Possible involvement of serotonergic neurons in the reduction of locomotor hyperactivity caused by amphetamine in neonatal rats depleted of brain dopamine

This experiment attempted to determine the mechanism by which amphetamine reduces locomotor hyperactivity in neonatal rats given brain dopamine (DA)-depleting 6-hydroxydopamine (6-OHDA) injections. Brain DA neurons were destroyed selectively in neonatal rats by intraventricular (i.v.t.) injections of 6-OHDA following desmethylimipramine (DMI) pretreatment. Control rats received DMI and i.v.t. injections of the 6-OHDA vehicle solution. Rats given the 6-OHDA treatment displayed 7-fold increases in locomotor activity compared to controls during days 16–55 of life. Throughout this period, amphetamine (1 mg/kg) reduced locomotor hyperactivity in 6-OHDA-treated rats but increased locomotor activity in control rats. The reduction of hyperactivity caused by amphetamine (0.5–4 mg/kg) was dose-related and was not accompanied by stereotyped behavior. Like amphetamine, methylphenidate (4 mg/kg) reduced locomotor hyperactivity in rats given 6-OHDA. The DA antagonist, spiroperidol (50–200 μg/kg) failed to attenuate the hyperactivity-reducing effect of amphetamine in 6-OHDA-treated rats at doses which abolished the stimulant effect of amphetamine in control rats. However, the serotonin antagonist methysergide (0.5–4 mg/kg) produced dose-dependent antagonism of the effect of amphetamine in 6-OHDA-treated rats. Pretreatment with propranolol (5 mg/kg), phentolamine (5 mg/kg), atropine (0.5 mg/kg) or naloxone (10 mg/kg) failed to alter the reduction in locomotor hyperactivity caused by amphetamine. The serotonin releasing agent, fenfluramine (3 mg/kg), and the serotonin agonist, quipazine (0.5–4 mg/kg), both reduced locomotor hyperactivity in 6-OHDA-treated rats while not altering locomotion in control rats. These results confirm previous observations that amphetamine reduces locomotor hyperactivity caused by neonatal 6-OHDA administration and suggest that this effect is mediated by increased serotonergic neurotransmission.     

Dentate granule cells in the rat hippocampal formation have the behavioral characteristics of theta neurons

These experiments examined the effects on locomotor activity of brain lesions that destroyed either mesocortical or nigrostriatal dopamine (DA) neuronal projections in neonatal rats. Electrolytic lesions of the medial ventral tegmental area in 4-day-old rats reduced the content of DA within the frontal cortex and septum by 42-57% and resulted in a 2-fold increase in locomotor activity during days 22-24 of life. In contrast, bilateral electrolytic lesions of the substantia nigra in 4-day-old rats reduced the content of DA within the caudate putamen by 68%, but failed to alter locomotor activity during days 22-24 of life. These results suggest that loss of mesocortical DA neurons may underlie the locomotor hyperactivity seen following brain DA-depleting 6-hydroxydopamine injections in neonatal rats and that these mesocortical DA neurons may normally influence the ontogeny of locomotion in the rat.     

