Correlated asymmetries in striatal D1 and D2 binding: relationship to apomorphine-induced rotation.

Long-Evans derived rats were tested for nocturnal, amphetamine-induced and apomorphine-induced rotation (circling behavior); the rats' left and right striata were subsequently dissected and D1 and D2 receptor densities (Bmax) were assayed in the same striatal homogenates using [3H]SCH-23390 and [3H]N-methylspiperone, respectively. D1 and D2 Bmax values were correlated (r = 0.68). Moreover, left-right asymmetries in D1 and D2 Bmax values were more highly correlated (r = 0.84). Although asymmetries in D1 and D2 binding were not by themselves related to rotational behavior, an asymmetry in the ratio or balance of D1 and D2 binding was associated with the direction of apomorphine-induced rotation: the D1/D2 ratio of Bmax values was significantly higher in the striatum ipsilateral to the preferred direction of apomorphine-induced rotation. These results suggest that normal variations in numbers of D1 and D2 receptors are determined by a common mechanism, that D1 and D2 receptors are functionally coupled, and that, with respect to activation of striatal receptors, D1 is inhibitory and D2 is excitatory. The effects of apomorphine, a mixed D1 and D2 agonist, appear to reflect the balance between D1 and D2 receptors.

Food deprivation alters dopamine utilization in the rat prefrontal cortex and asymmetrically alters amphetamine-induced rotational behavior.

The effects of 24 and 48 h of food deprivation on changes in the activity of dopaminergic (DAergic) neurons and D-amphetamine-induced rotational behavior were studied in male and female Long-Evans rats. Food deprivation selectively altered 3,4-dihydroxyphenylacetic acid (DOPAC) in the medial prefrontal cortex (PFC) but not in the nucleus accumbens or striatum: PFC DOPAC was significantly increased and decreased bilaterally after 24 and 48 h of food deprivation, respectively. Left greater than right hemispheric asymmetries were seen for DOPAC and DOPAC/DA in the control animals. In a separate experiment, 24 h of food deprivation enhanced right rotational behavior, while 48 h significantly increased left rotational behavior. The results are discussed in terms of food deprivation's effects on mesocortical DAergic neurons, previous work on cortical modulation of striatal function and how these effects on rotational behavior may be determined by brain asymmetry.

Two kinds of nigrostriatal asymmetry: relationship to dopaminergic drug sensitivity and 6-hydroxydopamine lesion effects in Long-Evans rats.

Recent work in this laboratory has provided evidence for a two-population model of normal rotational behavior: some rats circle predominantly away from the side containing the striatum with the greater dopamine levels and some rats circle predominantly towards the side containing the striatum with the greater dopamine levels. The two populations also respond differently to 6-hydroxydopamine lesions of the substantia nigra ipsilateral to the preferred direction of circling. The present study replicated these findings in another strain of rats and showed further that the two populations could be distinguished behaviorally by their relative responses to indirectly acting (D-amphetamine, cocaine) and directly acting (apomorphine, pergolide) dopamine agonists. The results suggest that the two populations differ with respect to the balance between pre- and postsynaptic elements within the striatum.

Changes in d-amphetamine elicited rotational behavior in rats exposed to uncontrollable footshock stress.

Male and female rats, selected on the basis of their rotational behavior in response to d-amphetamine, were exposed to either escapable footshock stress, inescapable footshock stress or no stress and were then given a shuttlebox escape task on the subsequent day. Following testing, the magnitude and direction of the animals' rotational responses to d-amphetamine were determined again. Inescapable footshock stress induced a selective change in the direction and intensity of rotational behavior that was dependent upon the subjects' sex and preexisting rotational bias. Right-rotating males and left-rotating females shifted their directional bias toward the opposite side, while left-rotating males and right-rotating females displayed increased rotation in their pre-stress direction. Significant correlations were also noted between the intensity of pre-stress rotational behavior and performance on the shuttlebox shock escape task. The results are discussed with respect to stress' actions on the mesocortical dopamine system and how this system's sex-dependent asymmetrical organization may subserve part of the organism's general reaction to uncontrollable stress.

