Behavioral effects of intraaccumbens transplants in rats with lesions of the mesocorticolimbic dopamine system.
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Animals↗
Biomedical subjects
J P Herman
Publications and source records attributed to J P Herman.
Selective cell death of magnocellular vasopressin neurons in neurohypophysectomized rats following chronic administration of vasopressin.
Regeneration and functional recovery of the hypothalamoneurohypophysial system (HNS) in neurohypophysectomized rats treated with either saline or vasopressin (VP) were analyzed utilizing specific immunohistochemical and physiological measures. Neural lobe ablation combined with VP administration precipitated a profound diabetes insipidus (following cessation of VP delivery) that persisted for the duration of the experiment. Diabetes insipidus was correlated with a drastic reduction in the number of VP-positive neurons in magnocellular hypothalamic nuclei. In contrast, large numbers of oxytocin (OT)-positive neurons survived neurohypophysectomy in VP-treated neurohypophysectomized rats; OT neurons accounted for the vast majority of magnocellular profiles observed in Nissl-counterstained sections. VP-immunoreactive fibers could be observed in limited quantities in the external lamina of the median eminence of VP-treated neurohypophysectomized rats, with little staining evident in the internal lamina. Saline-treated neurohypophysectomized rats exhibited the recovery of antidiuretic function characteristically seen following this lesion, with evidence of survival of considerable numbers of VP and OT neurons and median eminence hypertrophy. Both the internal and external laminae of the median eminence were densely innervated by large-caliber VP and OT fibers. Sham-operated animals receiving VP treatment did not show any long-term deficit in water metabolism, changes in the complement of VP or OT perikarya in hypothalamus, or changes in the innervation of the median eminence. Results indicate that VP treatment following neurohypophysectomy results in extensive retrograde degeneration of magnocellular VP neurons without affecting the survival of OT cells.
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Vasopressin administration prevents functional recovery of the vasopressinergic neurosecretory system following neurohypophysectomy.
The rodent hypothalamic neurosecretory system normally exhibits remarkable functional and structural plasticity following injury. However, the present study describes a newly observed phenomenon in which neurohypophysectomized animals receiving chronically administered exogenous vasopressin during the post-lesion period (a treatment which insures maximal renal antidiuresis over this time frame) lose all capacity for recovery of antidiuretic function. Functional deficits are accompanied by a severe reduction in the number of neurons exhibiting immunohistochemical staining for arginine vasopressin. These data indicate that the presence of neurological stimulation signaling vasopressin release may play an important role in promoting neural regeneration of the vasopressinergic component of the neurosecretory system.
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Ibotenate-induced cell death in the hypothalamic paraventricular nucleus: differential susceptibility of magnocellular and parvicellular neurons.
Injections of ibotenic acid (IBO) (0.5-2.0 micrograms) were made unilaterally into the hypothalamic paraventricular nucleus (PVN) of Sprague-Dawley rats. A distinct loss of parvicellular neurons was evident at all dosages examined, and cell death appeared uniform throughout the injection region at doses of 1.0 micrograms or greater. In contrast, magnocellular neurons were present following injections of all dosages, with a slight loss of neurons evident only at 2.0 micrograms doses. Magnocellular neurons killed at 2.0 micrograms doses were primarily vasopressinergic. Neuropeptide content per se was not the critical determinant of susceptibility to IBO, as parvicellular oxytocin neurons were destroyed by low to moderate doses of IBO. The results suggest that IBO may be useful neurotoxin with which to investigate differential connectional and functional properties of parvicellular and magnocellular PVN neurons.
Animals↗
Reinnervation of the nucleus accumbens and frontal cortex of the rat by dopaminergic grafts and effects on hoarding behavior.
