Ectopic noradrenergic hyperinnervation does not functionally compensate for neonatal forebrain acetylcholine lesion

Adult rats who have undergone neonatal 192 IgG-saporin induced lesions of forebrain acetylcholine (ACH) neurons are normal on many behavioral tasks. In this study we determined whether ectopic hippocampal ingrowths, a documented consequence of these neonatal cholinergic lesions, functionally compensate for ACH denervation in these rats. Neonatal rats underwent systemic 6-hydroxydopamine (6-OHDA) injections on postnatal days (PND) 1-3 to prevent the ingrowths, and/or intraventricular 192 IgG-saporin injections on PND 7. The 192 IgG-saporin profoundly reduced basal forebrain p75 neurotrophin receptor (p75(NTR)) immunoreactive (IR) neurons. The 6-OHDA treatment abolished hippocampal and cortical dopamine-beta-hydroxylase (DBH) IR terminals, indicating the absence of normal norepinephrine (NE) innervation. Ectopic DBH IR and p75(NTR) IR varicosities which occurred in the hippocampus of 192 IgG-saporin treated rats were also eliminated by 6-OHDA treatment. Behavioral testing in adulthood indicated no effect of the treatments on the Morris water maze. 192 IgG-saporin treatment caused perseveration during delayed spatial alternation (DSA) and increased working but not reference memory errors on the radial arm maze (RAM). The 6-OHDA plus 192 IgG-saporin treated rats did not differ from the 192 IgG-saporin only rats on any task. These results indicate that ectopic hippocampal NE ingrowths do not functionally compensate for neonatal ACH lesions. Neonatal forebrain ACH lesion impairs working memory on the RAM but the absence of an effect on DSA contraindicates a basic dysfunction of short term memory. Despite severe combined neonatal loss of forebrain ACH and NE innervation, behavior is remarkably intact.     

Selective lesioning of forebrain noradrenaline neurons at birth abolishes the improved maze learning performance induced by rearing in complex environment

The effect of selective destruction of forebrain noradrenaline (NA) neurons induced by 6-hydroxydopamine (6-OHDA) at Day 1 after birth on Hebb-Williams maze performance was investigated in adult rats housed after weaning in a complex environment (EC) or an isolated (IC) environment for 35 days. Saline treated control rats raised in the EC made fewer errors than those raised in the IC. This effect of EC was completely abolished in 6-OHDA treated rats; for these animals no improved performance due to the housing condition was obtained. Protection of the NA neurons against 6-OHDA neurotoxicity by pretreatment with desipramine (DMI) resulted in an effect of EC identical to that seen in saline-treated controls. Postweaning housing in the IC led to an increased locomotion as compared to housing in EC, but this effect was not affected by neonatal 6-OHDA and/or DMI treatment. Neurochemical analysis confirmed cortical NA and metabolite depletion as well as a good protection by the DMI pretreatment. The present results indicate that central NA neurons are involved critically in mediating mainly the cognitive components of behavioral alterations induced by EC.     

Depletion of brain norepinephrine does not reduce spontaneous ambulatory activity of rats in the home cage

6-Hydroxydopamine (6-OHDA) lesions of brain noradrenergic neurons and terminals were made in rats to assess the importance of forebrain norepinephrine (NE) for mediating circadian patterns of spontaneous ambulatory activity that rats show in the home cage. 6-OHDA was injected intracranially into the fibers of the ascending noradrenergic dorsal and ventral bundle pathways or infused into the lateral ventricle or both. Rats living in a 12/12 h light/dark cycle exhibit a marked increase in ambulatory activity during the dark period in comparison to the light period and a 'W-shaped' pattern of activity during the 12 h of the dark phase. Results showed that near-total depletion of brain NE did not impair the capacity to generate normal patterns of spontaneous ambulatory activity that occur in the home cage. In the animals that sustained the most complete NE lesions, the amounts of activity generated at times of peak activity were exaggerated in comparison to the control animals, which is consistent with the possibility that NE in the brain exerts a moderating influence on behavior.     

Facilitation of neocortical kindling by depletion of forebrain noradrenaline

The role of forebrain noradrenaline in seizures induced by electrical stimulation of the anterior neocortex (kindling) was investigated in control rats and rats pretreated with bilateral injections of 6-hydroxydopamine (6-OHDA) into the mesencephalic trajectory of the dorsal tegmental noradrenergic bundle. Extensive depletion of forebrain noradrenaline significantly facilitated the rate of development of cortico-generalized seizures.     

