Two views of the addiction elephant: Comment on McSweeney, Murphy, and Kowal (2005).

F. K. McSweeney, E. S. Murphy, and B. P. Kowal (see record 2005-10634-001) present a convincing case that the literature on habituation and sensitization to the sensory properties of conventional reinforcers is relevant to understanding a variety of addictive behaviors. They note that their model has advantages over a number of alternative formulations. However, in discussing one particular such alternative, a Pavlovian conditioning analysis of drug tolerance and withdrawal, F. K. McSweeney et al. overstate the advantages of their reinforcer habituation/sensitization model. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Does habituation play a role in drug habit? Comment on McSweeney, Murphy, and Kowal (2005).

Comment on the article, "Regulation of Drug Taking by Sensitization and Habituation," by McSweeney, et al (see record 2005-10634-001). McSweeney, Murphy, and Kowal offer the intriguing suggestion that the basic behavioral processes of habituation and sensitization play an important role in drug taking, specifically, repeated drug taking. The suggestion is noteworthy because, if correct, it, as the authors point out, could lead to new approaches to prevention and treatment, approaches that involve the use of environmental variables that are relatively accessible. I think their exposition raises several issues. A number of these questions are related to the phenomenon of drug tolerance, an outcome that can be understood as either an instance of or deriving from the process of habituation. The presentation also contains passages in which the logic is not fully clear. Another issue I have with the article is the overall logic approach on the basis of features of drug addiction. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

McSweeney, Murphy, and Kowal: Reply to Branch (2005), Rowlett (2005), and Siegel (2005).

The authors thank M. N. Branch (see record 2005-10634-002), J. K. Rowlett (see record 2005-10634-003), and S. Siegel (see record 2005-10634-004) for their comments. Branch's commentary contains many misconceptions. The authors try to clarify these issues. They agree with Rowlett that converging approaches to understanding drug consumption will ultimately yield the best results. The authors also agree that measuring reinforcer effectiveness is difficult. New techniques such as probe preference tests make this task more manageable. The authors thank Siegel for describing recent changes in his model. Nevertheless, the authors believe that their discussion of his compensatory response model helps to clarify their own model. They also believe Siegel defines homeostasis somewhat differently than they do; thus, their positions may be more similar than they appear. The details of their model remain to be worked out, but the authors believe that it provides a testable and parsimonious model for the regulation of drug consumption. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Getting back to basics: Commentary on McSweeney, Murphy, and Kowal (2005).

The review article "Regulation of Drug Taking by Sensitization and Habituation" by F. K. McSweeney, E. S. Murphy, and B. P. Kowal (see record 2005-10634-001) introduces 2 basic principles of behavior, sensitization and habituation, into a comprehensive model for studying drug intake and drug addiction. A key assumption of the model is that the reinforcing effectiveness of drugs sensitize and/or habituate; however, issues with the measurement of reinforcing effectiveness should be carefully considered. In addition, a multidisciplinary approach might broaden this model and increase its power. Other approaches include, but are not limited to, pharmacokinetic-pharmacodynamic modeling and in vivo measures of brain activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Morphine tolerance as habituation.

Demonstrates that the development of tolerance to morphine conforms to A. R. Wagner's (1979) priming model of habituation. Tolerance develops through both associational and nonassociational routes: The development of associational tolerance is attributed to retrieval-generated priming of memory, whereas nonassociational tolerance is attributed to self-generating priming. This model accounts for the effects of dose level, drug signaling, and interdose interval on tolerance development. Also, a habituation model is consistent with data showing that dose level and interdose interval affect the impact of drug signals on tolerance development. Limitations of the habituation model are noted with respect to the development of tolerance in vitro, sensitization, and CRs antagonistic to initial drug effects. (5 p ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioning of and contextual sensitization to apomorphine-induced climbing in mice: Evidence against the habituation hypothesis.

Several predictions of the habituation hypothesis of conditioned drug effects were tested by looking at contextual sensitization to apomorphine-induced climbing in mice (Mus musculus). Mice were first sensitized to that effect after 9 daily injections of 0.4 mg/kg apomorphine in the test context. Other mice received the same treatment outside the test context. On Day 10, all mice were challenged with either saline (conditioned drug effects test) or apomorphine (contextual sensitization test). On both tests, the levels of climbing of mice that received apomorphine paired with the test context during the intermittent treatment were significantly higher than those of mice that were experiencing the test context for the first time (unexposed mice). Also, the rate of extinction in conditioned mice did not parallel the rate of habituation in the unexposed mice. Results contradict the habituation hypothesis of conditioned drug effects and contextual sensitization. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The observing-response procedure: A novel method to study drug-associated conditioned reinforcement.

