Intraventricular Administration Of 6-hydroxydopamine Research Articles

Dopamine Cell Degeneration Induced by Intraventricular Administration of 6-Hydroxydopamine in the Rat: Similarities with Cell Loss in Parkinson's Disease

In an attempt to find a convenient rat model to study cell vulnerability in Parkinson's disease, we have investigated the cell-loss profile in different midbrain dopaminergic nuclei and subnuclei of rats injected with 6-hydroxydopamine (6-OHDA) in the third ventricle. Following administration of different doses (5–1000 μg) of 6-OHDA, motor behavior was evaluated and tyrosine hydroxylase-immunostained neurons were counted in the A8 group and different subdivisions of A9 and A10 groups. Animals developed hypokinesia, repetitive chewing movements, and catalepsia. Signs of cell degeneration were evident from the first day after injection, reaching the definitive pattern at the end of the first week. There was a similar degeneration in both brain sides, the A9 group showing the highest degree of cell-loss, followed by A8 and A10 groups. In the A9 group, the degeneration mostly affected those subgroups located in its ventral, lateral, and posterior regions. In the A10 group the degeneration mainly affected the parabrachial pigmented nucleus, the paranigral nucleus and the ventral tegmental area. This topographic pattern of degeneration is very similar to that previously described in Parkinson's disease, suggesting that this model may be a useful tool in the study of the cell vulnerability mechanisms in this neurodegenerative disorder. In addition, our results also showed that small dopaminergic neurons are more resistant to degeneration than the large ones. In some DA subgroups, the cells that contained calbindin but not calretinin were less vulnerable to the neurotoxic effect of 6-OHDA.

Differential effects of the intraventricular administration of 6-hydroxydopamine on the induction of type II beta-tubulin and tyrosine hydroxylase mRNA in the locus coeruleus of the aging Fischer 344 rat.

Noradrenergic neurons of the locus coeruleus have been shown to respond to injury by increasing the synthesis of neurotransmitter (via the activation and induction of tyrosine hydroxylase, the rate-limiting catalyst in the production of catecholamines) and initiating compensatory axonal sprouting. However, this laboratory has recently described a significant deficit in the activation of tyrosine hydroxylase in the aged Fischer 344 rat, in contrast to the young and mature rat, following partial damage to cortical and hippocampal noradrenergic terminals induced by the neurotoxin 6-hydroxydopamine. To extend these observations, we measured changes in the relative levels of neuron-specific type II beta-tubulin and tyrosine hydroxylase mRNA in locus coeruleus neurons of 2, 12, and 24-month-old Fischer 344 rats following intraventricular infusions of 6-hydroxydopamine by using in situ hybridization histochemistry. These measures were used as markers of the responsiveness of these neurons to injury. 6-Hydroxydopamine treatment induced a persistent increase (at least 10 days) in the expression of type II beta-tubulin mRNA only in 2-month-old animals; this marker decreased in the 12 and 24-month-old animals. Relative levels of tyrosine hydroxylase mRNA increased in 2 and 12-month-old lesioned animals both 3 and 10 days post-treatment. In contrast, the induction of tyrosine hydroxylase mRNA in 24-month-old animals, seen three days post-treatment, was attenuated by 10 days. These data indicate that the capacity of locus coeruleus neurons to compensate for injury by either initiating a potential sprouting response or increasing their capacity to synthesize neurotransmitter is reduced in older animals.

Functional influence of the central noradrenergic system on the skin conductance activity in rats

Pharmacological studies on neuroleptics and amphetamine strongly suggest that some dysfunction of the central catecholamine system may play a key role in the pathogenesis of schizophrenia. Our previous studies have demonstrated that intraventricular administration of 6-hydroxydopamine, a selective neurotoxin of the catecholamine neuron, can reproduce schizophrenia-like abnormalities in the skin conductance activity. In the present experiments, effects of pharmacological modulation of the central noradrenergic activity were studied in rats. Stimulation of the central noradrenergic activity by yohimbine (0.6 mg/kg, i.m.) slowed down the habituation of the skin conductance response (SCR) and increase the spontaneous fluctuation of the skin conductance (SF), while inhibition of the activity by clonidine (0.06 mg/kg, i.m.) accelerated or obliterated the SCR and decreased the SF frequency. If the functional significance of the central noradrenergic system lies in vigilance control, the present results are consostent with classical theory in psychophysiology: the habituation rate of SCR and the frequency of SF are correlated well with each other and both indices reflect arousal level. The disorder of the system should produce not only these psychophysiological abnormalities but also psychological disturbances; i.e., overarousal and underarousal syndromes. Therefore, the dysfunction of the noradrenergic system might constitute an essential aspect of schizophrenic disorder.