Embryonic dopaminergic neurons were implanted in the form of a cellular suspension in the nucleus accumbens previously deprived of its dopaminergic innervation by a local injection of 6-hydroxydopamine. The graft provided a dopaminergic reinnervation to the nucleus accumbens, the anteromedial striatum, the anteromedial frontal cortex and also, in some cases, of the septum. The pattern of reinnervation was specific for each structure and similar to the innervation provided by mesocorticolimbic dopaminergic neurons to these same structures in the normal animal. The graft restored the locomotor stimulatory action of amphetamine which was abolished in the lesioned controls. Hoarding behavior, which was disrupted following the lesion, was not reinstated by the graft alone. However, if the grafted neurons were stimulated by a small dose (0.2 mg/kg, i.p.) of (+)-amphetamine, hoarding reappeared in the grafted animals, while the same dose of amphetamine had no effect in the lesioned controls.
Animals↗
Behavioral variability within the Brattleboro and Long-Evans rat strains.
Samples of genetically diabetes insipidus (DI) and normal (NO) rats were obtained from American suppliers (Rochester (RO)/DI and NO) and from the colony maintained at Charing Cross Hospital in London (Charing Cross (CC)/DI and NO) to test the hypothesis that the behavior of vasopressin-deficient Brattleboro (DI) and possibly normal Long-Evans rats may vary significantly between different colonies. DI rats of both colonies exhibit longer latencies to emerge into an open field than do NO rats. RO/DI and CC/DI rats acquire goal-approach behavior in a straight runway at similar rates. Following shock in the runway goal box, however, RO/DI rats exhibit marked recovery of running behavior relative to CC/DI rats over the ten post-shock sessions. All DI animals show reductions in goal-approach speed on the first post-shock trial, indicating that the aversive experience is remembered. CC/NO rats acquire goal-approach behavior more slowly than RO/NO rats, but neither NO group shows substantial recovery of goal approach behavior following shock. CC/DI rats showed impaired acquisition of a delayed non-match to sample task relative to RO/DI rats. All groups demonstrated the ability to utilize representational memory to solve the delayed non-match to sample problem once the contingency was learned. The results indicate that DI and normal Long-Evans rats from different colonies show marked differences in behavior. Since differences between DI and normal rats on tests indicating memory are not consistent across colonies, it is unlikely that vasopressin deficit is solely responsible for memory deficiencies. However, vasopressin deficiency may result in changes in temperament.
Animals↗
Behavioral characteristics of Roman high avoidance rats homozygous for diabetes insipidus (RHA: di/di).
These experiments studied the behavior of an inbred strain of vasopressin-deficient rat, the Roman high avoidance rat homozygous for diabetes insipidus (RHA: di/di). The RHA: di/di rat has been bred to be congenic with the parent normal Roman high avoidance (RHA: +/+) strain, differing from it only by the gene(s) coding for diabetes insipidus. Therefore, the RHA: +/+ strain represents an improved model system with which to study the behavioral effects of vasopressin-deficiency, given recent findings suggesting that considerable behavioral variation exists within the Long-Evans derived Brattleboro strain of vasopressin-deficient rat. We examined the behavior of RHA: di/di and RHA: +/+ rats in the open field and on tests of approach-avoidance, spatial memory and passive avoidance. RHA: di/di rats showed retarded habituation of ambulation and elevated incidence of rearing, defecation, and ambulation in the central area of the open field, relative to RHA: +/+ rats. The RHA: di/di and RHA: +/+ rat did not differ on measures of adaptation to a novel straight runway and both groups increased latencies to enter the goal box of the runway following shock, indicating memory. RHA: di/di rats did exhibit substantial recovery of goal-approach following shock, whereas RHA: +/+ rats did not. Both groups were able to solve a delayed non-match to sample task to receive reward. RHA: di/di rats showed a slower acquisition of the contingency and significantly faster run times of choice trials of the paired run procedure. No differences were evident between groups in memory of passive avoidance. The results of these experiments suggest that hereditary deficiency of vasopressin may influence physiological processes which determine arousal or attentiveness. The effects of vasopressin deficiency on performance of memory-indicating tasks appears to be secondary to modulations in arousal.
