Rotational Behavior In Response Research Articles

Priming of rotational behavior by a dopamine receptor agonist in hemiparkinsonian rats: Movement-dependent induction

Repetitive stimulation of dopamine receptors located in the basal ganglia may lead to the manifestation of sensitized, abnormal, motor responses in dopamine-denervated rats. In order to study the role of motor behavior execution on the expression of these altered motor responses, we evaluated how “priming”, a phenomenon displaying neurochemical and behavioral features peculiar to a sensitized abnormal motor response in dopamine-denervated rats, depends on actual movement performance. To this end, unilaterally 6-hydroxydopamine-lesioned rats received apomorphine (0.2 mg/kg s.c.), being either allowed to move or immobilized (1 h) before, concomitantly to, or after its administration, respectively. Three days after apomorphine, the dopamine D1 receptor agonist 1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol (SKF 38393, 3 mg/kg s.c.) was administered to all animals. Rats that had performed rotational behavior following apomorphine administration displayed robust contraversive rotational behavior in response to SKF 38393, whereas rats that had been immobilized concomitantly to, but neither before nor after apomorphine, did not. To clarify whether stress, which may be increased by immobilization, mediated the results observed, additional rats received apomorphine paired with immobilization plus the corticosterone-synthesis inhibitor metyrapone (100 mg/kg i.p.), or apomorphine paired with a tail stressor, being not immobilized. Metyrapone did not affect the capacity of immobilization to prevent priming and tail stressor imposition did not affect priming magnitude, suggesting that stress has minimal or no effect on the results observed. This study demonstrates how movement performance following initial dopaminergic stimulation governs the occurrence of a sensitized, abnormal, motor response to a subsequent dopaminergic challenge in dopamine-denervated rats.

Human Interleukin-10 Gene Transfer Is Protective in a Rat Model of Parkinson's Disease

In Parkinson's disease (PD) chronic inflammation occurs in the substantia nigra (SNc) concurrently with dopaminergic neurodegeneration. In models of PD, microglial activation precedes neurodegeneration in the SNc, suggesting that the underlying pathogenesis involves a complex response in the nigrostriatal pathway, and that the innate immune system plays a significant role. We have investigated the neuroprotective effect of an adeno-associated viral type-2 (AAV2) vector containing the complementary DNA (cDNA) for human interleukin-10 (hIL-10) in the unilateral 6-hydroxydopamine (6-OHDA) rat model of PD. AAV2-hIL-10 reduced the 6-OHDA-induced loss of tyrosine hydroxylase (TH)-positive neurons in the SNc, and also reduced loss of striatal dopamine (DA). Pretreatment with AAV2-hIL-10 reduced glial activation in the SNc but did not attenuate striatal release of the inflammatory cytokine IL-1beta. Assessment of rotational behavior in response to apomorphine challenge showed absence of asymmetry, confirming protection of dopaminergic innervation of the lesioned striatum. At baseline, 6-OHDA-lesioned animals displayed a deficit in contralateral forelimb use, but pretreatment with AAV2-hIL-10 reduced this forelimb akinesia. Transcriptional analyses revealed alteration of a few genes by AAV2-hIL-10; these alterations may contribute to neuroprotection. This study supports the need for further investigations relating to gene therapies aimed at reducing neuroinflammation in early PD.

Magnetic resonance imaging of transplanted neural stem cells in parkinson disease rats

In this study we implanted magnetically labeled neural stem cells (NSCs) in PD rats and then monitored their survival and migration in the host brain by magnetic resonance imaging (MRI). The mesencephalic NSCs were obtained from the brain of SD rats. Superparamagnetic iron oxide (SPIO) was transferred to NSCs by Lipofectamine transfection. Eighteen PD lesioned rats were selected for transplantation by evaluation of their rotational behavior in response to amphetamine and randomly assigned to 3 groups, i.e., sham group, PBS group and NSCs transplanted group, with 6 rats in each group. MR scanning was performed at 1, 2, 4, 6, 8 and 10 week(s) following transplantation. At the meantime, rotational behavior was assessed in each group. Our results showed that SPIO particles were clearly visible with Prissian blue staining in neurospheres and cells derived from NSCs. The rotational behavior of the NSCs transplanted group was remarkably improved compared with that of sham group and PBS group (P < 0.05). In vivo MR tracking of NSCs showed that SPIO labeling led to a strong susceptibility change of signal 1 week after transplantation on T2 weighted images. And a large circular hypointense signal appeared in the transplanted area on T2* gradient echo images. Ten weeks following transplantation, the hypointense signal on T2 weighted and T2* gradient echo images was still displayed. It is concluded that SPIO particles could label NSCs effectively, and MRI detection of SPIO labeled cells is a promising method and novel approach to analyzing the NSCs following transplantation in the treatment of PD.