Skin conductance response after 6-hydroxydopamine lesion of central noradrenaline system in cats

Absence of skin conductance response (SCR) is a psychophysiological sign frequently observed among schizophrenic patients. This alteration of electrodermal activity can be reproduced in cats and rats by intraventricular administration of 6-hydroxydopamine (6-OHDA), a neurotoxin selectively destroying catecholamine neurons. The findings appears to be quite consistent with the catecholamine hypothesis of schizophrenia. To determine which catecholamine system—the dopamine (DA) or the noradrenaline (NA)—is responsible for the induction of this abnormality, the same dose of 6-OHDA was microinjected to either the ventral tegmental area (VTA, n = 3), through which most DA fibers ascend, or to the ascending noradrenergic bundle (ANB, n = 3), through which most NA fibers ascend. Four cats remained intact as a control for later brain catecholamine estimation. The skin conductance of all pretreatment intact cats ( n = 10) showed not only spontaneous fluctuations but also SCRs to auditory stimuli (5 kHz, 100 dB, 1 sec) which habituated with repetition. In contrast, ANB-lesioned cats showed a complete abolition of auditory SCRs, few spontaneous fluctuations, and a low basal skin conductance level. These abnormalities were statistically significant. On the other hand, no change was found in the skin conductance activity of the VTA-lesioned cats. Catecholamine estimation after the experiment confirmed selective destruction of the appropriate system corresponding to each type of lesion. These findings are discussed in the context of the DA or NA theory of schizophrenia, and involvement of the NA system in the pathogenesis of this illness is suggested.

Serotonin uptake into cerebrovascular nerve fibers of rat, visualization by immunohistochemistry, disappearance following sympathectomy, and release during electrical stimulation

Immunohistochemistry as well as in vitro uptake and release of [ 3H]5-HT were performed on pial arteries of rat to investigate the nature of 5-HT containing nerve fibers. Immunoreactive fibers were constantly found only in the basilar, vertebral and superior cerebellar arteries, while in the other parts of the circle of Willis, 5-HT immunofluorescent fibers were absent. After systemic treatment with tryptophan following inhibition of monoamine oxidase with nialamide the immunofluorescence intensity was markedly enhanced. The 5-HT immunoreactive fibers disappeared after superior cervical ganglionectomy or intraventricular administration of 6-hydroxydopamine, but persisted after administration of 5,6-dihydroxytryptamine. When isolated vessels were incubated in low concentration of 5-HT (1 nM) together with nialamide, a very dense plexus of 5-HT immunoreactive fibers appeared in all branches of the circle of Willis. Uptake and release experiments were carried out by incubation of arterial preparations with 3 nM [ 3H]5-HT (together with nialamide), followed by electrical field stimulation, or by exposure to tyramine or 124 mM potassium, all of which induced a 100%–350% increase in the tritium release over prestimulation values. Preincubation with cocaine and bilateral superior cervical ganglionectomy abolished or markedly attenuated the release upon all modes of stimulation. The results suggested that the 5-HT observed by immunohistochemistry in pial arteries is located in sympathetic nerve terminals where it may serve as a neuromodulator that is released during nerve activation.

Inhibition of striatal acetylcholine release by serotonin and dopamine after the intracerebral administration of 6-hydroxydopamine to neonatal rats

The intraventricular administration of 6-hydroxydopamine (6-OHDA) depletes the striatum of dopamine (DA). When given to rat pups at an early age, the toxin also increases striatal serotonin (5-HT) content. In the accompanying report we observed that endogenous 5-HT, like DA, exerts an inhibitory influence on the release of acetylcholine (ACh) from striatal slices prepared from control animals and that the extent if this inhibition is related to the degree of serotonergic innervation of the region being examined. To determine whether this hyperinnervation was accompanied by an increase in serotonergic influence on ACh release, striatal slices were prepared from adult rats, preincubated with [ 3H]choline, superfused, and exposed to electrical field stimulation. The efflux of tritrium into the superfusate was used as a measure of ACh release. In confirmation of previous reports, we observed that direct and indirect agonists of DA and 5-HT both reduced ACh overflow from control slices, whereas overflow was increased by antagonists of these amines. Slices prepared from rats given 6-OHDA-induced lesions as adults were responsive to each of these pharmacological manipulations, as well. In contrast, ACh overflow from slices prepared from animals lesioned with 6-OHDA as neonates was not modified by either dopaminergic or stereonergic drugs. These results suggest that the serotonergic hyperinnervation of striatum produced by neonatal 6-OHDA is accompanied by a loss of the inhibitory influence of endegenous 5-HT and DA on striatal ACh release and, thus, povide no evidence for a role for either transmitter in the behavioral sparing associated with such lesions.

