Carol Van Hartesveldt

Effects of estrogen on the basal ganglia

Recent research suggests that estrogen regulates the activity of dopamine-containing fibers originating in the midbrain and terminating in the basal ganglia, and/or dopamine-sensitive cells in the basal ganglia. The mechanism by which estrogen acts is not clear, since cells in neither of these regions concentrate estrogens. Nevertheless, estrogens clearly affect behaviors mediated by the basal ganglia, as illustrated in human patients suffering from extrapyramidal disorders. Both biochemical and behavioral research in animals has confirmed that estrogen modulates basal ganglia function, but there has not been agreement concerning either the locus, the direction, or the mechanism of its action. These topics are the focus of this review. The effects of estrogen on behaviors mediated by DA in the basal ganglia depend on the dose of estrogen administered, the time interval between estrogen treatment and testing, the behavior measured, and the part of the basal ganglia from which the behavior is elicited. A high dose of estrogen results in an initial suppression and later enhancement of DA-related behaviors elicited from the striatum. However, no later enhancement of these behaviors occurs if a low dose of estrogen is given. Even after low doses of estrogen, the latency to behavioral suppression varies depending upon the behavior measured. These varying latencies suggest that more than one mechanism is involved in the effects of estrogen on basal ganglia output. In addition, estrogen may also act on some regions in the mesolimbic DA system. While estrogen may act indirectly via the catechol estrogens and prolactin, it has been demonstrated that estrogen can act directly on the striatum. These findings are related to the effects of estrogen on human extrapyramidal disorders.

L-DOPA-INDUCED AIR-STEPPING IN DEVELOPING RATS

Rat pups at postnatal day (PN) 0, 5, 10, 15, and 20 were injected with 100 mg/kg L-3,4-dihydroxyphenylalanine (L-DOPA; s.c.) or the control vehicle and suspended in a sling. L-DOPA induced highly stereotyped air-stepping that varied along several dimensions across development. The latency to air-stepping was constant across age, but the duration was significantly shorter in the older pups. At all ages, air-stepping was preceded or accompanied by raising of the head and dorsiflexion of the tail. The rate of stepping increased across age and gait varied with age. At PN 0, L-DOPA induced alternating forelimb movements with little involvement of the hindlimbs. At PN 5 and 10, both forelimb and hindlimb alternation were observed. At PN 10 and 15 swimming-like behavior emerged, and at PN 10, 15, and 20, episodes of galloping were interspersed with limb alternation. Thus, highly coordinated activity can be elicited by L-DOPA at all ages studied when the rat pup needs not support its own body weight and has no contact with a substrate. Drug-induced air-stepping promises to be an important new paradigm for pharmacological and behavioral studies of the development of locomotor controls in mammals.

Behavioral effects of unilateral dopamine injection into dorsal or ventral striatum

Dopamine or its vehicle saline was injected unilaterally into dorsal striatum, ventral striatum, or sites outside the striatum in adult male rats. Direction, duration and frequencies of ongoing behaviors were measured. Dopamine injected into any site within the striatum immediately elicited more contralaterally directed behavior than the vehicle injected into the same site. The contralaterally directed behaviors were no longer duration when injected into the dorsal than into the ventral striatum, a result which might reflect regional differences in numbers of dopamine receptors or distribution of efferents. At the doses employed (25 and 100 microgram), dopamine injected unilaterally into the striatum did not induce rotation, stereotyped behavior, or even a significant change in the frequencies of ongoing behaviors; rather, all ongoing behaviors were expressed in a contralateral direction. Thus, the behavioral effects of dopamine in the striatum are best understood as a change in sensory-motor responsiveness.

L-DOPA and quipazine elicit air-stepping in neonatal rats with spinal cord transections

Acute mid-thoracic spinal cord transection eliminates hindlimb air-stepping in neonatal rats suspended in harnesses and administered L-DOPA. Because spinal cord transection eliminates all descending inputs to the hindlimb locomotor circuits, this experiment determined if coadministration of L-DOPA and quipazine (serotonin receptor agonist) would induce hindlimb air-stepping in rat pups 24 hr after transection. Hindlimb steps of spinally transected pups that received L-DOPA or quipazine alone were infrequent and slow; hindlimb steps induced by L-DOPA + quipazine occurred more frequently and were faster than those elicited by either drug alone. These findings suggest that catecholaminergic and serotonergic systems both contribute to hindlimb stepping.

Effects of intracerebral quinpirole on locomotion in rats

The effects of the dopamine D2 receptor agonist quinpirole (LY 171555) on locomotor activity and margin time (thigmotaxis or wall-hugging) were measured for 2 h in rats injected either s.c. (vehicle, 0.02, 2.0 mg/kg) or directly into either the dorsal striatum or nucleus accumbens (vehicle, 0.1, 1.0, 10, 20 or 40 micrograms bilaterally in each site). In all groups, margin time decreased as drug dose increased. As in previous research, quinpirole given s.c. decreased locomotor activity at a low dose and had a biphasic effect on locomotor activity at the high dose. Both of these effects were also elicited by quinpirole injected directly into the dorsal striatum; 10 and 20 micrograms decreased locomotion immediately, while 40 micrograms led to both the immediate decrease and a later increase. In contrast, the lowest doses of quinpirole (0.1 and 1.0 microgram) injected into the nucleus accumbens led to an increase in locomotion from 20 to 60 min, while the higher doses led only to the early decrease. Thus, both the locomotor activating and inhibiting effects of quinpirole are found in both the nucleus accumbens and the dorsal striatum, but the differing dose-response relationships indicate that the mechanisms are not the same in these two brain regions.