Loss of visual placing in rats after lateral hypothalamic microinjections of 6-hydroxydopamine

Visual placing responses were completely abolished in 29 albino rats after bilateral injection of 6-hydroxydopamine (6-OHDA) into the median forebrain bundle in the anterolateral hypothalamic region. This deficit persisted and appeared to be permanent. d-amphetamine (2 mg/kg, ip) temporarily restored visual placing in one group of rats 6 mo after 6-OHDA treatment. d-amphetamine did not restore visual placing, however, in a second group of rats tested 3–5 wk after intrahypothalamic injections of 6-OHDA. The loss of visual placing was an isolated deficit because somes-thetic placing, righting, and hopping reactions were normal after 6-OHDA. The loss of visual placing was a specific result of catecholaminergic damage in the anterolateral hypothalamus because vehicle injections there and anteromedial 6-OHDA injections did not abolish visual placing. These results provide the first evidence that catecholamine axons or terminals in the anterolateral hypothalamic region are an essential part of the neurological network for visual placing.     

Telencephalic but not diencephalic noradrenaline depletion enhances behavioural but not endocrine measures of fear conditioning to contextual stimuli

Three experiments investigated the effects of primarily cortical or hypothalamic noradrenaline depletion on aversive conditioning of explicit and contextual stimuli in rats. In Expt. 1, two groups of rats were trained to respond under a variable interval schedule for food reward. One group of rats subsequently received injections of 6-hydroxydopamine into the dorsal noradrenergic bundle, resulting in profound depletion of cortical noradrenaline; the second group received vehicle injections. All rats were exposed to 5 pairings of an auditory stimulus (CS) and footshock (UCS) in a distinctive environment (the dark chamber of a place preference apparatus). During testing in a separate, neutral environment, DNAB-lesioned rats suppressed responding for food reward, in the presence of the aversive CS, to a greater degree than controls. Lesioned rats also showed a greater aversion to the distinctive environment in which they were shocked. In contrast, plasma corticosterone concentrations, measured immediately following each of these behavioural tests, revealed no differences between DNAB-lesioned and control rats. Expt. 2 showed that the DNAB lesion did not affect habituation to the light chamber of the place preference apparatus used in Expt. 1. Expt. 3 showed that 6-OHDA injection into the ventral noradrenergic bundle component of the central tegmental tract, which damages primarily the noradrenergic innervation of hypothalamus, had no effect on either behavioural or endocrine responses to conditioned aversive, explicit or contextual cues. The results are discussed in relation to other reports of the effects of DNAB lesions on simple associative learning in an aversive context.     

Failure to replicate the dorsal bundle extinction effect: Telencephalic norepinephrine depletion does not reliably increase resistance to extinction but does augment gustatory neophobia

Depletion of telencephalic noradrenaline (Ne), caused by lesion of the dorsal tegmental bundle, has been reported to increase persistance of non-reinforced responding in various operant tasks. This has been referred to as the dorsal bundle extinction effect (DBEE). In an effort to reproduce this effect, rats receiving 6-hydroxydopamine lesions of the dorsal Ne bundle (DB-OHDA) were compared to controls during extinction of a continous food rewarded (CRF) lever-response. While the lesion group showed an increase in responding during initial extinction, no significant difference in resistance to extinction using a 2-min non-response criterion was obtained. Moreover, no differences in reinforced response rates were observed with CRF, fixed ratio (FR-15, FR-30, FR-60) or variable interval (VI-30, VI-60, VI-20 s) schedules of reinforcement. In order to test the hypothesis that the DBEE is dependent on time of behavioral testing after surgery, subsequent experiments were performed where rats began CRF operant training 5, 17, 31 or 110 days post-lesion. No differences in resistance to extinction were observed between lesion and control rats at any post-lesion interval. Neonatal treatment with 6-OHDA which permanently lesions forebrain Ne terminals also failed to prolong extinction. Finally, when both DB-OHDA and neonatal rats were given a choice between water and saccharine the lesioned animals exhibited a neophobic reaction whereby they drank significantly less saccharine. We conclude that while the DBEE is not a reliably reproducible phenomenon other effects of forebrain Ne lesions, such as neophobia, appear to be robust.     

Are the dorsal noradrenergic bundle projections from the locus coeruleus important for neocortical or hippocampal activation?