Abnormal gait sequence in locomotion after atropine treatment of catecholamine-deficient akinetic rats.

Excessive, abnormal locomotion occurs after a high dose (25-50 mg/kg) of atropine sulfate to rats already akinetic due to catecholamine deficiency from intraventricular administration of 6-hydroxydopamine. This abnormal locomotion involves an abnormal gait sequence [right (R) hindleg (H), left (L) foreleg (F), LH, RF] instead of the normal gait sequence (RH, RF, LH, LF). In such animals atropine progressively (i) decreases hindleg step size, (ii) decreases arching of the trunk, and (iii) increases foreleg step size. These factors combine to change the ratio of front/hind body support. If the body stretches too far and the hindleg step is too small, a given hindleg step supports insufficient weight to remove weight from the ipsilateral foreleg; consequently, the opposite foreleg must execute the next step, producing the abnormal gait sequence. Thus, atropine affects gait sequence indirectly; it acts on at least three variables that affect how body weight is distributed and shifted during locomotion. To maintain stability during such locomotion, gait sequence is appropriately altered.

Sequential changes of skin conductance activity in rats after intraventricular administration of 6-hydroxydopamine

1. Thirty two male Wistar strain rats were trained to have their skin conductance activity recorded through the soles of their hind limbs, and sequential changes of this activity after the intraventricular administration of 6-OHDA (200 μg) were studied. 2. The intact rats showed SCR and its habituation to repeated auditory stimuli (500 Hz, 90 dB, 1 sec). The 6-OHDA treatment obliterated SCR and reduced the rate of spontaneous fluctuation in the early stage after the treatment. From the second day to one week after the treatment, with recovery of the spontaneous fluctuation rate, the SCR tended to reappear, and its habituation gradually slowed down. Two and three weeks after the treatment, the 6-OHDA rats usually showed habituation failure of SCR, but default of SCR was still observed at times. 3. These findings suggest that denervation of the catecholaminergic fibers by intraventricular 6-OHDA is responsible for the obliteration of SCR, and denervation supersensitivity, which develops later, may be the cause of its habituation failure. 4. The mechanisms underlying abnormal skin conductance activity of schizophrenia were discussed in line with the catecholamine hypothesis of this disease.

Two types of changes in skin conductance activity after intraventricular administration of 6-hydroxydopamine in rats

1. Sixteen male Wistar strain rats were trained to have their skin conductance activity recorded through the soles of their hind limbs, and the effects of the intraventricular administration of 6-OHDA (200 ug) on this activity were studied. 2. The intact rats showed skin conductance response and its habituation to repeated auditory stimuli (500 Hz, 90 dB, 1 sec). The 6-OHDA-treated rats exhibited either obliteration of the response or impairement of the habituation. The nonresponding state tended to be accompanied by a low rate of spontaneous skin conductance fluctuation, but the nonhabituating state was not accompanied by changes of the rate. The vehicle-treated rats showed no change in these activities. 3. These electrodermal characteristics were discussed along with the CA hypothesis of schizophrenia.

Subtotal destruction of central noradrenergic projections increases the firing rate of locus coeruleus cells

The intraventricular administration of 6-hydroxydopamine was used to destroy 80–90% of the noradrenergic terminals in the forebrain of male rats with little apparent damage to the cells of origin in locus coeruleus. Both 36 h and 21 days later the basal firing rate of these cells was elevated 4-fold above control levels. Moreover, microiotophoretic application of norepinephrine was significantly less effective in inhibiting the spontaneous activity of locus coeruleus cells in these rats relative to control animals. The increased firing may represent a compensatory response to the injury, leading to increased transmitter release from terminals spared by the lesion.

Adrenomedullary secretory response to midbrain stimulation in rat: effects of depletion of brain catecholamines or serotonin.