Age-dependent effects of 6-hydroxydopamine on locomotor activity in the rat

This experiment examined the effects on locomotor activity of intraventricular 6-hydroxydopamine (6-OHDA) administered to developing and adult rats. 6-OHDA was administered subsequent to parygline desmethylimipramine (DMI) treatmen(6-OHDA/DMI) at 3 and 6 days of age, 11 and 14 days of age, 20 and 23 days of age, or 46 and 48 days of age. Locomotor activity of vehicle-treated rats assessed in stabilimeter cages peaked between 14 and 16 days of age and subsequently declined to levels characteristic of the adult. Treatment with pargyline and 6-OHDA at 3 days of age, or 6-OHDA/DMI at 3 and 6 or 11 and 14 days of age, did not alter the early rise in locomotor activity but prevented the decline in activity normally seen during the third and fourth weeks of life. When tested as adults, locomotor activity was greater in rats that had been treated with 6-OHDA/DMI at 3 and 6 and at 11 and 14 days of age than in those that had been treated at 20 and 23 days of age. Treatment with 6-OHDA/DMI at 46 and 48 days of age was without significant effect on locomotor activity. 6-OHDA (with pargyline pretreatment) produced large decreases in NE content in telencephalon and diencephalon and in dopamine (DA) content in striatum. 6-OHDA/DMI also produced large decreases in DA content in striatum and, in some of the treatment groups, only small decreases in norepinephrine (NE) content in telencephalon, diencephalon, and brain stem. These data suggest that the maturation of neuronal systems utilizing dopamine as a neurotransmitter is essential for the suppression of locomotor activity normally seen during development. The data further suggest that dopamine depletion per se does not lead to increased locomotor activity, but rather it is the destruction of dopamine-containing fibers prior to the normal period of locomotor suppression that increases locomotor activity.     

Effects of acute administration of DA agonists on locomotor activity: MPTP versus neonatal intracerebroventricular 6-OHDA treatment

The effects of several dopamine (DA) receptor agonists upon locomotor activity on adult MPTP-treated mice and postnatal 6-hydroxydopamine- (6-OHDA-) treated rats were assessed in ten experiments. C57 BL/6 mice were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 2 x 40 mg/kg, s.c., 24-hr interval between injections) at 5-months-age, while 1-day-old male Wistar rat pups were given intracisternal 6-OHDA (50 mg, once following desipramine, 25 mg/kg). MPTP-treated mice were tested 4-5 weeks following MPTP injections whereas neonatal 6-OHDA rats were tested at 3-months-age. Locomotor activity was measured in respective activity test chambers following acute administration of DA receptor agonists. In MPTP-treated mice, apomorphine failed to elevate locomotor activity but instead further exacerbated (1.0 and 3.0 mg/kg, s.c.) the hypokinesia of these animals while inducing marked increases in control mice. Cabergoline (0.3 mg/kg, s.c.) and bromocriptine (3.0 mg/kg, s.c.) caused dose-specific elevations of locomotion in MPTP and control mice but suppressed activity at the highest doses. Quinpirole (0.2 mg/kg) and 7-hydroxydipropylaminotetralin (7-OH-DPAT; 300 nmole/kg) increased locomotion in hypokinesic MPTP-treated mice; in control mice, activity was elevated by quinpirole (0.2 and 0.7 mg/kg) and 7-OH-DPAT (100 and 300 nmole/kg), while higher doses suppressed activity. Neither SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) nor FCE 23884 [4-(9,10-didehydro-6-methylergolin-8 beta-yl) methyl-piperazine-2,6-dione] affected locomotor activity. Apomorphine (0.3, 1.0 and 2.0 mg/kg), bromocriptine (3.0 mg/kg) and cabergoline (1.0 mg/kg) stimulated locomotion in sham-operated rats, and to a greater extent in the 6-OHDA-treated rats. Higher dose cabergoline (3.0 mg/kg) induced increased activity of similar extent in sham controls and 6-OHDA treated rats. Activity-enhancing effects of quinpirole (0.2, 0.7 and 2.1 mg/kg) in sham rats were attenuated in 6-OHDA treated rats. Both SKF 38393 (10 mg/kg) and FCE 23884 (0.3 and 1.0 mg/kg) induced locomotor activity increases in 6-OHDA, but not sham, rats. Finally, 7-OH-DPAT (1200 mg/kg) enhanced activity in 6-OHDA rats vs. shams. The effects of the DA agonists are discussed with regard to the putative antihypokinesic effects in MPTP mice and DA-receptor supersensitivity effects in neonatal 6-OHDA rats, pertaining to their more-or-less selective subreceptor profiles.     