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Characterization of a new rodent model of diabetes insipidus: the Roman high avoidance rat homozygous for diabetes insipidus.
These experiments were designed to characterize the nature and extent of diabetes insipidus present in a new model of genetic vasopressin (VP) deficiency, the Roman high avoidance rat homozygous for diabetes insipidus (RHA: di/di strain). The new strain was developed from an initial cross between Long-Evans derived Brattleboro (LE:di/di) rats and normal Roman high avoidance (RHA: +/+) rats, and has been bred to be congenic with the parent RHA: +/+ strain. RHA: di/di rats exhibited polydipsia, excreted dilute urine, and exhibited elevated plasma osmolality. RHA: di/di rats shows a similar urinary response to dehydration as LE: di/di rats. VP was undetectable by radioimmunoassay in the serum, brain, and neurohypophysis of RHA: di/di rats. VP-neurophysin containing cells were not observed in the brains of RHA: di/di rats upon immunocytochemical analysis. Thus, the new RHA: di/di strain exhibits essentially the same profile of diabetes insipidus as the LE: di/di rat. The congenic relationship between RHA: di/di and RHA: +/+ rats makes the RHA: di/di rat a useful model under circumstances where genetic variables unrelated to VP deficiency may confound the interpretation of data.
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Behavioral study after local injection of 6-hydroxydopamine into the nucleus accumbens in the rat.
Anatomically, the nucleus accumbens (n.Acc.) has been considered as an interface between limbic and striatal sensorimotor structures. In the light of this hypothesis we have investigated the behavioral effects of destruction of the dopaminergic innervation of the n.Acc. after local injection of 6-hydroxydopamine. The following behavioral deficits were observed: hypoexploration in a 4-hole box and 2-compartment field, failure to inhibit response strategies either with positive reinforcement in a straight alley test or negative reinforcement in a passive avoidance test. These disturbances comprise a syndrome of perseveration, reduced distraction by irrelevant information, decreased behavioral switching and flexibility, and a paradoxical locomotor disinhibition in an emotional context. Very similar behavioral changes are found following lesions of limbic structures. In addition, these lesioned animals exhibit an enhanced latency to initiate motor responses. This deficit of behavioral initiation is classically observed in motor striatal disease. It is suggested that the n.Acc. is a key structure for the integration of limbic and striatal sensorimotor functions.
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Hyper-reactivity to amphetamine in rats with dopaminergic grafts.
Rats with dopaminergic lesions were subsequently given grafts of dopaminergic (DA) neurons in various brain regions, and later tested for behavioral reactivity to amphetamine. Two experimental situations were used. Amphetamine-induced circling behavior was measured in animals with unilateral lesion of the nigrostriatal pathway implanted with intrastriatal grafts, locomotor activation by amphetamine was measured in animals with bilateral lesions and grafts in the nucleus accumbens. In both situations, behavioral overcompensation was observed after grafting. Ipsilateral circling, which is caracteristic of a unilateral lesion of the nigrostriatal pathway, gave way to contralateral circling, and locomotor activity was restored to levels above those observed for control animals. This behavioral overcompensation is a reflection of hyper-reactivity of grafted animals to amphetamine: they were found to respond to much lower doses than controls and the effect of the drug lasted longer. This enhanced response does not seem to be due to postsynaptic hypersensitivity, but rather to hyper-reactivity of the grafted neurons themselves to amphetamine. The mechanism of this phenomenon, which seems to be a general property of grafted DA neurons is discussed.
Amphetamine↗
Activation of striatal dopaminergic grafts by haloperidol.
The effect of haloperidol (0.5 mg/kg, 60 min) on striatal dopamine metabolism of intact rats and of rats bearing a dopaminergic graft implanted into the previously denervated striatum was investigated. The dopaminergic grafts increased dopamine and dihydroxyphenylacetic acetic acid (DOPAC) contents to 6.2 and 9.6% of their respective control levels (lesioned striatum: 0.5 and 0.7% respectively). Haloperidol increased both the DOPAC content and the DOPAC:DA ratio in the grafted striatum, and the magnitude of these increases were similar to those seen in intact controls. Furthermore a tendency for the high striatal DOPAC:DA ratio seen in lesioned striata to revert toward control values could also be observed in grafted animals. The significance of these results is discussed in terms of the in vivo regulation of graft activity.