Electrical stimulation of the periaqueductal gray substance (PAG) of the rostral midbrain of the rat produced biphasic or monophasic pressor responses depending on the duration of the stimulus train. Marked increases in plasma noradrenaline (NA) and adrenaline (A) levels accompanied the pressor responses, indicating the participation of the adrenal medulla. Depletion of central catecholamines (CA) by intraventricular administration of 6-hydroxydopamine (6-OHDA) did not affect the primary vasomotor component but markedly depleted adrenal CA levels and attenuated the adrenomedullary component of the response to brain stimulation. The intraperitoneal administration of p-chlorophenylalanine (pCPA) not only depleted brain serotonin (5-HT) levels but also reduced brain CA levels significantly. The adrenaline (A) levels were reduced in the adrenal glands of these rats and the adrenal secretory response to brain stimulation was attenuated. In contrast, the selective destruction of central 5-HT neurons by intraventricular injection of 5,7-dihydroxytryptamine (5,7-DHT) in rats pretreated with desmethylimipramine (DMI) did not influence either the pressor nor the plasma CA responses to brain stimulation. Furthermore, the adrenal glands of these rats were normal. The results suggest that: (i) the central catecholaminergic neurons play an important role in the regulation of the adrenal glands but are not essential for the activation of the sympathetic vasoconstrictor fiber system: (ii) the pressor and plasma CA responses to PAG stimulation are not dependent on the central serotonergic system.

The effect of haloperidol and 6-hydroxydopamine on oral drug taking behavior in rats.

Abstract In a free choice procedure, rats dependent on the opioid etonitazene prefer the drug solution to water. With simultaneous oral intake of haloperidol, the etonitazene consumption is reduced dose-dependently. The same phenomenon is observed after the partial destruction of catecholaminergic neurons by intraventricular administration of 6-hydroxydopamine.

The role of central serotoninergic and noradrenergic neurons in the regulation of nyctohemeral rhythm of plasma thyrotropin.

A possible participation of central serotoninergic or noradrenergic neurons on nyctohemeral periodicity of plasma TSH concentration was studied in the rat. Control rats exhibited normal nyctohemeral fluctuations of plasma TSH characterized by high AM (09:30) and low PM (18:30) values (397 +/- 45 vs. 207 +/- 28 ng/ml, p < 0.01). The daily ip administration of p-chlorophenylalanine (p-CPA, 100 mg/kg body weight) for 7 days produced significant decreases in plasma TSH concentration and hypothalamic TRH content in the AM. However, these parameters in the PM were unaffected by p-CPA administration. An inhibition of serotoninergic activity thus abolished nyctohemeral periodicity in plasma TSH by lowering only AM values (AM:253 +/- 32 vs. PM:236 +/- 30 ng/ml, p > 0.1). On the other hand, intraventricular administration of 6-hydroxydopamine (6-OHDA, 250 micrograms/rat), a drug able to deplete noradrenaline and possibly dopamine, had no appreciable effect on AM-PM fluctuations of either plasma TSH or hypothalamic TRH content. The rate of elevation of plasma TSH after thyroidectomy was not significantly different in p-CPA or 6-OHDA treated rats compared to the respective controls, suggesting that there is no significant contribution of these biogenic amines to feedback control of TSH secretion by thyroid hormones. The present study suggests that the nyctohemeral periodicity of pituitary TSH secretion can be produced by cyclic activation of hypothalamus brought about by the increased input of serotoninergic neurons in response to the periodicity of certain environmental cues and that central noradrenergic or dopaminergic neurons are not involved in this system.

Depletion of central catecholamines alters amphetamine- and fenfluramine-induced taste aversions in the rat.

Conditioned taste aversions induced by pairing the consumption of saccharin with an amphetamine injection are attenuated in rats with depletion of central catecholamines caused by intraventricular administration of 6-hydroxydopamine (6-OHDA). The hypothesis that dopamine (DA) depletion is responsible for this effect was tested. The reduction in conditioning caused by intraventricular 6-OHDA could not be duplicated either with injections of 6-OHDA into the substantia nigra (Experiment 1) or with intraventricular 6-OHDA injections in animals pretreated with desmethylimipramine (Experiment 2). Both treatments, however, produced large depletions of telencephalic DA. 6-Hydroxydopa infusions caused a preferential loss of telencephalic norepinephrine (NE) but also failed to alter taste aversion learning. It is concluded that the effect of intraventricular 6-OHDA on amphetamine-induced aversions was the result of depletion of both NE and DA. In a third experiment the generality of the effect was examined by pairing saccharin consumption with injections of the amphetamine congener fenfluramine. Depletion of both NE and DA failed to alter fenfluramine-induced aversions. Infusion of 6-OHDA into the substantia nigra, however, retarded the extinction of such an aversion. Evidence is discussed for a peripheral site of action for fenfluramine in the conditioned aversion paradigm.