Body weight changes after neurochemical manipulations of lateral amygdala: Noradrenergic and dopaminergic mechanisms

The feeding behavior of rats was studied after neurochemical lesions of lateral amygdalar terminal fields of mesolimbic dopaminergic (DA) and coerular noradrenergic (NA) systems. 6-Hydroxydopamine (6-OHDA) with or without desmethylimipramine (DMI) premedication was bilaterally injected into the lateral amygdala or periamygdaloid-piriform area. Lateral amygdalar injections of 6-OHDA resulted in hyperdipsia, hyperphagia and body weight increase with a relative decrease in amygdalar NA concentration, while 6-OHDA plus DMI treatments were followed by weight decrease and a mild decrease in DA level. When the cannulas were placed into the periamygdaloid-piriform cortex nothing but body weight increase developed. The importance of the actual balance of the two amygdalar catecholaminergic (CA) systems in feeding is discussed.     

Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage

Different parameters of motor behavior (locomotion, rearing and total activity counts) were studied in the adult rat following neonatal intracisternal 6-hydroxydopamine (6-OHDA, 50 micrograms) treatment combined with noradrenaline (NA) uptake blocker (desipramine) or dopamine (DA) uptake blockers (amfolenic acid or GBR 12909) to obtain selective DA or NA lesions respectively. At 61-65 days of age, selective DA-lesioned animals showed an initial decrease in spontaneous motor behavior at test days 1 and/or 2, while at test days 4 and 5 hyperactivity was observed. However, following amfolenic acid or GBR 12909 pretreatment leading to a selective NA lesion, no difference in spontaneous motor behavior was seen on any of the 5 test days. Determination of regional brain levels of NA and DA confirmed the type of lesion predicted from the various pretreatments with selective uptake blockers. These data suggest that changes in motor behavior in the adult rats, following neonatal 6-OHDA treatment, are specifically related to a DA-denervation, whereas an NA lesion does not seem to influence the spontaneous motor behavior. However, following the selective DA lesion, significant increases of serotonin levels in striatum and cerebellum were observed, while following selective NA lesions an increase of cerebellar NA levels was found concomitant with drastic reductions of NA levels in frontal cortex and spinal cord.     

Neonatal 6-hydroxydopamine-induced hypo/hyperactivity: blockade by dopamine reuptake inhibitors and effect of acute D-amphetamine

Five experiments were performed to assess the changes in motor activity resulting from neonatal administration of 6-hydroxydopamine (6-OHDA) on Days 1 or 2 postnatal, at doses of either 75 or 100 μg in a volume of 10 μl vehicle, following pretreatment with either GBR 12909 (40 mg/kg, s.c.) or amphonelic acid (4.0 mg/kg, s.c.) or saline. Motor activity was measured either over 60-min test periods on five consecutive days of testing or at 12-min intervals within a single 60-min test session. The initial extent of locomotor hyperactivity was dependent upon the neonatal dose of 6-OHDA: the 100 μg, but not 75 μg, dose induced marked hyperactivity from test day 1 onwards whereas the 75 μg dose did so from test day 3 onwards. The initial hypoactivity for rearing behaviour was observed for both doses of 6-OHDA: this hypoactivity was altered over successive test days so that by test day 5 an hyperactivity by the 75 μg, but not 100 μg, was observed. Pretreatment with either GBR 12909 or amphonelic acid abolished the effects of both doses of 6-OHDA. In the within 60-min test session procedure, 6-OHDA treated rats (both 75 and 100 μg) showed initial hyperactivity for locomotion that intensified, in relation to the other groups, over each 12-min interval and initial hypoactivity for rearing that developed into hyperactivity over each 12-min interval. Pretreatment with either GBR 12909 or amphonelic acid again abolished the effects of both doses of 6-OHDA (75 and 100 μg) rats, compared to the control groups in all four experiments. In Experiment V, a low dose of D-amphetamine abolished the hyperactivity of 6-OHDA (75μg) treated rats whereas a higher dose did so only transiently. Pretreatment with GBR 12909 abolished these effects. These findings underline the neuropharmacological utility of the neonatal 6-OHDA treatment for studying brain receptor system adaptive changes underlying the respective functional alterations and as a possible laboratory model for clinical disorders.     