Three different methods were used to examine the importance of the dorsal noradrenergic bundle projections from the locus coeruleus (LC) in activation of the neocortex and hippocampus in freely moving rats. (1) After cerebral norepinephrine (NE) was depleted by systemic neonatal injections of 6-hydroxydopamine (6-OHDA) both atropine-resistant and atropine-sensitive forms of hippocampal rhythmical slow activity (RSA; theta) and neocortical low voltage fast activity (LVFA) remained intact. Compared to controls the adult rats treated with 6-OHDA in infancy reared less in a 24 h time sample of behavior and ran less in running wheels. (2) Brain dopamine and NE were also depleted by systemic injections of alpha-methyl-p-tyrosine. Following this treatment rats were very inactive behaviorally. However, normal activation of the hippocampus and neocortex was still present. (3) In normal rats, electrical stimulation of the LC was relatively ineffective, compared to stimulation of nucleus reticularis pontis caudalis, in producing behavioral changes (especially locomotion) or either atropine-resistant or atropine-sensitive hippocampal RSA or neocortical LVFA. It is concluded that the locus coeruleus is not important for cerebral activation, and that mechanisms for cerebral activation are probably diffusely represented in the reticular core. The data also show that when attempting to assess the effect of experimental manipulations on brain activity it is essential to control for the possible effects of changes in behavior.     

Global Depletion of Dopamine Using Intracerebroventricular 6-Hydroxydopamine Injection Disrupts Normal Circadian Wheel-Running Patterns and PERIOD2 Expression in the Rat Forebrain

Normal circadian rhythms of behavior are disrupted in disorders involving the dopamine (DA) system, such as Parkinson’s disease. We have reported previously using unilateral injections of the catecholamine toxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle that DA signaling regulates daily expression of the clock protein, PERIOD2 (PER2), in the dorsal striatum of the rat. In the present study, we made widespread lesions of DA fibers using large injections of 6-OHDA into the third ventricle to determine the involvement of DA in normal daily rhythms of wheel-running activity and PER2 patterns in the suprachiasmatic nucleus (SCN) and several regions of the limbic forebrain. Rats injected with 6-OHDA and housed in constant darkness were less active in the wheel and showed a disorganized pattern of activity in which wheel running was not confined to a specific phase over 24 h. The 6-OHDA injection had no effect on the daily PER2 pattern in the SCN, but blunted the normal rise in PER2 in the dorsal striatum. 6-OHDA also blunted PER2 expression in the periventricular nucleus of the hypothalamus, a region in which a daily PER2 pattern has not been previously reported in male rats, and in the oval nucleus of the bed nucleus of the stria terminalis, but not in the central nucleus of the amygdala. These results indicate that DA plays a prominent role in regulating circadian activity at both behavioral and molecular levels.     

Loss of active avoidance of responding after lateral hypothalamic injections of 6-hydroxydopamine.

After injections of 6-hydroxydopamine (6-OHDA) along the medial forebrain bundle in the lateral hypothalamus, rats failed to acquire a one-way active avoidance response or failed to perform a previously acquired active avoidance response. Such rats, however, acquired a passive avoidance response and a conditioned taste aversion normally. Thus the effect of lateral hypothalamic injections of 6-OHDA was not a total loss of the capacity to acquire or perform conditioned responses, but was a failure to initiate forward movement in the presence of a conditional stimulus. Most of these rats could initiate a similar forward movement to escape from the unconditioned stimulus (foot shock). Failure to acquire or perform the active avoidance response was correlated with the loss of hypothalamic, striatal and forebrain catecholamines produced by lateral hypothalamic 6-OHDA injections. Identical injections of 6-ohda placed along the medial hypothalamus produced a similar loss of regional catecholamines, but medial 6-OHDA injections did not affect active avoidance responding. We interpret this dissociation between loss of catecholamines and the capacity for active avoidance responding to mean that medial 6-OHDA injections did not damage the same catecholaminergic terminal fields as lateral 6-OHDA injections and that the integrity of the terminal fields damaged by lateral 6-OHDA injections is necessary for active avoidance responding.     