The effect of selective lesions of brain noradrenergic systems on the development of barbiturate tolerance in rats

A method for chronic infusion of barbiturates into the central nervous system of rats was developed and used to study the importance of noradrenergic systems in the development of barbiturate tolerance. Destruction of noradrenergic neurons by intraventricular administration of 6-hydroxydopamine or by specific lesions of the dorsal or ventral noradrenergic bundles prevented the development of barbiturate tolerance without altering the animal's response to the acute administration of barbiturate.

Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. II. On the central monoaminergic innervation

Summary The intraventricular administration of 6-hydroxydopamine (6-OHDA) to kittens between 5 days and 4 months of age induced marked changes in the endogenous levels of DA, NE and 5-HT in various brain areas. In contrast to the well-known selective effect of 6-OHDA against catecholaminergic neurones in the rat, serotoninergic neurones were also markedly affected by 6-OHDA treatment in kittens; particularly in the hippocampus and the colliculi, 5-HT levels were markedly and permanently decreased after the intraventricular administration of 6-OHDA. A significant but less pronounced reduction in 5-HT levels was also noted in other areas such as the piriform cortex, the cerebral neocortex, the cerebellum and the septum. Only very discrete changes were detected in the caudate nucleus, the olfactory tubercle and the raphe area. The administration of chlorimipramine (10 mg/kg, i.p.) 1 h before 6-OHDA treatment completely prevented the effects of the neurotoxic agent on serotoninergic innervation. Marked regional differences were also noted concerning the effects of 6-OHDA treatment on dopaminergic neurones. Whereas DA levels in the raphe area and the hypothalamus were almost unaffected, they were permanently reduced by about 50% in the caudate nucleus and the olfactory tubercle after the intraventricular administration of 6-OHDA. In the caudate nucleus, the reduction was even much more pronounced (−90%) when 6-OHDA was administered during the first 3 postnatal weeks. In most forebrain areas (hippocampus, piriform cortex and cerebral neocortex) and in the cerebellum, NE levels were permanently reduced to about 10% of those of control kittens as soon as the third day following the intraventricular injection of 6-OHDA. In contrast, after a transient drop, NE levels in the lateral brain stem (containing the locus coeruleus) of 6-OHDA-treated kittens returned and even surpassed (+100%) those found in age-paired controls. Analyses of the characteristics of l -[ 3 H]NE uptake in synaptosomes indicated that 6-OHDA treatment resulted in both a striking loss of specific uptake sites in forebrain areas and a significant increase in the V max of the NE uptake process in synaptosomes from the lateral brain stem. However, in contrast to the rapid increase in NE levels, this change in V max occurred much later, since it was first detected at more than one month after 6-OHDA treatment. This delay suggests that the doubling in NE levels occurring for the first month following the intraventricular administration of 6-OHDA simply resulted from an increased accumulation of the catecholamine in noradrenergic terminals in the lateral brain stem. Later on, the change in V max might indicate a sprouting of new noradrenergic terminals in the vicinity of the locus coeruleus area. The intraventricular administration of 6-OHDA resulted in a significant increase in the maximal stimulatory effect of l -isoproterenol on adenylate cyclase activity in homogenates of the cerebral cortex and the lateral brain stem. Therefore, not only the degeneration (in the cerebral cortex) but also the proliferation (in the lateral brain stem) of noradrenergic terminals were associated with an increase in the density of beta-adrenergic receptors. These results are discussed in relation to the possible function of the noradrenergic sprouts in the lateral brain stem.

Effect of intraventricular administration of noradrenaline and dopamine on the levels of corticosterone in rats and denervation hypersensitivity resulting from intraventricular administration of 6-hydroxydopamine.