In this experiment, the observing-response procedure was adapted for use with drug self-administration. Rats' responding for oral ethanol was sometimes reinforced on a random-ratio schedule, whereas at other times it had no effect (i.e., extinction). Behavior producing stimuli associated with the otherwise unsignaled random-ratio and extinction periods (i.e., observing behavior) was acquired and maintained. In a vehicle control condition, both self-administration and observing behavior decreased, but observing decreased less rapidly proportionally to baseline than vehicle consumption. Thus, conditioned reinforcers may have persistent effects that are relatively independent of the current status of the primary reinforcer. The procedure allows long-term study of drug-associated conditioned reinforcement and provides independent indexes of the conditioned reinforcing and discriminative stimulus effects of drug stimuli. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spontaneous recovery and dishabituation of ethanol-reinforced responding in alcohol-preferring rats.

This study examined whether habituation, a decrease in responsiveness to a repeatedly presented stimulus, occurs to ethanol reinforcers in alcohol-preferring (P) rats. Three fundamental properties of habituation were evaluated: generality, spontaneous recovery, and dishabituation. In each experiment, P rats' lever pressing was reinforced by 10% ethanol on a variable-interval 15-s schedule during 50-min sessions. Experiment 1 evaluated the generality of habituation to repeatedly presented stimuli by using ethanol and water reinforcers. Rates of responding were higher for ethanol than they were for water. Additionally, the within-session patterns of responding differed for each reinforcer, suggesting that the pattern of responding was specific to the exact nature of the repeatedly presented reinforcer. Experiment 2 examined spontaneous recovery, an increase in responsiveness to a habituated stimulus when that stimulus is not presented for a time, by separating experimental sessions by 5 min, 2 hr, or 24 hr. Early-session rates of responding during Session 2 were slower than the corresponding rates during Session 1 when sessions were separated by 5 min or 2 hr. Response rates and within-session patterns of responding during Sessions 1 and 2 were similar when sessions were separated by 24 hr. Experiment 3 tested for dishabituation, a restoration of responsiveness following the presentation of an extraneous stimulus, by presenting a tone or a light 24 min and 55 s into the session. Rates of responding temporarily increased after the tone was presented. The results of these experiments support the idea that habituation contributes to the regulation of ethanol consumption. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Optimization of conformal radiation treatment of prostate cancer: report of a dose escalation study

Under some conditions, stimulant preexposure sensitizes rats to the reinforcing effects of cocaine and other stimulants, whereas under other conditions exposure decreases the reinforcing efficacy of cocaine. This paper reviews the literature on the effects of stimulant preexposure on self-administration, focusing on methodological and interpretative issues. It is concluded that both sensitization and tolerance occur following stimulant preexposure but that these two effects can be dissociated temporally, with sensitization occurring during the development of drug self-administration and tolerance occurring in response to high doses of stimulants administered to experienced self-administering rats. The relative contribution of both of these effects to compulsive drug-taking is discussed, with emphasis on the development of cocaine as a reinforcer, maintenance of self-administration, and relapse to drug-taking.     

A model for Pavlovian learning: Variations in the effectiveness of conditioned but not of unconditioned stimuli.

Part 1 of this discussion summarizes several formal models of exicitatory classical conditioning. It is suggested that a central problem for all of them is the explanation of cases in which learning does not occur in spite of the fact that the CS is a signal for the reinforcer. A new model is proposed that deals with this problem by specifying that certain procedures cause a CS to lose effectiveness; in particular, it is argued that a CS will lose associability when its consequences are accurately predicted. In contrast to other current models, the effectiveness of the reinforcer remains constant throughout conditioning. Part 2 presents a reformulation of the nature of the learning produced by inhibitory-conditioning procedures and a discussion of the way in which such learning can be accommodated within the model outlined for excitatory learning. (47 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Detection of Legionella pneumophila in wastewater by nested polymerase chain reaction