Dimerizer regulation of AADC expression and behavioral response in AAV-transduced 6-OHDA lesioned rats

Recombinant AAV vectors containing a dimerizer-inducible system of transcriptional activation provide a strategy for control of therapeutic gene expression in the CNS. Here we explored this system for regulated expression of human aromatic l-amino acid decarboxylase (hAADC) in a rodent model of Parkinson disease. Expression of hAADC, the enzyme that converts l-dopa to dopamine, was dependent on reconstitution of a functional transcription factor (TF) by the dimerizer rapamycin. Two vectors, AAV-CMV-TF and AAV-Z12-hAADC, were infused into striata of 6-OHDA-lesioned rats. Rapamycin-induced increases in expression of hAADC repeatedly produced robust rotational behavior in response to low doses of l-dopa. Seven weeks after vector infusion, AADC expression in brain was quantitated by both stereology and Western blot analysis following the final rapamycin treatment. While a low level of hAADC was observed in rats that were not induced with rapamycin, this basal expression was not significant enough to elicit a rotational response to l-dopa. This study demonstrated a robust behavioral response of parkinsonian rats to regulated hAADC expression. Recombinant AAV vectors controlled by rapamycin or its analogs show promise as candidates for CNS therapies in which regulation of the transgene is desired.

Behavioral evaluation of hemiparkinsonian MPTP monkeys following dopamine pharmacological manipulation and adrenal co-graft transplantation.

Bradykinesia and rigidity are the symptoms that most directly correlate with loss of striatal dopamine in Parkinson's disease. In the hemiparkinsonian (HP) monkey, this is represented by paucity of movement as measured by coli puterized movement analysis, diminished manual dexterity on clinical examination, and diminished performance on operant behavioral tasks. The present study used an MPTP-induced HP model in rhesus monkeys to evaluate the effectiveness of adrenal medullary and peripheral nerve co-grafts in diminishing parkinsonian symptoms. Unoperated controls (N = 4), surgical controls with caudate lesioning (N = 4), and caudate co-grafted (N = 4) HP monkeys demonstrated diminished movement in the home cage following MPTP. This behavior persisted in unoperated controls, but improved in both surgical control and co-grafted monkeys. Functional hand dexterity evaluations demonstrated similar impairment in all three groups but only surgical controls and co-grafted monkeys demonstrated improvement. In general, rotational behavior in response to apomorphine was consistent with recovery of function in surgical controls and co grafted monkeys, but marked between-subject variability precluded group statistical analyses. None of the monkeys could perform the operant task using the affected limb following MPTP. However, the performance of two co-grafted animals demonstrated partial recovery. L-dopa improved operant performance, demonstrating a dopaminergic component to the task. The results demonstrate recovery of behavioral function after surgical treatment, with adrenal co-grafted monkeys showing the greatest degree of improvement.

Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease

The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 μg) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor. D 1 and D 2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [ 3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [ 3H]choline and [ 3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated by intraventicular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 μg/day) over a two-week period did not afford notable improvement compared to the single injection of 10 μg. In contrast, continuous infusion of brain-derived neurotrophic factor (10 μg/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 μg/day) delivery into the striatum significantly increased [ 3H]GABA uptake, but only modestly affected [ 3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.

Intranigral grafts of fetal ventral mesencephalic tissue in adult 6-hydroxydopamine-lesioned rats can induce behavioral recovery.