Alteration of seizures resulting from pinealectomy in the rat after neonatal treatment with 6-hydroxydopamine

Convulsions from combined pinealectomy and parathyroidectomy were examined in rats treated as neonates with 6-hydroxydopamine (6-OHDA). Injection of 6-OHDA caused a significant reduction in the average latency to onset of clonic-tonic convulsions. Moreover, of the 6-OHDA-treated rats which convulsed, nearly half of them died during a seizure. In sham-pinealectomized rats, neonatal treatment with 6-OHDA reduced norepinephrine (NE) and increased dopamine levels in the forebrain while brainstem levels of NE were increased. Pretreatment with desmethylimipramine reversed the effects of 6-OHDA on convulsions and catecholamine levels. The results indicate that catecholamine lesions with 6-OHDA exacerbate convulsions from pinealectomy.     

Evidence for a norepinephrine-dependent brain-stem substrate in the development of kindling antagonism

Kindling antagonism' is a modification of the standard kindling paradigm in which two limbic system structures are stimulated on alternate trials. The consistent outcome of this procedure is that one site ('dominant site') develops typical generalized seizures, while kindled seizure development from the other site ('suppressed site') is arrested at an intermediate stage. Our recent research suggests that kindling antagonism is dependent on hindbrain norepinephrine (NE) systems. The present study explores this relationship further. Neonatal rats were treated with intracerebral injections of 6-hydroxydopamine (6-OHDA). At adulthood, these animals received either (1) a low dose of 6-OHDA (75 micrograms), (2) a high dose of 6-OHDA (200 micrograms), or (3) vehicle. Regional NE concentrations were determined by high pressure liquid chromatography. Neonatal 6-OHDA followed by vehicle resulted in decreases in forebrain and increases in hindbrain NE concentrations. Low dose 6-OHDA at adulthood depleted cerebellar, but not pontine-medullary NE. High dose 6-OHDA resulted in depletions of both cerebellar and pontine-medullary NE. Only high dose 6-OHDA significantly interfered with the development of antagonism. Neonatal 6-OHDA facilitated the rate of dominant site kindling independently of subsequent adult treatment regimens. Results suggest that the influence of NE on kindling antagonism is mediated through a brain-stem substrate and that the influence of NE on kindling rate is mediated through a forebrain substrate.     

Effects of dopamine depletion from the caudate-putamen and nucleus accumbens septi on the acquisition and performance of a conditional discrimination task

Three experiments compared the effects of dopamine depletion from the caudate-putamen (CAUD; dorsal striatum) or nucleus accumbens septi (NAS; ventral striatum), or a systemically administered dopamine receptor antagonist (alpha-flupenthixol) on the acquisition and performance of a conditional discrimination task involving temporal frequency. In Expt. 1, rats receiving 6-hydroxydopamine (6-OHDA) lesions of the CAUD were impaired in the acquisition of a visual version of the task, and rats with 6-OHDA lesions of the NAS were not reliably impaired. Even when the rats with CAUD lesions had acquired the discrimination, they were still significantly slower to collect earned food pellets. Both CAUD and NAS lesions reduced a bias to respond to the faster of the two discriminative stimuli. In Expt. 2, rats with 6-OHDA lesions of CAUD were markedly impaired in their accuracy and speed of responding when they had been trained to criterion preoperatively. These effects could not be mimicked in controls by prefeeding (which had only minor effects on performance). Rats with 6-OHDA-induced lesions of the NAS were unimpaired in either visual or auditory discrimination performance, but were slower to extinguish responding than controls. In Expt. 3, alpha-flupenthixol (0.1-0.56 mg/kg, i.p.) produced dose-dependent impairments in both latency to respond and choice accuracy in visual and auditory versions of the task. In conjunction with other results, these data suggest that (1) dopamine receptor blockade and central dopamine depletion can impair discrimination performance under certain conditions (2) dopamine depletion from the ventral and dorsal striatum, respectively, have dissociable effects on behaviour controlled by conditioned reinforcers and discriminative stimuli and (3) the disruption of discrimination performance by dorsal striatal dopamine depletion is probably attributable to several factors.     

Changes in brain norepinephrine content in mice following neonatal 6-hydroxydopamine

Treatment of mice with various doses of 6-hydroxydopamine (6-OHDA) between days 1 and 5 after birth produced decreases in body, forebrain and cerebellum weights at 6 and 18 days of age. Doses of 6-OHDA larger than 3 injections of 50 mg/kg did not augment the norepinephrine (NE) depletion in the cerebellum at 6 days of age. Different patterns of NE depletion and recovery were observed in the cerebellum, cerebral cortex and brainstem after injections of 50 mg/kg on day 1, days 1 and 3 or days 1, 3, and 5. In the cerebellum, but not in the cortex, NE content increased significantly between 8 and 24 hr post-injection. Sequential injections of 6-OHDA produced additional NE depletion 24 hr post-injection only in the cortex. At 18 days of age the extent of NE recovery in the cerebellum, but not in the brainstem or cortex, depended on the number of 6-OHDA injections. After 2 or 3 injections, NE concentrations in the cortex were significantly higher at 18 days (50–60% of control) than at 24 hr post-injection (10–15% of control).     