Behavioral economics defines unit price (UP) as the ratio of the response requirement to magnitude of reinforcer. When applied to drug self-administration, the UP model defines UP as the ratio of the response requirement to the unit dose of drug. This model makes two predictions about drug self-administration: increasing UP decreases consumption and consumption at a given UP will be constant regardless of the response requirement and dose that make up the UP. In previous experiments conducted in rhesus monkeys allowed to choose between an i.v. injection of cocaine and food, the UP model has failed to adequately predict drug consumption in that consumption varied (increased with dose) at a given UP. However, previous experiments have allowed a fixed number of choice trials/day, thereby imposing a procedural ceiling on consumption that may have influenced conformity to the UP model. In the present experiment, the number of choice trials available was varied in such a way that constant drug consumption was possible over the range of UPs tested. The response requirement for cocaine was varied between 15 and 1200 lever presses/injection and the dose of cocaine was varied between 0.05 and 0.2 mg/kg/inj, yielding UPs from 300 to 5600 responses/mg/kg. The response requirement for food was always 30. As predicted by the UP model, cocaine consumption decreased as UP increased. Moreover, in contrast to previous experiments, consumption did not vary significantly across the response requirement/dose combinations that made up a UP. A detailed analysis suggested that a decrease in magnitude of the alternative reinforcer (one rather than three food pellets), rather than the increase in trials, was responsible for the improved conformity to the UP model in the present experiment relative to previous experiments. Taken together with previous experiments, the present experiment suggests that conformity to the UP model of drug consumption in a choice situation is dependent upon the magnitude of alternative reinforcers that are available. Consumption was best predicted by the UP model when the magnitude of the alternative reinforcer was small.     

Quantification of reinforcing effectiveness: Comment on Meisch (2000).

R. A. Meisch (see record 2000-00465-009) introduces an innovative method for quantifying the reinforcing effectiveness of drugs and other substances. Advantages are that it models the persistence of drug use in humans and its persistence ratios are the same whether responding or consumption is measured. Data indicate that the method is sensitive to factors that affect drug self-administration. The measure's core feature is "the systematic variation of both reinforcer magnitude and schedule size" (Meisch, 2000, p. 347); however, the method may not be widely used with such extensive parametric analysis. Variation of only reinforcer magnitude (or dose/concentration) seems to produce similar results, and this abbreviated analysis is similar to the behavioral economic analysis of demand. When responding is plotted as a function of unit price (responses/milligram), the peak of the curve (where maximum responding occurs) is a measure of persistence. Further work will determine how these and other measures of reinforcing effectiveness agree. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Behavioral tolerance and sensitization to alcohol in humans: The contribution of learning.

This experiment tested the hypothesis that tolerance or sensitization to repeated alcohol doses is predicted by the particular response (diminished or augmented impairment) that is reinforced under drug. Twelve male social drinkers were assigned to a tolerance (T) or sensitization (S) group (n?=?6) and performed a psychomotor task under 0.62 g/kg of alcohol on 5 separate sessions. The 1st session preceded training and determined that the groups' drugged performance did not differ. On 3 subsequent sessions verbal feedback reinforced diminished impairment in Group T and augmented impairment in Group S. During these sessions, Groups T and S displayed tolerance and sensitization, respectively. The final session showed that training effects were retained without reinforcement. The results extend the evidence on the effect of reinforcement to show that it can enhance sensitization as well as tolerance. The findings demonstrate that behavioral variables modulate the response to alcohol and imply that tolerance and sensitization may be affected by a common learning process. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Habituation model of systematic desensitization.

Discusses the relevance of habituation as a model for response decrement in desensitization. A discussion of the relationship between habituation and extinction leads to the view that there are no sound reasons for explaining desensitization as an extinction rather than as a habituation phenomenon. The maximal habituation theory of desensitization proposed by M. H. Lader and A. M. Mathews (1968) is discussed and relevant evidence reviewed. Finally, a revised habituation theory of desensitization, based on the dual-process theory of habituation, is elaborated, and the role in desensitization of relaxation, stimulus intensity, stimulus lengths, and interstimulus interval lengths are discussed in the context of this theory. It is suggested that relaxation and an incremental stimulus hierarchy may reduce sensitization rather than facilitate habituation. (60 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Biological consequences of drug administration: Implications for acute and chronic tolerance.

The authors presented a model that extrapolates the biological consequences of drug administration to account for acute and chronic tolerance. Drug-induced changes of regulated parameters provide detectable perturbations to which the brain responds. With experience, these centrally mediated responses are learned and can be activated in the absence of the drug-induced perturbation. Although neural responses following drug administration are often obscured, the model shows how these responses may be identified and provides a reinterpretation of drug conditioning paradigms. The authors made comparisons between the present empirical model of drug administration and existing theories of drug tolerance. The authors also presented a unified framework for understanding the consequences of repeated drug use and made specific predictions as to the relationships among acute and chronic tolerance, drug sensitization, and individual differences in vulnerability to drug addiction. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Tolerance and sensitization to the behavioral effects of cocaine in rats: relationship to benzodiazepine receptors

Tolerance and sensitization to the behavioral effects of cocaine were investigated in rats responding under a fixed-consecutive-number eight schedule of food reinforcement. The development of tolerance or sensitization was induced by delivering the drug either immediately before or after each behavioral session during chronic administration. Chronic cocaine administered before each session resulted in tolerance, as indicated by the shift to the right in the cocaine dose response curve. This tolerance was more likely to develop in the presence of an external discriminative stimulus. On the other hand, when cocaine was delivered after each session, the injections did not disrupt responding and sensitization or increased sensitivity rather than tolerance developed. This sensitization was more likely to occur when the external discriminative stimulus was not present. These data suggest that either tolerance or sensitization to the behavioral effects of cocaine can occur following the same number of chronic injections, with the effect dependent on the context under which the drug is delivered. Significant differences in benzodiazepine receptor binding measured autoradiographically using [3H]flumazenil were observed between rats that received cocaine before or after each session, suggesting that the development of tolerance and sensitization may be mediated through changes in benzodiazepine receptors in discrete brain regions.     