Intrastriatal grafts of fetal ventral mesencephalon in rats with unilateral 6-hydroxydopamine lesions can reduce and even reverse rotational behavior in response to direct and indirect dopamine agonists. These grafts can ameliorate deficits on simple spontaneous behaviors, but do not improve complex behaviors that require the skilled integration of the use of both paws. We report here that rats with grafts into the DA-depleted substantia nigra, that receive cyclosporine A, can experience recovery on spontaneous behaviors that mimic those observed in Parkinson's disease. Specific cyclosporine A treatment conditions can differentially affect whether intranigral grafts normalize paw use during initiation or termination of a movement sequence. These findings may have important implications for the treatment of Parkinson's disease.

Intranigral grafts of fetal ventral mesencephalic tissue in adult 6-hydroxydopamine-lesioned rats can induce behavioral recovery

Intrastriatal grafts of fetal ventral mesencephalon in rats with unilateral 6-hydroxydopamine lesions can reduce and even reverse rotational behavior in response to direct and indirect dopamine agonists. These grafts can ameliorate deficits on simple spontaneous behaviors, but do not improve complex behaviors that require the skilled integration of the use of both paws. We report here that rats with grafts into the DA-depleted substantia nigra, that receive cyclosporine A, can experience recovery on spontaneous behaviors that mimic those observed in Parkinson's disease. Specific cyclosporine A treatment conditions can differentially affect whether intranigral grafts normalize paw use during initiation or termination of a movement sequence. These findings may have important implications for the treatment of Parkinson's disease.

Synergistic effect of D1 and D2 dopamine receptors on AP-1 DNA-binding activity in the striatum and globus pallidus of the rat with a unilateral 6-OHDA lesion of the medical forebrain bundle.

The synergistic effect of D1 and D2 dopamine receptors on transcription factor AP-1 was studied in the striatum and globus pallidus of rats with unilateral 6-OHDA lesions of the medial forebrain bundle. Contralateral rotational behavior in response to a challenge dose of D1 agonist with and without D2 agonist was determined by behavioral observation, and AP-1 induction was studied by a gel mobility-shift assay. Single administration of vehicle and of a low dose of the D1 agonist (SKF38393, 0.5 mg/kg, i.p.) failed to induce rotational behavior, while the D2 agonists bromocriptine (2.5 mg/kg, i.p.) and quinpirole (1 mg/kg. i.p.) induced low rate rotations. High dose of SKF38393, 10 mg/kg, i.p., and low dose D1 and D2 agonists administered together induced a higher rate of rotation. The gel mobility-shift assay also suggested a synergistic interaction between D1 and D2 receptors on AP-1 induction in both the striatum and globus pallidus ipsilateral to the 6-OHDA lesioned nigrostriatal pathway. However, the mode of AP-1 induction via each dopamine receptor subtype appeared to differ between these brain structures. Thus, in the striatum of the lesioned side, single administration of a high dose of D1 agonist, and combined administration of D1 agonist with either of the D2 agonists resulted in AP-1 induction, while in the globus pallidus, AP-1 binding was induced by the D2 agonist bromocriptine and combined administration of a low dose D1 agonist with D2 agonists, but not by D1 agonist alone, even at a high dose. These results demonstrate that a D1/D2 dopamine receptor synergism is involved is the induction of AP-1 both in the striatum and globus pallidus of the rat with ipsilateral dopamine depletion. The induction of AP-1 via each receptor subtype appears, however, to be differently regulated in these two structures.

Asymmetrical motor behavior in rats with unilateral striatal excitotoxic lesions as revealed by the elevated body swing test

Severe degeneration of basal ganglia neurons, particularly the intrinsic neurons of the striatum, is the major underlying neuropathology implicated in clinical attributes of Huntington's disease (HD). The excitotoxin-lesioned striatum provides a useful model for evaluating behavioral parameters of HD. Animals with unilateral excitotoxic lesions exhibit asymmetrical rotational behavior in response to dopamine agonists, such as apomorphine. However, the observed behavior is a pharmacological reaction, and subject to sensitization effects. A behavioral test using undrugged animals may demonstrate a more natural response of the animals to the lesion effects. Recently, we have developed the ‘drug-free’ elevated body swing test (EBST), and demonstrated that hemiparkinsonian rats exhibited significant biased swing activity. In the present study, we observed that animals with unilateral intrastriatal 3-nitropropionic acid or quinolinic acid lesions displayed a significant biased swing activity with the direction ipsilateral to the lesioned side of the brain. This ipsilateral swing corresponded to the ipsilateral rotational behavior exhibited by the lesioned animals when challenged with apomorphine. The present results demonstrated that the EBST is a sensitive measure for characterizing asymmetrical behavior in animals with striatal lesions.

