Peter G. Roma

BEHAVIORAL ECONOMICS AND EMPIRICAL PUBLIC POLICY

The application of economics principles to the analysis of behavior has yielded novel insights on value and choice across contexts ranging from laboratory animal research to clinical populations to national trends of global impact. Recent innovations in demand curve methods provide a credible means of quantitatively comparing qualitatively different reinforcers as well as quantifying the choice relations between concurrently available reinforcers. The potential of the behavioral economic approach to inform public policy is illustrated with examples from basic research, pre-clinical behavioral pharmacology, and clinical drug abuse research as well as emerging applications to public transportation and social behavior. Behavioral Economics can serve as a broadly applicable conceptual, methodological, and analytical framework for the development and evaluation of empirical public policy.

Apparatus bias and the use of light and texture in place conditioning

In a typical conditioned place preference (CPP) preparation, animals alternately experience drug and vehicle effects in distinct chambers of an apparatus, spending more time in the drug-paired chamber post-conditioning. However, if all animals prefer the same chamber before conditioning, data interpretation may be compromised. Unbiased apparatus has been systematically validated with ethanol in mice ([Cunningham, C.L., Feree, N.K., Howard, M.A. Apparatus bias and place conditioning with ethanol in mice. Psychopharmacology (Berl) 2003;170:409-422]); the present study sought to identify and eliminate bias in a standard black-and-white apparatus and validate that apparatus for CPP with morphine and cocaine in rats. Apparatus bias was assessed in 24 adult female Sprague-Dawley rats. Subjects preferred the black chamber under bright lighting conditions, with no preference in the dark. Subjects then underwent a counterbalanced CPP regimen to 5 mg/kg SC morphine (n=12) or 20 mg/kg IP cocaine (n=12) using only tactile conditioned stimuli. Significant absolute preferences for the drug-paired chamber were produced by both drugs, with no effect of drug-paired chamber assignment on CPP expression; vehicle-treated controls (n=12) showed no preferences. Bias-free CPP to morphine and cocaine using standard apparatus in rats is possible. Implications for place conditioning are discussed, including the potential value of systematically exploiting apparatus bias in addition to eliminating it.

Demand for cocaine and food over time

When reinterpreted, data from Ahmed and Koob [Ahmed, S.H., Koob, G.F., Transition from moderate to excessive drug intake: Change in hedonic set point. Science 1998; 282:298-301.] show that the reinforcing strength of cocaine, an inessential good, increases with experience. However, no such effect obtains with a homeostatically regulated good such as food. The present study evaluated whether this difference could serve to distinguish abused drugs from biologically necessary goods. In Experiment 1, five rats from Christensen, Silberberg, Hursh, Huntsberry and Riley [Christensen, C.J., Silberberg, A., Hursh, S.R., Huntsberry, M.E., Riley, A.L., Essential value of cocaine and food in rats: tests of the exponential model of demand. Psychopharmacology 2008;198(2):221-229.] earned cocaine under a Fixed-Ratio 3 schedule for 7 sessions. Thereafter, in a demand procedure identical to that in Christensen et al., demand was re-assessed by measuring consumption at Fixed Ratios between 3 and 560. In Experiment 2, five different rats from Christensen et al. had their food demand curves re-determined using an identical procedure as the first. When fit with the exponential model, the second determination of cocaine demand in Experiment 1 showed greater essential value than the first, indicating that strength increased with cocaine exposure. In Experiment 2, the re-determined food demand curves showed no change from their initial determination. These results show that the strength of cocaine, but not food, increases with increased experience. Measures of time-based changes in essential value may serve as a basis for distinguishing addictive from non-addictive reinforcers.

