BACKGROUND:Ethanol withdrawal alters brain neurochemistry, causes asymmetric activation of neurons in the medial prefrontal cortex (mPFC) and amygdala (AMY), and increases ethanol craving and drinking. Rats with intrinsic rightward-turning preferences drink more ethanol than those with left or no preferences; they also exhibit an ethanol-induced neurochemical activation that favors the right side of the mPFC. Our experiments used rats with different turning preferences to assess differences in withdrawal effects on mPFC and AMY neurochemistry as well as ethanol self-administration.METHODS AND RESULTS:Rats with left-turning, right-turning, and nonturning preferences were fed a 6% ethanol-containing liquid diet (WD) or a pair-fed control diet for 14 days. Differences in dopamine (DA), serotonin (5HT), norepinephrine (NE), and metabolite [3,4-dihydroxphenylacetic acid, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid) concentrations were assessed in each side of the mPFC and AMY during acute withdrawal. Similar groups were fed the same diets and tested for consumption of 10% ethanol versus water and 1% sucrose versus water. WD increased HVA/DA in the mPFC and caused depletions of DA and 5HT in the mPFC and 5HT in the AMY. These effects were greater in the right than in the left side of these structures in rats with right-turning preferences. WD reduced ethanol drinking but right turners drank significantly more than left turners on day 2 of testing and drank more on days 2 and 3 than on day 1. No effects were observed on sucrose drinking. Similar groups were also trained to self-administer ethanol using a sucrose-fade sipper tube procedure that separated measures of ethanol seeking (bar pressing) and consumption. Following 14 days of vapor chamber exposure to ethanol, rats of all turning preferences had a lower rate of bar pressing on the first postwithdrawal day and shorter latencies to begin bar pressing on the third withdrawal day versus prewithdrawal baseline. Only right-turning-preference rats consumed more ethanol following withdrawal.CONCLUSIONS:These studies show that individual rats differ in postwithdrawal brain neurochemistry and ethanol consumption and that these differences are associated with differences in functional brain asymmetry.

The anti-obesity agent, racemic (RS)-sibutramine, has two active metabolites, desmethylsibutramine and didesmethylsibutramine. To the extent that sibutramine itself mediates some of its side effects, desmethylsibutramine and/or didesmethylsibutramine might be safer and just as therapeutically effective. Because both desmethylsibutramine and didesmethylsibutramine are also optically active, the present study assessed the anorexic effects (2.5-10 mg/kg, i.p., for all drugs), in rats, of the R(+)-and S(-)-enantiomers of both metabolites and compared them to the effects of racemic sibutramine. Locomotor activity (2.5-10 mg/kg, i. p., for all drugs), a dopamine dependent behavior, was also measured in view of some uncertainty regarding dopaminergic effects of sibutramine. In view of sibutramine's antidepressant profile in animal models, the same drugs were also tested in the Porsolt swim test (0.1-2.5 mg/kg, i.p., for all drugs). Lastly, the IC(50)s of all drugs to inhibit uptake in vitro of norepinephrine, serotonin and dopamine were determined. Both (R)-enantiomers had significantly greater anorexic effects than those of their respective (S)-enantiomers as well as of sibutramine. All of the agents increased locomotor activity and reduced immobilized time ("behavioral despair") in the swim test; again, the (R)-enantiomers were more potent than the (S)-enantiomers and sibutramine. However, the anorexic and locomotor effects could be dissociated from each other as well as from effects in the swim test. Both (R)-desmethylsibutramine and (R)-didesmethylsibutramine as well as sibutramine decreased food intake at a time (24-42 h post-treatment) when locomotor activity was unaffected. All of the drugs appeared to be more potent in the swim test than in the other tests and all of the drugs were more potent at inhibiting uptake of norepinephrine and dopamine than of serotonin. The results suggest that these enantioselective metabolites of sibutramine could be safe and effective treatments for obesity as well as possibly for depression.

Functional and anatomical laterality of the human brain has been studied since the early neurologist Broca reported that lesions of the left cerebral hemisphere resulted in language disorders. His findings suggested a specialized role for this hemisphere in controlling speech (Broca, 1861). Since these early reports, numerous differences between the left and right hemispheres of the human brain have been reported. Many hemispheric asymmetries have been shown to involve dominance where one hemisphere plays a greater role in control of a specific behavior (Corballis, 1991; Hellige, 1993). It has been shown, for example, that while the human left hemisphere is specialized for the processing of language, the right hemisphere has a dominant role for the processing of musical, visuospatial and emotional information (Springer and Deutsch, 1981). Lateralization of brain function often indicates that the two hemispheres are differentially proficient in controlling various behavioral activities. Differential degrees of brain lateralization appear to occur within the population. Variation in human functional brain asymmetry is associated with differences in handedness (Annett, 1985; Bryden, 1982), cognitive ability (O’Boyle and Hellige, 1989), emotional function (Davidson, 1992) and psychopathology (Flor Henry, 1986).

Circling is a readily measurable behavior that is exhibited by many organisms and that may indicate that a lateral preference is present for carrying out other behavioral functions. In this respect, it is similar to handedness, the best known human index of lateral preference. Most modern accounts of the determinants of lateral preference suggest that it occurs as a result of some functional lateralization of systems in the brain. Lateralization simply means that the two hemispheres are differentially proficient in controlling various behavioral activities. The significance of lateralization extends beyond the simple fact of brain asymmetry. Rather, it implies that certain features of behaviors that are controlled by asymmetric brain areas will vary according to the kind and degree of asymmetry that is present. In this chapter, we will assess the utility of circling behavior as an index of brain asymmetry and the relationship of this asymmetry to various aspects of behavioral function.

The human brain has been shown to be laterally specialized with regard to a variety of functions. The genetic determinants of this specialization have also been explored. There has been some emphasis placed on individual differences in the degree of this specialization and the determination of its significance for lending a predisposition toward behavioral dysfunction and psychiatric disease. Whereas many animal models of human behavioral dysfunction have been developed, there has been relatively little interest and consequently relatively little data bearing on the issue of how differences in brain asymmetry in animals may be important parameters in determining the modeled dysfunction. However, over the past 15 years, data have accumulated to suggest that morphologic, chemical, and behavioral indices of brain asymmetry are present in animals. It has also been suggested that variations in the magnitude and direction of these indices are determined by a complex interaction of genetic, hormonal, and experiential factors. Individual differences in cerebral laterality have been shown to covary with or predict individual differences in drug responses, spatial behavior, and stressor reactivity as well as susceptibility to stressor-evoked behavior pathology and drug abuse predilection. Such findings suggest that it is possible to study genetically influenced individual differences in lateralized brain function as they exist in animals and to relate these differences to those seen in humans.

Experiments were conducted which assessed the effects of low doses of an environmental contaminant in conjunction with various forms of stress. Rats were given acute doses (0, 0.5, 1.5, 4.5 mg/kg) of the chemical dieldrin and subsequently exposed to a series of 40 escapable shocks, identical inescapable shocks, or no shock in an operant chamber. Eight hours later, the subjects were re-exposed in a shuttlebox to footshock which was escapable upon performance of an FR-2 shuttle response. Escape deficits which were related in magnitude to the size of the dieldrin dose were found in the inescapable shock group but not in the escapable shock or no shock groups. The data suggest that experience with the lack of control over stress is critical in determining the behavioral effects of the agent and that the behavioral effects caused by uncontrollable stress may be exacerbated by concurrent exposure to such compounds. These results are discussed in terms of previous studies on the behavioral actions of dieldrin, the response to uncontrollable stress and the common neuronal systems that may be involved.