Influence of novel versus home environments on sensitization to the psychomotor stimulant effects of cocaine and amphetamine

The acute psychomotor response (rotational behavior in rats with a unilateral 6-OHDA lesion), and the development of sensitization, were studied in rats that received seven consecutive daily injections of amphetamine (Experiment 1) or cocaine (Experiment 2) either at home or in a ‘novel’ test environment. The home (HOME) and novel (NOVEL) cages were physically identical, but one group lived and was tested in these cages, whereas the rats in the other group were transported from the stainless steel hanging cages where they lived, to these NOVEL test cages, for each test session. In Expt. 1, the acute psychomotor response to 3.0 mg/kg of amphetamine i.p. and the development of sensitization (increase in the rotational response between the first and the seventh test session) were greater in the NOVEL than in the HOME environment. In Expt. 2, there were no significant group differences in the acute response to 20 mg/kg of cocaine i.p., but the animals tested in the NOVEL environment showed greater sensitization than animals tested in the HOME environment. In addition, the animals pretreated with cocaine in the NOVEL environment, but not those pretreated with cocaine in the HOME environment, showed conditioned rotational behavior in response to an injection of saline. These data indicate that: (i) sensitization to the psychomotor activating effects of both amphetamine and cocaine is enhanced in a NOVEL environment; (ii) this phenomenon appears to be independent of the effects of the NOVEL environment on the acute response to these drugs; (iii) a robust conditioned psychomotor response to contextual cues develops only when cocaine treatments are given in the NOVEL test environment.

Roles of dopamine D 1 receptors in striatal fos protein induction associated with methamphetamine behavioral sensitization in rats

To elucidate the roles of dopamine D 1 and D 2 receptors in mediating striatal Fos protein induction and behavioral sensitization after methamphetamine administration, we examined the effects of the D 1 receptor antagonist SCH 23390 and D 2 receptor antagonist sulpiride on these phenomena in rats. Intraperitoneal administration of 5.0 mg/kg methamphetamine produced a significant increase in Fos-immunoreactive cells in the medial striatum. Prior exposure to 5.0 mg/kg methamphetamine enhanced ipsilateral rotational behavior in response to subsequent methamphetamine administration in unilateral nigral-lesioned rats (sensitization). Pretreatment with SCH 23390 (0.32 mg/kg IP) suppressed significantly the expression of striatal Fos protein and the development of acute behavioral sensitization following a single injection of 5.0 mg/kg methamphetamine. Sulpiride (50 mg/kg IP) was also effective in suppressing methamphetamine behavioral sensitization, but did not affect the striatal Fos induction. These results suggest that dopamine D 1 receptor-mediated mechanisms are involved in the striatal Fos protein induction associated with behavioral sensitization following exposure to methamphetamine.

Asymmetrical behavior in rats following striatal lesions and fetal transplants: the elevated body swing test

Animals with unilateral neurotoxic lesions in the striatum exhibit a stereotypical biased rotational behavior in response to dopamine agonists. We recently argued that the rotational test may be subject to sensitization effects of the drug. Accordingly, we proposed the drug-free elevated body swing test (EBST) as an alternative behavioral index of motor asymmetry in striatal lesioned animals. EBST involves elevating the animal from the ground by holding its tail and simply recording the number of swings to either side made by the animal over 30 s. We previously reported that Sprague-Dawley, male 8-week-old rats, intrastriatally lesioned with 500 nanomoles of 3-nitropropionic acid or 225 nanomoles of quinolinic acid, exhibit biased swing activity at 7, 14, 21 and 28 days post-lesion. In the present study, we extended the efficacy of the EBST in measuring the recovery of motor function following fetal striatal transplants. At 2 months post-lesion, lesioned animals which show 70% or higher biased swing activity were transplanted with rat fetal striatal lateral eminence (16-day-old gestational age). When tested in the EBST at 1 and 3 months post-transplant, these transplanted animals displayed normalization of the biased swing activity. In contrast, animals transplanted with medium alone continued to exhibit a biased swing activity. The present study thus extends our previous EBST data to include successful behavioral characterization by EBST of recovery of motor function in lesioned animals receiving fetal transplants.

