Interoceptive conditioning with the nicotine stimulus: extinction learning as a method for assessing stimulus similarity across doses.

Interoceptive conditioning involving the nicotine stimulus likely contributes to chronic tobacco use. To better understand the nature of this interoceptive conditioning, we compared generalization during repeated extinction with generalization in a 'transfer of extinction' test using a wide range of test doses. Rats were first trained in the discriminated goal-tracking task in which nicotine (0.2 or 0.4 mg/kg), but not saline, was paired with repeated intermittent access to sucrose. Across sessions, nicotine acquired control of approach behavior directed at the location of previous sucrose deliveries. Extinction followed with eight 20-min sessions without sucrose access; extinction doses of nicotine ranged from 0.05 to 0.6 mg/kg. In rats trained with 0.4 mg/kg, the 0.1, 0.2, and 0.6 mg/kg doses evoked comparable responding across extinction sessions; substitution was only partial at 0.05 and 0.075 mg/kg (i.e. above saline controls, but less than the training dose). With the 0.2 mg/kg training dose, complete generalization was seen only at the 0.1 and 0.4 mg/kg doses. After extinction, rats were given a transfer test with their training dose. Rats trained with 0.4 mg/kg showed full transfer of extinction learning with 0.1, 0.2, and 0.6 mg/kg (i.e. responding comparable with extinction with the training dose). Partial transfer was observed at 0.075 mg/kg. With the 0.2 mg/kg nicotine dose, only 0.4 mg/kg fully generalized; 0.075, 0.1, and 0.6 mg/kg showed partial transfer. Extinction with 0.05 mg/kg dose did not show transfer to either training dose. These findings indicated that conclusions regarding stimulus similarity across nicotine doses can vary with testing protocol.

Disentangling the nature of the nicotine stimulus.

Learning involving interoceptive stimuli likely plays an important role in many diseases and psychopathologies. Within this area, there has been extensive research investigating the interoceptive stimulus effects of abused drugs. In this pursuit, behavioral pharmacologists have taken advantage of what is known about learning processes and adapted the techniques to investigate the behavioral and receptor mechanisms of drug stimuli. Of particular interest is the nicotine stimulus and the use of the two-lever operant drug discrimination task and the Pavlovian drug discriminated goal-tracking task. There is strong concordance between the two methods when using "standard" testing protocols that minimize learning on test days. For example, ABT-418, nornicotine, and varenicline all fully evoked nicotine-appropriate responding. Notably, research from our laboratory with the discriminated goal-tracking task has used an alternative testing protocol. This protocol assesses stimulus substitution based on how well extinction learning using a non-nicotine ligand transfers back to the nicotine stimulus. These findings challenge conclusions based on more "standard" testing procedures (e.g., ABT-418 is not nicotine-like). As a starting point, we propose Thurstone scaling as a quantitative method for more precisely comparing transfer of extinction across doses, experiments, and investigators. We close with a discussion of future research directions and potential implications of the research for understanding interoceptive stimuli.

An examination of NMDA receptor contribution to conditioned responding evoked by the conditional stimulus effects of nicotine.

RATIONALE: Research using a drug discriminated goal-tracking (DGT) task showed that the N-methyl-D: -aspartate (NMDA) channel blocker MK-801 (dizocilpine) reduced the nicotine-evoked conditioned response (CR). OBJECTIVES: Given the unknown mechanism of the effect, Experiment 1 replicated the MK-801 results and included tests with NMDA receptor ligands. Experiments 2a and 2b tested whether MK-801 pretreatment blocked DGT via a state-dependency effect. METHODS: In Experiment 1, adult male Sprague-Dawley rats received intermittent access to liquid sucrose following nicotine (0.4 mg base/kg); no sucrose was delivered on intermixed saline sessions. Conditioning was indicated by increased anticipatory dipper entries (goal-tracking) on nicotine compared to saline sessions. Antagonism and/or substitution tests were conducted with MK-801, phencyclidine, CGP 39551, d-CPPene (SDZ EAA 494), Ro 25,6981, L-701,324, ACPC, and NMDA. In Experiment 2a, rats received nicotine and sucrose on every session-no intermixed saline sessions without sucrose. Tests combined MK-801 or the non-competitive nicotinic acetylcholine receptor antagonist, mecamylamine with either nicotine or saline. Experiment 2b had sucrose delivered on saline sessions and no sucrose on intermixed nicotine sessions followed by MK-801 antagonism tests of the saline CS. RESULTS: MK-801 and phencyclidine dose-dependently attenuated the CR in Experiment 1. Ro-25,6981 enhanced the CR, but did not substitute for nicotine. Other ligands showed inconsistent effects. In Experiment 2a, MK-801 pretreatment reduced goal-tracking when given before nicotine and saline test sessions; mecamylamine pretreatment had no effect. In Experiment 2b, MK-801 dose-dependently attenuated the saline-evoked CR. CONCLUSIONS: Combined, the results suggest that MK-801 blocks discriminated goal-tracking by virtue of state-changing properties.

A Cartesian reflex assessment of face processing.

Commands to blink were embedded within pictures of faces and simple geometric shapes or forms. The faces and shapes were conditioned stimuli (CSs), and the required responses were conditioned responses, or more properly, Cartesian reflexes (CRs). As in classical conditioning protocols, response times (RTs) were measured from CS onset. RTs provided a measure of the processing cost (PC) of attending to a CS. A PC is the extra time required to respond relative to RTs to unconditioned stimulus (US) commands presented alone. They reflect the interplay between attentional processing of the informational content of a CS and its signaling function with respect to the US command. This resulted in longer RTs to embedded commands. Differences between PCs of faces and geometric shapes represent a starting place for a new mental chronometry based on the traditional idea that differences in RT reflect differences in information processing.