Interhemispheric gene expression differences in the cerebral cortex of humans and macaque monkeys.

Handedness and language are two well-studied examples of asymmetrical brain function in humans. Approximately 90% of humans exhibit a right-hand preference, and the vast majority shows left-hemisphere dominance for language function. Although genetic models of human handedness and language have been proposed, the actual gene expression differences between cerebral hemispheres in humans remain to be fully defined. In the present study, gene expression profiles were examined in both hemispheres of three cortical regions involved in handedness and language in humans and their homologues in rhesus macaques: ventrolateral prefrontal cortex, posterior superior temporal cortex (STC), and primary motor cortex. Although the overall pattern of gene expression was very similar between hemispheres in both humans and macaques, weighted gene correlation network analysis revealed gene co-expression modules associated with hemisphere, which are different among the three cortical regions examined. Notably, a receptor-enriched gene module in STC was particularly associated with hemisphere and showed different expression levels between hemispheres only in humans.

Comparative analysis of Meissner's corpuscles in the fingertips of primates.

Meissner's corpuscles (MCs) are tactile mechanoreceptors found in the glabrous skin of primates, including fingertips. These receptors are characterized by sensitivity to light touch, and therefore might be associated with the evolution of manipulative abilities of the hands in primates. We examined MCs in different primate species, including common marmoset (Callithrix jacchus, n = 5), baboon (Papio anubis, n = 2), rhesus macaque (Macaca mulatta, n = 3), chimpanzee (Pan troglodytes, n = 3), bonobo (Pan paniscus, n = 1) and human (Homo sapiens, n = 8). Fingertips of the first, second and fourth digits were collected from both hands of specimens, dissected and histologically stained using hematoxylin and eosin. The density (MCs per 1 mm(2) ) and the size (cross-sectional diameter of MCs) were quantified. Overall, there were no differences in the densities of MCs or their size among the digits or between the hands for any species examined. However, MCs varied across species. We found a trend for higher densities of MCs in macaques and humans compared with chimpanzees and bonobos; moreover, apes had larger MCs than monkeys. We further examined whether the density or size of MCs varied as a function of body mass, measures of dexterity and dietary frugivory. Among these variables, only body size accounted for a significant amount of variation in the size of MCs.

Outcome specificity in deepened extinction may limit treatment feasibility: co-presentation of a food cue interferes with extinction of cue-elicited cocaine seeking.

BACKGROUND: We previously showed that presenting two cocaine cues simultaneously during extinction deepens the extinction of cue-elicited cocaine seeking (Kearns et al., 2012). The present study investigated whether compounding a non-drug appetitive cue with a cocaine cue would similarly deepen extinction. METHODS: In Experiment 1, tone and click were each first established as discriminative stimuli for cocaine-reinforced responding and light was a cue for food-reinforced responding. In an initial extinction phase, all stimuli were presented individually. Then, during an additional compound extinction session, rats received 8 presentations of one of the cocaine cues (counterbalanced over subjects) simultaneously with light and 8 presentations of the other cue alone. A spontaneous recovery test was used to evaluate the effectiveness of the extinction treatments. Experiment 2 was performed under conditions designed to match those of Experiment 1, except food was the reinforcer in tone and click instead of cocaine. RESULTS: In Experiment 1, the cocaine cue compounded with the food cue during extinction controlled greater spontaneous recovery of cocaine seeking than the cocaine cue always presented alone. In contrast, Experiment 2 demonstrated deepened extinction of responding to a food cue when both compounded cues were food cues. CONCLUSIONS: Results suggest that deepened extinction depends on the compound presentation of cues associated with the same reinforcer. Compound presentation of cues associated with different reinforcers could lead to an enhancement of responding. Care is urged in attempts to deepen the extinction of cue-elicited drug seeking by compounding drug cues with non-drug cues.

The role of the aversive effects of drugs in self-administration: assessing the balance of reward and aversion in drug-taking behavior.

Since the first experimental demonstration that a drug of abuse supports instrumental behavior, drugs have been discussed in the context of their rewarding effects, which are assumed to drive and maintain drug-taking behavior. Indeed, drug reward has been fundamental in the formulation of most models of drug use, abuse, and addiction. Over the last several decades, however, drugs of abuse have been increasingly recognized as complex pharmacological compounds producing multiple stimulus effects, not all of which are rewarding. The aversive effects of such drugs, for example, have been described by a number of researchers working in the field, although few attempts have been made to investigate the role of these aversive effects in drug taking. The present paper offers a historical perspective on the view that drugs of abuse are complex pharmacological compounds with multiple stimulus effects. In doing so, we argue that the discussion of drug reward only may be insufficient in accounting for drug taking and we present evidence for the theoretical position that both the rewarding and the aversive effects of drugs should be taken into consideration in ongoing attempts to model drug-taking behavior. The present review summarizes several decades of research characterizing the aversive effects of major drugs of abuse, as well as more recent studies seeking to assess directly the role of drug aversion in drug taking.

A comparison of therapies for the treatment of drug cues: counterconditioning vs. extinction in male rats.