NMDA receptor-mediated expression of Fos protein in the rat striatum following methamphetamine administration: relation to behavioral sensitization

In order to clarify the possible involvement of N-methyl- d-aspartate (NMDA) receptors in mediating striatal Fos protein induction and behavioral sensitization after methamphetamine administration, we examined the effects of non-competitive NMDA receptor antagonist MK-801 on these phenomena in rats. A single administration of 1.0 and 5.0 mg/kg methamphetamine resulted in a dose-dependent increase in Fos-immunoreactive cells in the medial striatum. Prior exposure to 5.0 mg/kg methamphetamine enhanced ipsilateral rotational behavior in response to subsequent methamphetamine administration in unilateral nigral-lesioned rats (sensitization). Pretreatment with 1.0 mg/kg MK-801 completely prevented both the expression of striatal Fos protein and the development of acute behavioral sensitization following a single injection of 5.0 mg/kg methamphetamine. These results suggest that NMDA receptor-mediated mechanisms contribute to the expression of striatal Fos protein associated with behavioral sensitization that follows exposure to methamphetamine.

Adrenal medulla grafts in the hemiparkinsonian rat: profile of behavioral recovery predicts restoration of the symmetry between the two striata in measures of pre- and postsynaptic dopamine function

Following unilateral striatal dopamine depletion, the hemiparkinsonian rat exhibits rotational behavior in response to amphetamine and apomorphine. The rotational behaviors induced by these drugs are thought to reflect an asymmetry in presynaptic striatal dopamine release and an asymmetry in postsynaptic striatal dopamine receptor function, respectively. Grafts of adrenal medulla cells in the lateral ventricle of hemiparkinsonian rats have been reported to reduce behavioral asymmetry. More than one profile of behavioral recovery, however, is observed. Some animals show a graft-induced decrease only in the response to apomorphine, but others show a decrease in the response to amphetamine, and still others show a decrease in the behavioral responses to amphetamine and apomorphine. In this report, amphetamine- and apomorphine-induced turning behaviors were determined in hemiparkinsonian rats prior to and following intraventricular grafts of adrenal medulla or control tissue. Both bilateral intrastriatal microdialysis in freely moving animals and quantitative dopamine receptor autoradiography procedures were conducted in each animal so as to determine the relations between pre- and postsynaptic dopaminergic measures as well as the association between these measures and the different profiles of behavioral recovery after adrenal medulla grafts. We report here that in animals with an adrenal medulla graft-induced decrease in the behavioral response to amphetamine, the balance between the two striata in extracellular striatal dopamine concentrations and D2 dopamine receptor binding was restored. Furthermore, enhanced extracellular striatal dopamine concentrations were highly correlated with the graft-induced symmetry in striatal D2 dopamine receptor binding. In contrast to animals with decreased amphetamine-induced turning, in animals with a graft-induced decrease exclusively in response to apomorphine, the presynaptic symmetry was not restored and there was a significantly smaller effect on D2 receptor binding. We conclude that those animals that show decreased amphetamine-induced turning after adrenal medulla grafts had the most effective grafts, and suggest that methods designed to optimize this behavioral profile are most likely to lead to enhanced clinical efficacy with this procedure.

Induction of D 2 dopamine receptor mRNA synthesis in a 6-hydroxydopamine Parkinsonian rat model

By injecting 6-hydroxydopamine into the pars compacta of the substantia nigra, we produced a hemiparkinsonian rat model in which there is almost complete destruction of the dopaminergic nigrostriatal pathway but sparing of the dopaminergic mesolimbic system. The lesion has been characterized by several criteria: a rotational behavior in response to apomorphine, a complete loss of tyrosine hydroxylase immunoreactivity in the lesioned substantia nigra, a near total depletion of dopamine and metabolites in the striatum ipsilateral to the lesion and a supersensitivity of the dopamine D 2 receptors in the ipsilateral striatum. Dopaminergic striatal deefferentation was accompanied by an increase of D 2 receptor mRNA synthesis in the striatum ipsilateral to the lesion, suggesting that the increased D 2 receptor density observed after the lesion is due to an increase of the synthesis of receptor molecules. This synthesis appears to be regulated at the transcriptional level.

