Interoception and Learning: Import to Understanding and Treating Diseases and Psychopathologies

Chemotherapeutic agents nauseate cancer patients. Some individuals with schizophrenia hear voices. Chronic pain can be reduced by analgesics. Nausea, voices, and pain are examples of internal (interoceptive) stimuli closely linked with a disease and/or its treatment. There is evidence that the perception and, hence, role of these internal stimuli can be modified by one’s learning history. There is also increased awareness by researchers and practitioners of the potential import of learning involving internal states to some diseases and psychopathologies. Unfortunately, the science, theory, and practice appear to be trailing behind awareness. In this mini-review, we describe two examples: smoking and panic disorder. While doing so, we discuss the need to develop translationally relevant animal models that will allow investigators to better understand the behavioral and neural mechanisms underlying interoception and learning

Impact of Nicotine Withdrawal on Novelty Reward and Related Behaviors

The authors tested the decreased reward function hypothesis of nicotine withdrawal using a novel-object place conditioning task. A conditioned place preference was evident in controls and in rats that had experienced 4 nicotine withdrawal days, but not in rats that had experienced 1–3 withdrawal days. This implies that the rewarding properties of interacting with novel objects were not readily associated with the environment in which they were paired. Follow-up experiments eliminated other explanations based on withdrawal-induced failures to process object or environment information. Also, expression of conditioning was not affected, indicating that withdrawal likely altered acquisition. Further investigation into the neurochemical and behavioral changes that accompany nicotine withdrawal will lead to a better understanding of the withdrawal syndrome

Timing of conditioned responding in a nicotine locomotor conditioning preparation: Manipulations of the temporal arrangement between context cues and drug administration

Using a locomotor conditioning preparation, we examined whether manipulating time between exposure to distinct environmental cues and nicotine administration affected conditioned responding. Rats that received nicotine (0.42 mg/kg base) immediately before placement in an environment for 30 min on eight separate occasions displayed hyperactivity relative to controls in a subsequent injection/drug-free test. This conditioned hyperactivity was weaker if nicotine was administered 15 min before environment exposure. Conditioning was not evidenced when nicotine was administered 15 min after placement or upon removal from the environment. In a follow-up experiment, rats received 45 min in the environment; nicotine was administered 15 min after placement. This group showed conditioning that was localized to the last two-thirds of a 45 min test indicating that a 15 min delay did not prevent conditioning given 30 min of environment/nicotine overlap. This apparent timing of conditioned responding was not due to increasing environment exposure to 45 min. Further, a state-dependent environmental familiarization account of locomotor hyperactivity during testing was eliminated by the finding that rats displayed temporally specific increases in activity on the test day despite the fact that the context was previously experienced without drug for 15 min on eight consecutive days

The nicotine + alcohol interoceptive drug state: contribution of the components and effects of varenicline in rats

Nicotine and alcohol co-use is highly prevalent, and as such, individuals experience the interoceptive effects of both substances together. Therefore, examining sensitivity to a compound nicotine and alcohol (N+A) interoceptive cue is critical to broaden our understanding of mechanisms that may contribute to nicotine and alcohol co-use

Pharmacological and Anatomical Evidence for an Interaction Between mGluR5- and GABAA α1-Containing Receptors in the Discriminative Stimulus Effects of Ethanol

The discriminative stimulus properties of ethanol are mediated in part by positive modulation of GABAA receptors. Recent evidence indicates that metabotropic glutamate receptor subtype 5 (mGluR5) activity can influence GABAA receptor function. Therefore, the purpose of this work was to examine the potential involvement of mGluR5 in the discriminative stimulus effects of ethanol. In rats trained to discriminate ethanol (1 g/kg, intragastric gavage (i.g.)) from water, 2-methyl-6-(phenylethyl)-pyridine (MPEP) (1–50 mg/kg, i.p.) a selective noncompetitive antagonist of the mGlu5 receptor did not produce ethanol-like stimulus properties. However, pretreatment with MPEP (30 mg/kg) reduced the stimulus properties of ethanol as indicated by significant reductions in ethanol-appropriate responding, specifically at 0.5 and 1 g/kg ethanol, and a failure of ethanol test doses (1 and 2 g/kg) to fully substitute for the ethanol training dose. To test whether mGluR5 antagonism altered the GABAA receptor component of the ethanol stimulus, the ability of MPEP to modulate pentobarbital and diazepam substitution for ethanol was assessed. Pentobarbital substitution (1–10 mg/kg, i.p.) for ethanol was not altered by MPEP pretreatment. However, MPEP pretreatment inhibited the ethanol-like stimulus properties of diazepam (5 mg/kg, i.p.). To examine a potential anatomical basis for these pharmacological findings, expression patterns of mGluR5- and benzodiazepine-sensitive GABAA α1-containing receptors were examined by dual-label fluorescent immunohistochemistry with visualization by confocal microscopy. Results indicated that mGluR5- and GABAA α1-containing receptors were both coexpressed in limbic brain regions and colocalized on the same cells in specific brain regions including the amygdala, hippocampus, globus pallidus, and ventral pallidum. Together, these findings suggest an interaction between mGluR5- and benzodiazepine-sensitive GABAA receptors in mediating ethanol discrimination