Morphine-induced place conditioning in Fischer and Lewis rats: Acquisition and dose-response in a fully biased procedure

The Fischer (F344) and Lewis (LEW) rat strains differ on a variety of behavioral assays examining the effects of morphine, with many of the differences observed during acquisition of behavioral responses. The results of these studies and others examining endogenous physiology and the biochemical effects of morphine suggest that F344 rats are more sensitive to morphine than LEW rats. However, LEW animals have shown greater conditioned place preferences (CPP) to 4 mg/kg than F344 rats. CPP is a popular assay of drug reward in which acquisition of the preference can be measured across multiple conditioning cycles, yet this aspect of CPP has not been assessed in F344 and LEW rats. As part of an ongoing effort to fully characterize the conditioned rewarding effects of abused drugs in these strains, the present study assessed the effects of 0, 1, 4 and 10 mg/kg subcutaneous (SC) morphine in adult male F344 and LEW rats (n=12/strain/dose). A fully biased place conditioning procedure was employed where morphines effects were paired with the initially non-preferred chamber on Day 1, saline was paired with the preferred chamber on Day 2 and drug-free access to the entire apparatus was allowed on Day 3. This conditioning and testing regimen was repeated for four consecutive cycles. The F344 animals acquired CPP at 1 mg/kg only; this effect emerged after only two conditioning cycles. LEW rats never acquired a CPP at any dose tested. Peak blood morphine levels following SC injections of 1, 4 or 10 mg/kg revealed no significant strain or dose effects. These behavioral data are consistent with the hypothesis that F344 rats are more sensitive to the rewarding effects of morphine than LEW rats. Additional implications for the Fischer-Lewis model of drug abuse and the utility of CPP acquisition procedures are discussed.

Individual Differences in Attentional Deficits and Dopaminergic Protein Levels following Exposure to Proton Radiation

To assess the possible neurobehavioral performance risks to astronauts from living in a space radiation environment during long-duration exploration missions, the effects of head-only proton irradiation (150 MeV/n) at low levels (25–50 cGy, approximating an astronauts exposure during a 2-year planetary mission) were examined in adult male Long-Evans rats performing an analog of the human psychomotor vigilance test (PVT). The rodent version of PVT or rPVT tracks performance variables analogous to the human PVT, including selective attention/inattention, inhibitory control (“impulsivity”) and psychomotor speed. Exposure to head-only proton radiation (25, 50, 100 or 200 cGy) disrupted rPVT performance (i.e., decreased accuracy, increased premature responding, elevated lapses in attention and slowed reaction times) over the 250 day testing period. However, the performance decrements only occurred in a subgroup of animals at each exposure level, that is, the severity of the rPVT performance deficit was unrelated to proton exposure level. Analysis of brain tissue from irradiated and control rats indicated that only rats with rPVT performance deficits displayed changes in the levels of the dopamine transporter and, to a lesser extent, the D2 receptor. Additional animals trained to perform a line discrimination task measuring basic and reversal learning showed no behavioral effects over the same exposure levels, suggesting a specificity of the proton exposure effects to attentional deficits and supporting the rPVT as a sensitive neurobehavioral assay.

ON LOSS AVERSION IN CAPUCHIN MONKEYS

Chen, Lakshminarayanan, and Santos (2006) claim to show in three choice experiments that monkeys react rationally to price and wealth shocks, but, when faced with gambles, display hallmark, human-like biases that include loss aversion. We present three experiments with monkeys and humans consistent with a reinterpretation of their data that attributes their results not to loss aversion, but to differences between choice alternatives in delay of reinforcement.

The medial preoptic area modulates cocaine-induced activity in female rats

Drugs of abuse exert their effects by exploiting natural neurobiological reward mechanisms, especially the mesolimbic dopamine (DA) system. However, the mesolimbic system does not operate in isolation, and input from other reward-relevant structures may play a role in cocaines rewarding effects. The medial preoptic area (mPOA) of the hypothalamus is involved in the regulation of two essential and naturally rewarding behaviors: sexual and maternal behaviors. It also makes strong neuroanatomical connections with areas of the mesolimbic system, particularly the ventral tegmental area (VTA). As such, the mPOA is a logical candidate for a neuroanatomical locus modulating activity in the mesolimbic system and emergent behavioral expressions of drug reward, yet the role of this structure is largely unexplored. Here, using a female rat model, we show that the mPOA innervates the VTA in a region-specific manner, that lesions of the mPOA augment cocaine-induced Fos expression in the nucleus accumbens (NAc) and cocaine-induced conditioned place preference. We also show that approximately 68% of mPOA-VTA efferents release γ-aminobutyric acid (GABA), over 75% are sensitive to DA as evidenced by colocalization with DA receptors, and nearly 60% of these contain both DA receptors and GABA, which suggests a novel key role for the mPOA in the inhibition of the mesolimbic DA circuit. Combined, these results reveal the mPOA as a critical modulating structure in cocaine-induced mesolimbic activity and behavioral manifestation of reward, at least in part, via GABAergic output that is sensitive to DA input.