3,4-Dihydroxyphenylacetic Acid↗
Alternation behavior, spatial discrimination, and reversal disturbances following 6-hydroxydopamine lesions in the nucleus accumbens of the rat.
The effects of dopaminergic depletion of the nucleus accumbens was tested in various behavioral tasks such as alternation, spatial discrimination, and reversal learning, and in an extinction paradigm in a T maze. Animals with lesions showed impairment of spontaneous alternation behavior, disturbances in the acquisition of spatial discrimination, and great difficulty in reversing previously learned habits. In the extinction phase, experimental animals are unable to adjust their behavior, and continue to choose the previously reinforced arm of the T maze. It is suggested that the nucleus accumbens plays an important role in the transition of motivation into action, and that dopamine has a facilitatory influence on the mediation of these processes.
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Functional recovery following transplantation of ventral mesencephalic cells in rat subjected to 6-OHDA lesions of the mesolimbic dopaminergic neurons.
Lesion of mesolimbic dopaminergic neurons induces hypoactivity and hypo-exploration in a new environment, lack of hyperactivity to amphetamine and hyperresponsiveness to apomorphine. Transplantation of embryonic dopaminergic cells from rat embryos into the deafferented nucleus accumbens restores, 8 weeks after grafting, some of the deficits obtained after the lesion. Spontaneous activity and behavioral responses in an open-field are improved and some of the grafted rats show a complete recovery of amphetamine-induced hyperactivity. However, hyperresponsiveness to apomorphine has not been significantly reduced by the treatment. These results indicate that transplanted dopaminergic neurons can restore some of the functional activities of the n. accumbens.
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Neuroleptic-like disruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems.
An examination of the ability to learn an active avoidance response was made in rats subjected to 6-hydroxydopamine (6-OHDA) lesions of the individual terminal areas of the midbrain dopamine (DA) system or a lesion to all these terminal regions in one group. Lesions were made by infusing 8 micrograms (base) of 6-OHDA in 2 microliter of vehicle into the following forebrain regions (each region representing a separate group of rats); frontal cortex, nucleus accumbens, corpus striatum and a double lesion of nucleus accumbens and corpus striatum. A separate group of rats received a smaller 6-OHDA lesion of the ventral substantia nigra. Only those rats with the combined double lesion of both the nucleus accumbens and corpus striatum (90% total depletion of dopamine) showed a severe deficit in acquisition of active avoidance. However, the rats with the separate 6-OHDA lesions to the mesolimbic or nigrostriatal DA systems did show the appropriate blockade of the amphetamine-induced locomotion or stereotyped behavior, respectively. In contrast, the rats with the double lesion showed no response to a low or high dose of amphetamine, remained cataleptic for the duration of the experiment but rapidly recovered from transient aphagia and adipsia (less than 10 days post lesion). Results suggest that a severe deficit in acquisition of an active avoidance response, similar to that observed with high doses of neuroleptics, requires destruction of all of the dopamine innervation of nucleus accumbens and corpus striatum. Results also suggest that both the mesolimbic and nigrostriatal dopamine systems act in concert to produce response enabling to important environmental events, and that the severe response enabling deficits observed in Parkinson's disease involves not only degeneration of the nigrostriatal dopamine system, but of the mesolimbic dopamine system as well.
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Mapping of LH-RH-containing projections to the mediobasal hypothalamus by differential deafferentation experiments.
