DA is not critically involved in the CDP cue and that local pharmacological manipulations of PFC DA do not affect discriminative abilities per se. The DAergic innervation of the PFC is directly involved in the behavioral effects of PTZ suggesting a role for it in anxiety.

Pavlovian psychopharmacology: the associative basis of tolerance.

The Pavlovian conditioning analysis of drug tolerance emphasizes that cues present at the time of drug administration become associated with drug-induced disturbances. These disturbances elicit unconditional responses that compensate for the pharmacological perturbation. The drug-compensatory responses eventually come to be elicited by drug-paired cues. These conditional compensatory responses (CCRs) mediate tolerance by counteracting the drug effect when the drug is administered in the presence of cues previously paired with the drug. If the usual predrug cues are presented in the absence the drug, the unopposed CCRs are evident as withdrawal symptoms. Recent findings elucidate intercellular and intracellular events mediating CCRs and indicate the importance of internal stimuli (pharmacological cues and interoceptive cues inherent in self-administration) to the acquisition of drug tolerance and the expression of withdrawal symptoms.

Discriminative Stimulus Properties of mCPP and Alprazolam Are Not Mediated by Anxiety

We investigated whether the interoceptive cues mediated by the anxiolytic benzodiazepine receptor agonist alprazolam and the anxiogenic serotonin (5-HT) 1B/2C receptor agonist 1-(3-chlorophenyl)piperazine (mCPP) in rats are related to anxiety. mCPP-induced anxiety in humans can be blocked with alprazolam, and if mCPP drug discrimination is to be used as a model of anxiety, mCPP's stimulus should be blocked by alprazolam. Therefore, two groups of rats were trained to discriminate either alprazolam (2 mg/kg, PO) or mCPP (2 mg/kg, PO) from vehicle in a two-level operant drug discrimination procedure. Cross antagonism tests were performed with alprazolam and mCPP. mCPP did not antagonize alprazolam's stimulus to any extent, but disrupted responding severely. Low and intermediate doses of alprazolam (1.0–4.0 mg/kg, PO) did not antagonize the mCPP discriminative stimulus; only a high dose of 8.0 mg/kg (PO) partially antagonized mCPP but disrupted responding in most of the animals. We conclude that, at best, there is only weak evidence to suggest that the interoceptive cues of alprazolam and mCPP are mediated by modulation of anxiety processes, and that the mCPP drug discrimination as a model for anxiety is unreliable.

Response patterns to repeated CO 2 inhalation in individuals with high anxiety sensitivity

The present report extends previous work which has documented two distinct response patterns to repeated presentation of interoceptive cues (using CO 2 inhalation) in PD patients [Beck, J. G. & Shipherd, J. C. (1997). Repeated exposure to interoceptive cues: does habituation of fear occur in panic disorder patients? Behaviour Research and Therapy, 35, 551–557]. We were interested in determining if these two patterns of fear habituation and sensitization would be noted in panic-naive individuals who reported high levels of Anxiety Sensitivity. A second aspect of this report examined whether attention to bodily sensations versus to neutral material would impact fear habituation and sensitization. Participants included 43 panic-naive individuals who scored at least 1 standard deviation above norms on the Anxiety Sensitivity Index. Results indicated that 37% of the sample reported habituation of fear, 47% reported fear sensitization and 16% demonstrated relatively stable fear levels across 12 inhalations of CO 2 during session 1. The attentional manipulation did not exert a pronounced influence on anxiety, panic symptom severity, skin conductance, or heart rate in either Habituators or Sensitizers during session 2. These results are discussed in light of their relevance in understanding fundamental psychopathological processes underlying Panic Disorder.

Discriminative Stimulus Properties of Ethanol in Rats: Studies on the Role of Nitric Oxide

The present study examined the role of the l-arginine–nitric oxide pathway in mediation of the ethanol interoceptive (discriminative) cue. Adult male Wistar rats (n = 16) were trained to discriminate ethanol (1 g/kg, 10% v/v) from saline under a fixed-ratio 10 (FR10) schedule of sweetened milk reinforcement. A nonselective nitric oxide synthase (NOS) inhibitor, N G-nitro- l-arginine methyl ester ( l-NAME; 10–540 mg/kg) did not substitute for ethanol. Similarly, a relatively selective neuronal NOS inhibitor, 7-nitroindazole (7-NI; 10–80 mg/kg), did not mimic the ethanol cue. However, both l-NAME and 7-NI produced significant reduction in the rate of operant responding. A nitric oxide precursor, l-arginine (100–500 mg/kg) neither substituted for nor antagonize the ethanol stimulus. Taken together, these results suggest that the l-arginine–nitric oxide pathway is not involved in mediation of the discriminative stimulus effects of ethanol in the rat.