Food deprivation and stimulant self-administration in rats: differences between cocaine and d-amphetamine.

The effects of food deprivation (24 h) on response rates of rats self-administering d-amphetamine and cocaine were compared. Food deprivation clearly increased rates of responding for both drugs but did so to a significantly greater extent for cocaine than for d-amphetamine. Consistent with other findings, the results suggest that the neural substrates underlying cocaine and d-amphetamine reinforcement are not identical.

Differences in spontaneous and amphetamine-induced rotational behavior, and in sensitization to amphetamine, among Sprague-Dawley derived rats from different sources.

Nocturnal rotational behavior was found to vary severalfold among Sprague-Dawley derived rats obtained from seven different breeders; net rotations per night (18 hours) varied from 5.0 to 31.0 in males and from 6.2 to 42.4 in females. Rats from three sources were tested twice (a week between tests) for rotation induced by d-amphetamine. Rats from two sources showed evidence of sensitization to d-amphetamine, there being significantly greater rotation in response to the second dose than in response to the first dose; the d-amphetamine-induced rotational behavior of rats from the third source did not significantly change from one week to the next. However, the latter rats had a greater initial response to the first dose of d-amphetamine than did rats from the other two breeders. Further analysis revealed that, among rats from all three breeders, rats rotating weakly in response to d-amphetamine on the first test tended to rotate more on the second test whereas rats rotating strongly in response to d-amphetamine on the first test tended to rotate less on the second test. This relationship was found to apply to previously collected data as well and was discussed with reference to a proposed mechanism involving asymmetry in sensitization to d-amphetamine-induced release of striatal dopamine. Interindividual differences among seemingly similar experimental subjects appear to contribute importantly to reported differences in results among laboratories.

Differences in amphetamine and morphine sensitivity in lateralized and non-lateralized rats: locomotor activity and drug self-administration.

Morphine and d-amphetamine were tested for their effects on locomotor activity and for their propensities to be intravenously self-administered in rats that had been screened for their tendencies to rotate (turn in circles) spontaneously at night; noctural rotation was used as a behavioral index of asymmetry in the dopaminergic nigrostriatal system. Lateralized (rotating) rats were more sensitive to the locomotor stimulant effects of d-amphetamine than non-lateralized (non-rotating) rats. The stimulant effects of low doses of morphine were also greater in lateralized rats, whereas the depressant effects of high doses of morphine were greater in non-lateralized rats. Lateralized rats self-administered more d-amphetamine than non-lateralized rats whereas non-lateralized rats self-administered more morphine than lateralized rats. The data indicate that the degree of lateralization in some brain pathways is a source of interindividual variation in drug sensitivity--this may in part be responsible for the individual tendencies of humans to selectively abuse particular types of drugs.

Modulation of turning preferences by learning.

Rats were trained, using water reinforcement, to turn in circles (rotation) during 1 h daily test sessions. Different groups of rats were reinforced for turning either in the same or opposite direction as that elicited previously by D-amphetamine. All rats (n = 14) trained in the 'same' direction readily acquired the task whereas only 13 of 33 rats trained in the 'opposite' direction showed evidence of learning. Two days after cessation of training, the effect of D-amphetamine was greater in rats trained in the 'same' direction and decreased or reversed in rats successfully trained in the 'opposite' direction - these changes were transient, mostly disappearing a week later.

Sex differences in sensitization to cocaine-induced rotation.

Sensitization to cocaine- and d-amphetamine-induced rotation was studied in male and female rats. A single injection of cocaine (20 mg/kg) sensitized female rats to a subsequent dose administered 1 or 7 days later; sensitivity returned to normal within 14 days. Sensitization to cocaine did not occur in male rats nor to d-amphetamine in either sex.

Cocaine-induced rotation: sex-dependent differences between left- and right-sided rats.

Cocaine elicited dose-related rotation (circling) in naïve rats. The maximum effect was greater than observed previously with other drugs. Overall, females were more sensitive to cocaine than males. However, right-biased females were more sensitive than left-biased females, whereas left-biased males were more sensitive than right-biased males. The results suggest that sex-dependent differences in brain asymmetry may be an important determinant of cocaine sensitivity.