Role of central noradrenaline neurons in the contextual control of latent inhibition in taste aversion learning

Three experiments were performed to examine the effects of noradrenaline (NA) depletion, using 3 different methods: lesions of the dorsal noradrenergic bundle (DB) with 6-hydroxydopamine (6-OHDA), lesions induced by neonatal treatment with 6-OHDA and lesions induced by systemic DSP4 upon latent inhibition, using the taste-aversion learning procedure. NA depleted and control (sham, vehicle or saline) rats were given pre-exposure trials to either novel saccharin or to novel saccharin in a novel type of drinking bottle (the noisy bottle). Later, during conditioning trials saccharin was presented in the noisy bottles for all the rats, followed by lithium chloride injections. Saccharin aversions, tested for in the noisy bottles, indicated considerably weaker saccharin aversions (i.e. more latent inhibition) by the control groups pre-exposed to both saccharin and the noisy bottles. These context-dependent latent inhibition effects were clearly attenuated by all 3 treatments that depleted central NA. Biochemical assays confirmed the NA depletions in each case. The results, demonstrating the intimate role of central NA neurons in contextual control of latent inhibition in taste-aversion learning, appear to conform with current attentional theories of NA function in the forebrain.     

Damage to ceruleo-cortical noradrenergic projections impairs locally cued but enhances spatially cued water maze acquisition

A series of 4 experiments tested the effects of central catecholamine depletion on acquisition of an escape response in a spatial water maze. In Expt. 1, local infusions of 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle (DNAB) enhanced efficient acquisition of the spatial water maze in a stressful condition (cold water), but had no effect in warm water. In Expt. 2, lesions of the ventral noradrenergic bundle did not affect acquisition of the maze, indicating that the changes observed in Expt. 1 were unlikely to have been the result of incidental damage to the noradrenergic innervation of the hypothalamus. Measures of core body temperature and plasma corticosterone were taken in parallel with the behavioral experiments and revealed that central noradrenaline (NA) depletion did not alter these responses to cold or warm water swims. Expt. 3 revealed a contrasting pattern of effects following dopamine (DA) depletion from the caudate-putamen: swimming speed was reduced in warm, but not cold water and maze acquisition was impaired, to an equal extent in warm and cold water. Finally, in Expt. 4, rats with 6-OHDA lesions of the DNAB were impaired in discriminating local cues in a simultaneous visual discrimination water maze. These results support the hypothesis that ceruleo-cortical NA depletion broadens the span of attention, particularly under stressful circumstances. In contrast, the results also indicate that striatal DA depletion mainly affects vigour of responding, as measured by swim speed, and that this effect can be reversed by the stressful effects of cold water.     

Sleep-inducing function of noradrenergic fibers in the medial preoptic area

The aim of the investigation was to find out the role of noradrenergic (NE) terminals of the medial preoptic area (mPOA), in the regulation of sleep-wakefulness. Studies were conducted on free-moving adult male rats with chronically implanted cannulae in the mPOA. Sleep-wakefulness was assessed on the basis of EEG, EMG, and EOG recordings along with behavioral observations. Lesioning of catecholamine terminals (with 6-hydroxydopamine) in the mPOA produced an increase in quiet wakefulness. Prevention of NE fiber destruction, by pretreating the rats with imipramine, prevented this effect. This demonstrated that the increased quiet wakefulness produced by 6-OHDA was the result of NE fiber destruction. Changes in sleep-wakefulness were also assessed after microinjection of NE into the mPOA, in normal and ventral noradrenergic bundle (VNA)-lesioned rats. NE administration induced sleep in VNA-lesioned rats, and arousal in normal rats. The findings suggest that the NE terminals in the mPOA, projecting via VNA, play a role in the induction of sleep.     