The effects of intraventricular administration of noradrenaline (NA) on the resting levels, stress-induced rises and dexamethasone-induced decreases of plasma corticosterone (B) were studied in rats. The effect of pretreatment with intraventricular administration of 6-hydroxydopamine (6-OHDA) on the effects of NA or dopamine (DA), which was injected intraventricularly, was also examined. The results obtained were as follows: 1) Intraventricular administration of 1.0 μg of NA did not cause a decrease in concentrations of plasma B. 2) Ten μg of NA injected intraventricularly resulted in a rise of the levels of plasma B. 3) The stimulating action of centrally administered NA was more marked when the pre-injection concentrations of B were lower. 4) Pretreatment with intraventricular administration of 6-OHDA facilitated the action of intraventricularly administered NA in the regulation of pituitary-adrenocortical functions. The result suggests a development of denervation hypersensitivity caused by the pretreatment. 5) Intraventricular administration of NA did not block stress-induced rises of plasma B. 6) Intraventricular administration of NA counteracted dexamethasone-induced decrements of plasma B. 7) This counteraction was enhanced by pretreatment with intraventricular administration of 6-OHDA. This also suggests a development of denervation hypersensitivity resulting from intraventricular administration of 6-OHDA. 8) Intraventricular administration of 1.0 μg of DA caused no change in the concentrations of plasma B in either control or 6-OHDA treated animals.

Binding of α- and β-adrenergic ligands to cerebral cortical membranes: Effect of 6-hydroxydopamine treatment and relationship to the responsiveness of cyclic AMP-generating systems in two rat strains

The binding of an α-adrenergic antagonist, WB 4101 and of a β-adrenergic antagonist, dihydroalprenolol, to cerebral cortical membranes fromo two rat strains, Sprague-Dawley and F-344, was examined after intraventricular administration of 6-hydroxydopamine. Cyclic AMP-generating systems in cerebral cortical slices from Sprague-Dawley rats respond to norepinephrine with an accumulation of cyclic AMP which is increased twofold after 6-hydroxydopamine treatment, while the cyclic AMP systems in slices from F-344 rat respond to norepinephrine with a relatively large accumulation of cyclic AMP which is not further increased after 6-hyxdroxydopamine treatment. The binding of WB 4101 to cerebral cortical membranes was similar in both rat strains and was unchanged after 6-hydroxydopamine treatment. The binding of dihydroalprenolol to membranes was similar in both rat strains and increased about 25% in both strains after 6-hydroxydopamine. Thus, the number of binding sites for these ligands does not correlate well with the magnitude of responses of cyclic AMP-generating systems to norepinephrine. Activity of cyclic AMP-phosphdiesterases in cerebral cortical homogenates was similar in both rat strains and was unchanged after 6-hydroxydopamine. Fluoride-stimulated adenylate cyclase activity in cerebral cortical homogenates appeared to be slightly higher in F-344 rats compared to Sprague-Dawley rats before but not after 6-hydroxydopamine treatment suggesting that changes in responsiveness of the cyclic AMP system might not be dependent upon changes in receptor density but in a post-receptor alteration such as adenylate cyclase activity.

Strain differences in responsiveness of norepinephrine-sensitive adenosine 3′,5′-monophosphate-generating systems in rat brain slices after intraventricular administration of 6-hydroxydopamine

The development of hyperresponsiveness in cyclic AMP-generating has been investigated in brain slices of Sprague-Dawley and F-344 rats following intraventicular administration of 6-hydroxydopamine. Hyperresponsiveness to adrenergic agonists in cerebral cortical slices of Sprague-dawley rats pertained during the period 5–25 days after treatment with 6-hydroxydopamine. In contrast, hyperresponsiveness did not develop in cerebral cortical slices of F-344 rats. Reductions in norepinephrine levels of the cerebral cortex and hypothalamus following 6-hydroxydopamine treatment were comparable in the two rat strains. A hyperresponsiveness to norepinephrine and isoproterenol failed to develop in mesencephalic slices of either strain 12–14 days after treatment with 6-hydroxydopamine. The accumulation of cyclic AMP elicited by Norepinephrine in cortical slices of F-344 rat is normally about 50% greater than the accumulation elicited in slices from Sprague-Dawley rats. However, after 6-hydroxydopamine treatment, there was no significant difference in the accumulations of cyclic AMP elicited in cortical slices from the two rat strains. These data indicate there may be a limit to the responsiveness of catecholamine-sensitive cyclic AMP generating systems which can develop following alterations in synaptic input.

Beta-Adrenergic receptor involvement in 6-hydroxydopamine-induced supersensitivity in rat cerebral cortex.

The intraventricular administration of 6-hydroxydopamine, a procedure which destroys noradrenergic nerve terminals in the central nervous system, caused an increase in the density of beta-adrenergic receptors in rat cerebral cortex, without affecting their affinity for isoproterenol. The results suggest that changes in the density of adrenergic receptors are involved in 6-hydroxydopamine-induced supersensitivity at central noradrenergic synapses.