Luteinizing hormone-releasing hormone (LH-RH) was immunoassayed in several hypothalamic structures of male rats after complete, anterior, posterior or lateral deafferentation of that structure performed with a rotating knife, as well as after discrete frontal or sagittal transections placed with a glass knife in various parts of the mediobasal hypothalamus (MBH). Survival time in all cases was two weeks. Taken together, the results indicate that most fibers containing LH-RH and originating in the preoptic area of the hypo-thalamus (APO) take a lateral course upon leaving that structure and travel along the medial forebrain bundle (MFB). Along that tract, they proceed caudally over some distance and enter the median eminence from the side; fibers innervating the posterior median eminence bend back towards the midline at a more posterior level than those terminating in the zona externa. A limited amount of fibers also reaches the median eminence from a midsagittal location. In addition, a few medial arcuate-median eminence connections may account for the small proportion of MBH LH-RH spared by complete, anterolateral or lateral transections. Projections to the organum vasculosum laminae terminalis, whether proceeding from the APO in an independent manner or as collaterals of fibers terminating in the median eminence, are unaffected by any of the transections tested. A partly common organization pattern of fibers supplying the median eminence in several neuropeptides (for instance somatostatin, CRF, cholecystokinin or dynorphin) is suggested.
Afferent Pathways↗
6-Hydroxydopamine lesion of the dopamine mesocorticolimbic cell bodies increases (+)-amphetamine self-administration.
The effect of 6-OHDA lesions of the dopaminergic mesocorticolimbic cell bodies on intravenous (+)-amphetamine self-administration in the rat was assessed. An acquisition paradigm was used in which the rat had to discriminate between an active and an inactive lever. Each press on the active lever delivered 7.5 micrograms/kg (+)-amphetamine. The lesioned animals acquired this discrimination faster and hence self-administered a larger amount of drug. Thus dysfunction of dopaminergic neurons can induce an enhanced vulnerability to drugs which may be abused by humans.
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Repeated stress increases locomotor response to amphetamine.
Adult male rats submitted to mild, 20 min electric foot shock sessions for 10 days displayed an enhanced locomotor response to 0.75 mg/kg (+)amphetamine 24 h after the last shock session, when compared to non-stressed controls. This effect was still present in rats specifically deprived of their forebrain noradrenergic innervation, suggesting the involvement of a dopaminergic mechanism. Cortical and limbic dopamine turnover which increased immediately after acute and repeated foot shocks returned to normal 24 h later, at the time of the pharmacological testing. This fact indicates that a permanent modification of the basal DA activity is not responsible for the above effect of stress. Locomotor hyperactivity produced by 0.6 mg/kg apomorphine was enhanced in experimental animals, while hypoactivity resulting from the injection of 0.05 mg/kg apomorphine was similar in control and shocked rats. This latter result suggests the existence of an increased postsynaptic DA sensitivity as a result of repeated stress.
3,4-Dihydroxyphenylacetic Acid↗
Contributions of the mesencephalic dopaminergic system and the trigeminal sensory pathway to the ventral tegmental aphagia syndrome in rats.
Four experiments examined the neural substrates for the aphagia and adipsia syndrome resulting from damage of the ventral tegmental region. Radiofrequency (RF) lesions at the level of the mesencephalon in rats showed that the most effective site for producing aphagia and adipsia was in an intermediate zone between the substantia nigra and the ventral tegmental area. Injection of the neurotoxin 6-hydroxydopamine (6-OHDA) into this intermediate zone led to a less severe feeding deficit, suggesting that both dopaminergic and non-dopaminergic neurons are involved in the mesencephalic aphagic syndrome. As the lemniscus trigeminalis was destroyed after the RF lesion of the intermediate zone, the hypothesis of trigeminal projection involvement was tested by lesioning (RF) the sensory trigeminal nucleus. These rats were aphagic but they recovered and their deficit was less severe than after RF lesion of the mesencephalic intermediate zone. In the last experiment, a combined 6-OHDA lesion of the mesencephalic intermediate zone and RF lesion of the trigeminal sensory nucleus led to a more severe deficit in feeding behavior than either lesion alone. These results further demonstrate that feeding behavior is under the control of a complex system involving several neural pathways.
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