Effects of 6-hydroxydopamine-induced norepinephrine depletion on cerebellar development

In order to investigate the possible influence of norepinephrine (NE) on neuronal development, the effects of neonatal NE depletion on postnatally developing cell populations were characterized in (1) the normal mouse cerebellum, and (2) a cerebellar model system with delayed germinal cell development produced by neonatal methylazoxymethanol acetate (MAM) administration. Reduction in NE content was achieved by neonatal 6-hydroxydopamine (6-OHDA) injections. In the MAM-treated groups, 6-OHDA did not produce significant changes in external germinal layer (EGL) reconstitution. In the other groups, 6-OHDA treatment produced a reduction in the vermis area, alterations in foliation, and changes in the schedule of EGL development. These results support a role for NE in regulation of neuronal development in the cerebellum.     

Evidence for an interaction of opioid and noradrenergic locus coeruleus systems in the regulation of environmental stimulus-directed behavior

The roles of opioid and noradrenergic (NE) dorsal bundle systems in an animal's response to particular environmental stimuli were examined in a multicompartment exploration chamber. The opiate antagonist naloxone (NAL) produced a stereospecific increase in environmental stimulus interaction, while the opiate agonist morphine induced a NAL-reversible reduction in stimulus contact. Thus, a specific opioid role in environmental stimulus-directed behavior is indicated. Several reports suggest inhibitory actions of opioids on NE locus coeruleus (LC) activity. Consistent with these reports, we observed that 6-hydroxydopamine (6-OHDA) lesions of the NE dorsal bundles of the LC produced a morphine-like reduction in stimulus contact. Naloxone, which increased stimulus interaction in sham-lesioned rats, had no effect in dorsal bundle lesioned animals. These findings indicate an interaction between opioid and LC systems in the regulation of environmental stimulus-directed behavior.     

Effect of manipulating central catecholamines on puberty and the surge of luteinizing hormone and gonadotropin releasing hormone induced by pregnant mare serum gonadotropin in female rats

We have investigated the effect of manipulating central catecholamines on the timing of puberty (as assessed by vaginal opening) in female rats and the surge of luteinizing hormone (LH) and gonadotropin releasing hormone (GnRH) induced by pregnant mare serum gonadotropin (PMSG) in immature female rats. Manipulation of the catecholamines was carried out with either 6-hydroxydopamine (6-OHDA) administered with or without either desipramine (DMI) or pargyline, orα-methyl-p-tyrosine (α-MPT).The neonatal administration of 6-OHDA delayed puberty, an effect which was potentiated by pretreatment with DMI and was associated with a reduction in the rate of body growth. Catecholamine fluorescence in animals aged 60–65 days that had been treated with DMI followed by 6-OHDA was diminished only in the caudatus-putamen; treatment with 6-OHDA alone resulted in diminished fluorescence in the hypothalamus and in the intermediate but not the external layer of the median eminence. The neonatal administration of α-MPT had no significant effect on either the growth rate or the timing of puberty. Regular oestrous cycles occured after puberty in animals treated with either 6-OHDA or α-MPT.The PMSG-induced LH surge was significantly enhanced by 6-OHDA (administered i.v.) plus DMI, and reduced by 6-OHDA injected into the lateral ventricle (v). The inhibitory effect of 6-OHDA (v) wasreduced by DMI, but in animals given 6-OHDA (i.v.) after pargyline there was a marked reduction in the height of the LH surge. There was a good correlation between the changes in the concentrations of LH in peripheral plasma and the concentrations of GnRH in pituitary stalk plasma in that the PMSG-induced surge of GnRH was significantly increased by 6-OHDA (i.v.) plus DMI and reduced by 6-OHDA (v). In animals treated with 6-OHDA (i.v.) plus DMI catecholamine fluorescence was reduced only in the external layer of the median eminence, while after 6-OHDA (v) plus DMI degeneration was seen in the medial forebrain bundle.These results demonstrate a marked difference between the long-term and acute effects of 6-OHDA on the gonadotropin control system. Neonatal treatment with 6-OHDA plus DMI significantly delays puberty and the rate of body growth, but does not affect cyclical gonadotropin release and has no persistent effect on the hypothalamic catecholaminergic systems. The acute administration of 6-OHDA, depending upon the route of administration and whether it is given after DMI, can either potentiate or inhibit the PMSG-induced surge of GnRH and consequently LH by mechanisms which involve destruction, respectively, of either dopaminergic terminals in the median eminence or catecholaminergic fibres in the dorsal hypothalamus.