Amphetamine-induced conditioned activity and sensitization: the role of habituation to the test context and the involvement of Pavlovian processes

Behaviours associated with drug action can sometimes be elicited, in the absence of drug, by exposure to stimuli that were present during drug administration. Such a finding is usually interpreted as a conditioned drug effect. Often, however, the outcome could arise if drug administration in a particular environment retarded behavioural habituation to that environment. To test the 'habituation hypothesis' of conditioned drug effects, mice received 10 daily injections of d-amphetamine ('paired' group) or saline ('unpaired') in test boxes, and the converse injections in the colony room. Another group received saline in both environments. The apparatus and procedures yielded minimal habituation of behaviours (ambulation and rearing) over sessions. Only the paired group demonstrated behavioural sensitization, indicating environment-specific sensitization. The paired group also showed more ambulation and rearing than the others on the critical test of conditioning (saline injection in test box); moreover, their conditioning test scores were higher than those of the other groups on their first exposure to the test boxes, contradicting the habituation hypothesis. Further supporting the involvement of Pavlovian conditioning, levels of ambulation and rearing measured for 10 min before each injection increased in the paired group, relative to the unpaired groups, over successive pairing sessions. Tests controlling for differential handling/injection experience produced results consistent with those previously obtained. Together, the findings are incompatible with the habituation hypothesis, and further support the role of Pavlovian conditioning.     

Tolerance to morphine in the rat: Associative and nonassociative effects.

Two experiments were conducted to examine the impact of dose level and interdose interval (IDI) on the development of tolerance to the analgesic effect of morphine. In Exp I, rats were administered a series of low- (5 mg/kg) or high- (30 mg/kg) dose injections of morphine either explicitly paired or unpaired with a distinctive context at a 48-hr IDI. The development of tolerance following this regimen was assessed by shifts in dose-response curves to the right when animals were tested on a tail-flick device in the distinctive context. Only animals that had received morphine paired with the distinctive context were tolerant to morphine; the magnitude of this associative tolerance was a positive function of the level of the conditioning dose. In Exp II, rats were exposed to a high dose of morphine (30 mg/kg) either paired or unpaired with a distinctive context at one of two IDIs (24 or 96 hr). Tolerance testing revealed that at the long IDI, only associative tolerance was evident, whereas at the short IDI, tolerance in the unpaired condition was more pronounced with a corresponding decline in the development of associative tolerance. The relevance of these findings for psychological theories of drug tolerance are discussed. Results are consistent with the predictions of an habituation model of drug tolerance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitization of the rat startle response by noise.

In a series of 6 experiments with a total of 160 male Sprague-Dawley albino rats, it was found that the startle response showed a progressive increase in amplitude when tones were presented against a high level of background noise. This sensitization effect was not a result of repetitive exposure to tones but rather a result of continuous exposure to noise. The size of the effect was directly related to noise intensity and required about 30-45 min to reach a maximum. The effect did not dissipate when the noise was maintained but did dissipate once the noise was turned down. Results are discussed in terms of the experimental conditions under which repetitive stimulus exposure produces either sensitization or habituation of the startle reflex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Contextual effects in conditioning, latent inhibition, and habituation: Associative and retrieval functions of contextual cues.

Rats were used as subjects in four experiments to investigate the transfer of learning from one context to another. Subjects received two sessions of training each day, one in each of two different contexts. Experiment 1 showed that the habituation of the unconditioned response to a stimulus presented in one context was left intact when the stimulus was presented in another context, but that latent inhibition was attenuated when preexposure and conditioning phases occurred in different contexts. Experiments 2 and 3 demonstrated that a conditioned response made on the basis of an appetitive reinforcer was diminished when conditioning and testing occurred in different contexts, but that aversive conditioning was not influenced by the context in which testing occurred. In Experiment 4, the presence of an aversive reinforcer during training did not preclude the occurrence of context-specific conditioning on the basis of an appetitive reinforcer. Associative and retrieval-based interpretations of the results are explored. (PsycINFO Database Record (c) 2010 APA, all rights reserved)