Modulation of sensitivity to alcohol by cortical and thalamic brain regions

The nucleus accumbens core (AcbC) is a key brain region known to regulate the discriminative stimulus/interoceptive effects of alcohol. As such, the goal of the present work was to identify AcbC projection regions that may also modulate sensitivity to alcohol. Accordingly, AcbC afferent projections were identified in behaviorally naïve rats using a retrograde tracer which led to the focus on the medial prefrontal cortex (mPFC), insular cortex (IC) and rhomboid thalamic nucleus (Rh). Next, to examine the possible role of these brain regions in modulating sensitivity to alcohol, neuronal response to alcohol in rats trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water was examined using a two-lever drug discrimination task. As such, rats were administered water or alcohol (1g/kg, IG) and brain tissue was processed for c-Fos immunoreactivity (IR), a marker of neuronal activity. Alcohol decreased c-Fos IR in the mPFC, IC, Rh, and AcbC. Lastly, site-specific pharmacological inactivation with muscimol+baclofen (GABAA agonist+GABAB agonist) was used to determine the functional role of the mPFC, IC and Rh in modulating the interoceptive effects of alcohol in rats trained to discriminate alcohol (1 g/kg, IG) vs. water. mPFC inactivation resulted in full substitution for the alcohol training dose, and IC and Rh inactivation produced partial alcohol-like effects, demonstrating the importance of these regions, with known projections to the AcbC, in modulating sensitivity to alcohol. Together, these data demonstrate a site of action of alcohol and the recruitment of cortical/thalamic regions in modulating sensitivity to the interoceptive effects of alcohol

Preclinical Evaluation of Riluzole: Assessments of Ethanol Self-Administration and Ethanol Withdrawal Symptoms

Many of the neurobehavioral effects of ethanol are mediated by inhibition of excitatory N-methyl-d-aspartate (NMDA) and enhancement of inhibitory γ-amino-butyric-acid (GABA) receptor systems. There is growing interest in drugs that alter these systems as potential medications for problems associated with alcoholism. The drug riluzole, approved for treatment of amyotrophic lateral sclerosis (ALS), inhibits NMDA and enhances GABAA receptor system activity. This study was designed to determine the preclinical efficacy of riluzole to modulate ethanol self-administration and withdrawal

Increased sensitivity to alcohol induced changes in ERK Map kinase phosphorylation and memory disruption in adolescent as compared to adult C57BL/6J mice

Adolescence is a critical period of brain development that is accompanied by increased probability of risky behavior, such as alcohol use. Emerging research indicates that adolescents are differentially sensitive to the behavioral effects of acute ethanol as compared to adults but the neurobiological mechanisms of this effect remain to be fully elucidated. This study was designed to evaluate effects of acute ethanol on extracellular signal-regulated kinase phosphorylation (p-ERK1/2) in mesocorticolimbic brain regions. We also sought to determine if age-specific effects of ethanol on p-ERK1/2 are associated with ethanol-induced behavioral deficits on acquisition of the hippocampal-dependent novel object recognition (NOR) test. Adolescent and adult C57BL/6J mice were administered acute ethanol (0 0.5, 1, or 3 g/kg, i.p.). Brains were removed 30-min post injection and processed for analysis of p-ERK1/2 immunoreactivity (IR). Additional groups of mice were administered ethanol (0 or 1 g/kg) prior to the NOR test. Analysis of p-ERK1/2 IR showed that untreated adolescent mice had significantly higher levels of p-ERK1/2 IR in the nucleus accumbens shell, basolateral amygdala (BLA), central amygdala (CeA), and medial prefrontal cortex (mPFC) as compared to adults. Ethanol (1 g/kg) selectively reduced p-ERK1/2 IR in the dentate gyrus and increased p-ERK1/2 IR in the BLA only in adolescent mice. Ethanol (3 g/kg) produced the same effects on p-ERK1/2 IR in both age groups with increases in CeA and mPFC, but a decrease in the dentate gyrus, as compared to age-matched saline controls. Pretreatment with ethanol (1 g/kg) disrupted performance on the NOR test specifically in adolescents, which corresponds with the ethanol-induced inhibition of p-ERK1/2 IR in the hippocampus. These data show that adolescent mice have differential expression of basal p-ERK1/2 IR in mesocorticolimbic brain regions. Acute ethanol produces a unique set of changes in ERK1/2 phosphorylation in the adolescent brain that are associated with disruption of hippocampal-dependent memory acquisition

Gabapentin potentiates sensitivity to the interoceptive effects of alcohol and increases alcohol self-administration in rats

Gabapentin, a drug used in the treatment of epileptic seizures and neuropathic pain, has shown efficacy in the treatment of alcohol dependence. Moreover, given that gabapentin is used in the general population (e.g., non-dependent individuals, social drinkers), we sought to utilize preclinical assessments to examine the effects of gabapentin on sensitivity to moderate alcohol doses and alcohol self-administration in rats with a history of moderate drinking. To this end, we assessed whether gabapentin (0, 10, 30, 120 mg/kg, IG) pretreatment alters sensitivity to experimenter- and self-administered alcohol, and whether gabapentin alone has alcohol-like discriminative stimulus effects in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, we assessed whether gabapentin (0, 10, 30, 60 mg/kg, IG) would alter alcohol self-administration in rats with a history of moderate alcohol consumption. Gabapentin pretreatment potentiated the interoceptive effects of both experimenter-administered and self-administered alcohol in discrimination-trained rats. Additionally, the highest gabapentin doses tested (30 and 120 mg/kg) were found to have partial alcohol-like discriminative stimulus effects when administered alone (e.g., without alcohol). In the self-administration trained rats, gabapentin pretreatment (60 mg/kg) resulted in an escalation in alcohol self-administration. Given the importance of interoceptive drug cues in priming and maintaining self-administration, these data define a specific behavioral mechanism (i.e., potentiation of alcohol effects) by which gabapentin may increase alcohol self-administration in non-dependent populations