Estradiol application to one striatum produces postural deviation to systemic apomorphine

In order to test whether estrogen acts directly in the dorsal striatum to affect dopamine-mediated behavior, ovariectomized female Long-Evans rats were given a unilateral striatal application of estradiol, injected systemically with apomorphine (APO), and tested for lateralization of stereotypic behaviors. In the first experiment, estradiol, cholesterol, or an empty cannula was inserted and the rat given 0.7 mg/kg APO 1-4 hours later. Rats directed their stereotypic behaviors to the side ipsilateral to the insert of estradiol with dorsal striatal inserts, but not with inserts in ventral striatum or neocortex. Neither cholesterol nor the empty cannula inserts were effective in producing lateralization of the stereotypic behaviors. In the second experiment, intrastriatal inserts of 17 alpha-estradiol were ineffective in producing a lateralization of APO-induced stereotyped behavior. In the third experiment, several doses of APO (0.07, 0.75 and 3.0 mg/kg) were tested. At the highest dose no lateralization of APO-induced stereotypic behavior was observed. These results strongly suggest that estradiol acts directly in the dorsal striatum to antagonize APO and thus produce a lateralization of stereotypic behaviors (postural deviation).

Behavioral and hormonal effects of hippocampal lesions on male and female rats

Male and female rats with hippocampal lesions and controls were compared with respect to activity, body weight, performance on a DRL schedule, and extinction. Normal females acquired the DRL schedule faster than normal males. For both sexes, hippocampal lesions resulted in poor DRL performance and more responses during extinction. Male rats with hippocampal lesions were further below their target deprived weight each day than their controls; the lightest animals had the worst DRL performance. Sex-lesion interactions were found for activity in the operant chamber during DRL performance and for DRL extinction: females with hippocampal lesions were more active and made more responses during extinction than males with hippocampal lesions. Corticosterone levels were manipulated prior to DRL sessions, and resting and stress levels of corticosterone were measured at the end of the experiment. While females had higher corticosterone levels than males, brain lesions did not affect corticosterone levels, nor did hormone manipulations affect DRL performance for either sex.

Locomotion elicited by MK801 in developing and adult rats: temporal, environmental, and gender effects.

The effects of environmental novelty on locomotion elicited by an N-methyl-D-aspartate (NMDA) receptor antagonist, (+)MK-801 hydrogen maleate [(5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine], were investigated. Male and female rats aged 10, 20, 30 or 54-68 days were injected s.c. with MK801 and placed in activity monitors either immediately (no-delay) or after a 60 min delay (delay). In the no-delay condition, MK801 induced an inverse U-shaped dose-response effect on locomotion; peak activation occurred with 0.1 mg/kg and ataxia occurred with higher doses. The introduction of a novel environment 60 min after drug injection shifted the dose-effect function of MK801 to the left; i.e., in rats 20 days of age and older, the activity induced by 0.1 mg/kg MK801 was potentiated in the delay condition. For the 0.5 mg/kg dose, 20-day-olds showed activation in the no-delay condition but ataxia in the delay condition. This dose induced ataxia followed by activation in 30-day-olds and adult males or ataxia in adult females, regardless of delay condition. Age-, gender-, and novelty-dependent variations in MK801-induced locomotion may reflect differences in limbic-motor circuitry.

Behaviors induced by intrastriatal dopamine vary independently across the estrous cycle.

Unilateral intrastriatal injections of dopamine (DA; 25 micrograms/0.25 microliters) or amphetamine ( AMPHET ; 25 micrograms/0.25 microliters) induced contralateral postural deviation and contralateral rotation that varied systematically across the estrous cycle of Long-Evans hooded rats. Both the deviation and rotation elicited by either drug were suppressed during the early part of the day of proestrus (2-6 hours after lights on) and were enhanced on the day of estrus, compared to the other days of the estrous cycle. However, when the behaviors elicited by the two drugs were examined across the day of proestrus, it was found that postural deviation and rotation changed independently. Postural deviation elicited by intrastriatal DA and AMPHET was suppressed on the day of proestrus at 4 and 7 hours after lights on, but was enhanced to the level seen during estrus at 11 hours after lights on. In contrast, contralateral rotation induced by either drug was suppressed 4, 7 and 11 hours after lights on and was enhanced only by the morning of estrus. These data suggest that there are separate DA-modulated mechanisms within the striatum for postural deviation and contralateral rotation, and that these mechanisms are differentially affected across the estrous cycle.

The locomotor effects of a putative dopamine D3 receptor agonist in developing rats

Dopamine receptors have been categorized into subfamilies D1 and D2, each with separate roles in dopamine-mediated behaviors. Of the D2 subfamily, the dopamine D3 receptor has been cloned, but the behavioral effects of selectively stimulating the D3 receptor are largely unknown. The purpose of this study was to quantify the locomotor responses of developing rats to the putative dopamine D3 receptor agonist, 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT). One of three doses of 7-OH-DPAT (0.01, 0.10, 1.00 mg/kg) or saline was injected subcutaneously into rats at the age of 10,20,30, or 60 days. Five minutes after the injection, rats were placed in automated activity monitors which recorded locomotor behavior at 5 min intervals for 2 h. The high dose of 7-OH-DPAT increased locomotor activity in rats of all ages. The medium and low doses increased activity in 10- and 20-day-old rats but not in 30- or 60-day-old rats. The level of drug-induced activation peaked at 20 days of age. In 30- and 60-day-old rats, but not 10- and 20-day-old rats, a period of locomotor suppression preceded the activation in response to the high dose of 7-OH-DPAT. In rats aged 20 days and older, the middle and low doses decreased locomotion early in the test session, but activation did not ensue. This dose-response pattern across ontogeny closely resembles that induced by quinpirole, an agonist at the dopamine D2 receptor subfamily.