Although extinction has been used as a treatment to reduce the power of drug cues, a better method is needed. Research with traditional reinforcers has shown that counterconditioning--pairing an appetitive cue with an aversive stimulus--can suppress cue-controlled behavior. The present experiment compared the counterconditioning and extinction of cocaine cues. Male rats were first trained to self-administer cocaine during a light cue. In the second phase, the light was paired with footshock in the counterconditioning group. The extinction group was treated similarly, except light presentations did not end in footshock. Counterconditioning suppressed cocaine seeking to a greater extent than extinction while the counterconditioning treatment was actively administered. On a subsequent stimulus compounding test, where footshock was discontinued and the light was presented simultaneously with an untreated cocaine cue (a tone), suppressive effects of counterconditioning were evident during the early portion of the test but not during later trials. Overall, results of the present experiment suggest that counterconditioning produces only temporarily suppressive effects on cue-controlled cocaine seeking. Methods for directly weakening the cue-drug association (e.g., "deepened extinction") may prove to be more useful drug cue treatments.

Conditioned taste aversion and drugs of abuse: history and interpretation.

Conditioned taste aversion (CTA) learning describes a phenomenon wherein an animal learns to avoid consumption of a particular taste or food following its pairing with an aversive stimulus. Although initially demonstrated with radiation and classical emetics, CTAs have also been shown with drugs of abuse. The ability of rewarding drugs to support CTA learning was described as paradoxical by many investigators, and a number of attempts have been made to resolve this paradox. The present review offers a historical perspective on the CTA literature with a particular focus on CTAs induced by self-administered drugs. Specifically, this review describes and summarizes several interpretations of CTA learning that offer possible mechanisms by which drugs of abuse support CTAs, including sickness, drug novelty, reward comparison and conditioned fear. It is concluded that the reported "paradox" is no paradox at all in that drugs of abuse are complex pharmacological compounds that produce multiple stimulus effects, not all of which are positive reinforcing. Finally, a possible role of drug aversion in drug self-administration is discussed.

Relationship between the rewarding and aversive effects of morphine and amphetamine in individual subjects.

Drugs of abuse have been reported to produce both rewarding and aversive effects, as evidenced by their ability to induce both conditioned place preferences (CPPs) and conditioned taste aversions (CTAs), respectively. Although several attempts have been made to assess the relationship between the rewarding and aversive effects of drugs in independent groups, it is unknown to what extent (if any) preferences and aversions are related in individual animals. The present study assessed this relationship by examining the ability of morphine (5 and 10 mg/kg) and amphetamine (3 and 5 mg/kg) to induce both place preferences and taste aversions in the same animal, using a concurrent CTA/CPP design. There was no consistent relationship between the ability of morphine or amphetamine at either dose to increase time spent on the drug-paired side and the ability to suppress consumption of the drug-paired taste. These results support the position that drugs of abuse have multiple stimulus effects, both rewarding and aversive, that condition place preferences and taste aversions independently.

Noradrenergic antagonism enhances the conditioned aversive effects of cocaine.

The propensity to self-administer cocaine may be a function of both its positively reinforcing and aversive effects, with the latter acting as a limiting factor on overall drug taking. However, relative to what is known about the physiological underpinnings of cocaine's positively reinforcing effects, little is known about its aversive effects. There is some evidence that cocaine's aversive effects, as indexed in the conditioned taste aversion (CTA) preparation, are catecholaminergically mediated, i.e., through cocaine's actions on the dopaminergic and noradrenergic neurotransmitter systems. Although limited evidence suggests a role for dopamine, there has yet to be a direct assessment of noradrenergic involvement. To better characterize a role for this system, cocaine-induced CTAs (10, 18 and 32 mg/kg) were conducted under conditions of antagonism at the norepinephrine alpha(1) and beta receptors using prazosin (0.3 mg/kg; Experiment 2) and propranolol (10 mg/kg; Experiment 3), respectively, at doses that were determined to be non-aversive (Experiment 1). In each case of noradrenergic antagonism, CTAs with cocaine were not attenuated, suggesting that this drug's conditioned aversive effects are mediated by non-noradrenergic NT activity. Furthermore, prazosin and propranolol administration appeared to facilitate the conditioned aversive effects of cocaine. The implications of these findings in regards to other neurochemical processes are discussed.

The effects of cocaine, alcohol and cocaine/alcohol combinations in conditioned taste aversion learning.

We have recently reported that alcohol attenuates cocaine place preferences. Although the basis for this effect is unknown, alcohol may attenuate cocaine reward by potentiating its aversive effects. To examine this possibility, these experiments assessed the effects of alcohol on cocaine-induced taste aversions under conditions similar to those that resulted in attenuated place preferences. Specifically, Experiments 1 and 2 assessed the effects of alcohol (0.5 g/kg) on taste aversions induced by 20, 30 and 40 mg/kg cocaine. Experiment 3 examined the role of intertrial interval in the effects of alcohol (0.5 g/kg) on cocaine (30 mg/kg) taste aversions. In Experiments 1 and 2, cocaine was effective at conditioning aversions. Alcohol produced no measurable effect. Combining cocaine and alcohol produced no greater aversion than cocaine alone (and, in fact, weakened aversions at the lowest dose of cocaine). In Experiment 3, varying the intertrial interval from 3 days (as in the case of Experiments 1 and 2) to 1 day (a procedure identical to that in which alcohol attenuated cocaine place preferences) resulted in significant alcohol- and cocaine-induced taste aversions. Nonetheless, alcohol remained ineffective in potentiating cocaine aversions. Thus, under these conditions alcohol does not potentiate cocaine's aversiveness. These results were discussed in terms of their implication for the effects of alcohol on cocaine-induced place preferences. Further, the effects of alcohol on place preferences conditioned by cocaine were discussed in relation to other assessments of the effects of alcohol on the affective properties of cocaine and the implications of these interactions for alcohol and cocaine co-use.