Early maternal separation and sex differences in the aversive effects of amphetamine in adult rats.

Early life stress increases vulnerability to psychostimulant abuse, sometimes in a sex-dependent manner. These effects are presumably produced by modulation of neurobiological reward mechanisms; however, drug intake is also influenced by sensitivity to the drugs aversive properties, and little is known about the effects of early life stress on stimulant aversion. To assess this possibility, Sprague-Dawley rat litters experienced daily separation from the dam for 3 h (MS) or 15 min (H) on post-natal days 2-14; control litters (AFR) experienced twice-weekly routine animal facility care only. As adults, the animals were tested for conditioned taste aversions (CTA) induced by 1.5, 2.0 or 3.0 mg/kg d-amphetamine administered intraperitoneally over three acquisition trials followed by six drug-free extinction trials (n=7-8/sex/dose/rearing group). All groups acquired significant aversions compared to their vehicle-treated controls, but differential rearing had no effect on CTA acquisition or extinction. Collapsed across rearing groups, females exhibited significantly stronger aversions and slower extinction than their male counterparts at the low 1.5 mg/kg dose, and unlike the males, failed to fully extinguish relative to their vehicle controls at 1.5 and 2.0 mg/kg. These data underscore the importance of sex differences in assays of stimulant abuse liability, and further support the hypothesis that the effects of post-natal stress on the reinforcing efficacy of psychostimulants may be predominantly due to modulation of reward mechanisms.

Maximizing information from space data resources: a case for expanding integration across research disciplines

Regulatory systems are affected in space by exposure to weightlessness, high-energy radiation or other spaceflight-induced changes. The impact of spaceflight occurs across multiple scales and systems. Exploring such interactions and interdependencies via an integrative approach provides new opportunities for elucidating these complex responses. This paper argues the case for increased emphasis on integration, systematically archiving, and the coordination of past, present and future space and ground-based analogue experiments. We also discuss possible mechanisms for such integration across disciplines and missions. This article then introduces several discipline-specific reviews that show how such integration can be implemented. Areas explored include: adaptation of the central nervous system to space; cerebral autoregulation and weightlessness; modelling of the cardiovascular system in space exploration; human metabolic response to spaceflight; and exercise, artificial gravity, and physiologic countermeasures for spaceflight. In summary, spaceflight physiology research needs a conceptual framework that extends problem solving beyond disciplinary barriers. Administrative commitment and a high degree of cooperation among investigators are needed to further such a process. Well-designed interdisciplinary research can expand opportunities for broad interpretation of results across multiple physiological systems, which may have applications on Earth.

Genetic and early environmental contributions to alcohol's aversive and physiological effects

Genetic and early environmental factors interact to influence ethanols motivational effects. To explore these issues, a reciprocal cross-fostering paradigm was applied to Fischer and Lewis rats. The adult female offspring received vehicle or the kappa opioid antagonist nor-BNI (1 mg/kg) followed by assessments of conditioned taste aversion (CTA), blood alcohol concentrations (BACs) and hypothermia induced by 1.25 g/kg intraperitoneal ethanol. CTA acquisition in the in-fostered Fischer and Lewis animals did not differ; however, the Fischer maternal environment produced stronger acquisition in the cross-fostered Lewis rats versus their in-fostered counterparts. CTAs in the Fischer rats were not affected by cross-fostering. In extinction, the in-fostered Lewis animals displayed stronger aversions than the Fischer groups on two trials (of 12) whereas the cross-fostered Lewis differed from the Fischer groups on nine trials. Despite these CTA effects, Lewis rats exhibited higher BACs and stronger hypothermic responses than Fischer with no cross-fostering effects in either strain. No phenotypes were affected by nor-BNI. These data extend previous findings dissociating the aversive and peripheral physiological effects of ethanol in female Fischer and Lewis rats, and highlight the importance of genetic and early environmental factors in shaping subsequent responses to alcohols motivational effects in adulthood.