Effects of intraventricular substantia nigra allografts as a function of donor age

Transplantation of fetal substantia nigra into the brain can alleviate some of the manifestations of animal models of Parkinson's disease. The purpose of the present experiment was to determine the optimal embryonic donor age for solid tissue substantia nigra grafts. Rats with unilateral substantia nigra lesions were tested for rotational behavior in response to apomorphine. Animals then received intraventricular grafts of ventral mesencephalon from fetal donors of 11, 13, 15, 17, or 19 days gestational age, and were tested for rotational behavior 6 and 12 weeks after transplantation. After 12 weeks, animals receiving grafts from donors of 11 through 17 days gestation showed similar decreases (means= 42−58%) in rotation. All 4 groups showed greater decreases in rotation than the 19 day group (17%). In both the 11 and 13 day groups, however, there were substantial decreases in rotational behavior from the 6th to the 12th week testing periods. This study confirms that during a critical period of rat fetal development, between 17 and 19 days gestational age, the substantia nigra loses much of its ability to produce functional effects after transplantation. Grafts from very immature donors did not, however, produce markedly greater effects, and the youngest grafts required more time for the development of maximal effects.

A 6-hydroxydopamine-induced selective parkinsonian rat model

Previous parkinsonian rat models have generally been characterized by unilateral destruction of both the nigrostriatal pathway and the mesolimbic pathway using the neurotoxin 6-hydroxydopamine (6-OHDA). We created a hemiparkinsonian model in which there is 6-OHDA-induced destruction of the dopaminergic nigrostriatal pathway but sparing of the dopaminergic mesolimbic pathway. This resulted in reproducible, quantifiable rotational behavior in response to either amphetamine or apomorphine and a near total depletion of dopamine in the striatum ipsilateral to the lesion with a dorsolateral distribution of supersensitive dopaminergic D 2 receptors. This model parallels the MPTP (1-methy-4-phenyl-1,2,3,6-tetrahydropyridine)-induced hemiparkinsonian model in primates and more closely approximates the extent of neurodegeneration seen in human idiopathic Parkinson's disease than previous parkinsonian rat models. It may therefore prove a convenient model for studying the recently reported phenomenon of sprouting from host dopaminergic neurons following tissue implantation.

Rotational behavior induced by 8-hydroxy-DPAT, a putative 5HT-1A agonist, in 6-hydroxydopamine-lesioned rats.

Rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of the ascending nigro-striatal pathway have been shown to rotate in response to dopamine (DA) agonists that are not considered to have postsynaptic DA stimulant properties in intact animals, suggesting a relative loss of DA receptor selectivity in the denervated striatum. The present experiments assessed the possibility that this loss of selectivity may extend to serotonin (5HT) agonist drugs. The 5HT-1a agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), at doses of 0.3-3 mg/kg SC, induced robust contralateral rotational behavior (RB) in 6-OHDA-lesioned rats that had been preselected on the basis of high responsiveness to the atypical DA agonists 3-PPP and SKF 38393. Rats with unilateral dorsal raphe lesions induced by 5,7-dihydroxytryptamine (5,7-DHT) showed contralateral RB in response to similar doses of 8-OH-DPAT but with a different behavioral pattern. The putative 5HT-1b agonist RU 24969 produced contralateral RB in 5,7-DHT-lesioned rats while showing a much weaker effect in 6-OHDA-lesioned rats. Striatal DA levels were depleted by 99% in representative 6-OHDA-lesioned rats but striatal 5HT levels were unaffected. The effects of 8-OH-DPAT in 6-OHDA-lesioned rats were therefore not attributable to destruction of ascending 5HT-containing neurons. These effects may result from indirect actions, mediated by 5-HT neurons or neuronal receptors, that result from asymmetry of brain DA systems.(ABSTRACT TRUNCATED AT 250 WORDS)

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.