Effects of unilateral microinjections of sulpiride into the medial prefrontal cortex on circling behavior of rats

1. Bilateral 6-OHDA lesions of rats' medial prefrontal cortex increased locomotor activity after 7–10 days suggesting that cortical DA may normally inhibit motor behaviour. However, hyperactivity may have resulted from enhanced subcortical DA function.

2. Acute manipulation of frontal cortical DA neurotransmission in the present experiment avoided lesion-induced subcortical changes.

3. Sulpiride (0, 6, 12, 24 ug in 1 ul) was Injected unilaterallv into the medial prefrontal cortex of rats pretreated with (+)-amphetamine (1.5 mg/kg i.p.).

4. Circling behavior was scored during four 5-min intervals of a 60-min test session which began with injections and placement in a flat, circular arena.

5. SUL resulted in ipslversive circling whereas its vehicle did not. These results were consistent with those seen with other DA drugs and suggest an excitatory influence of frontal cortical DA on locomotor activity.     

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.     

The effect of water-deprivation on locomotor activity in rats treated with 6-hydroxydopamine

Male albino rats treated with 6-hydroxydopamine (6-OHDA) became more hyperactive than did vehicle-treated controls when both groups were water-deprived. Rats were treated with vehicle, 150 or 250 micrograms of 6-OHDA intraventricularly, after pretreatment with desmethylimpramine (25 mg/kg) and pargyline (50 mg/kg). Eleven days after these treatments, under ad libitum water conditions, the 6-OHDA-treated rats were slightly hypoactive. After several days of water-deprivation all three groups showed increased mean locomotor activity levels, but rats treated with 6-OHDA showed a much greater increase than did vehicle-treated rats. Under subsequent ad libitum and deprivation conditions, locomotor activity decreased and increased, respectively, in all 3 groups. Again, the changes in activity levels of the 6-OHDA-treated groups were greater than those of the vehicle-treated group. In addition, rats treated with 250 micrograms 6-OHDA seemed to become sensitized to the novel environment of the stabilimeter rather than habituating to it. Dopamine (DA) levels were decreased as a result of the injections of 6-OHDA, and significant correlations were found between DA levels in the caudate-putamen and nucleus accumbens, and locomotor activity levels. These results, as well as those obtained by others, suggest that there is an interaction among DA levels, deprivational states, and locomotor activity levels in rats.     

Proposed animal model of attention deficit hyperactivity disorder

Dopamine (DA) neurons are implicated in the hyperlocomotion of neonatal 6-hydroxydopamine (6-OHDA)-lesioned rats, an animal model of attention deficit hyperactivity disorder (ADHD). Because serotonin (5-HT) neurons mediate some DA agonist effects, we investigated the possible role of 5-HT neurons on locomotor activity. Rats were treated at 3 days after birth with vehicle or 6-OHDA (134 μg ICV; desipramine pretreatment, 20 mg/kg IP, 1 h), and at 10 weeks with vehicle or 5,7-dihydroxytryptamine (5,7-DHT; 75 μg ICV; pretreatment with desipramine and pargyline, 75 mg/kg IP, 30 min), to destroy DA and/or 5-HT fibers. Intense spontaneous hyperlocomotor activity was produced in rats lesioned with both 6-OHDA and 5,7-DHT. Locomotor time in this group was 550 ± 17 s in a 600 s session, vs. 127 ± 13 s in the 6-OHDA group and <75 s in 5,7-DHT and intact control groups (p < 0.001). Oral activity dose-effect curves established that 5,7-DHT attenuated DA D₁ receptor supersensitivity and further sensitized 5-HT_2c receptors. Acute treatment with dextroamphetamine (0.25 mg/kg SC) reduced locomotor time in 6-OHDA+5,7-DHT-lesioned rats to 76 ± 37 s (p < 0.001). Striatal DA was reduced by 99% and 5-HT was reduced by 30% (vs. 6-OHDA group). Because combined 6-OHDA (to neonates) and 5,7-DHT (to adults) lesions produce intense hyperlocomotion that is attenuated by amphetamine, we propose this as a new animal model of ADHD. The findings suggest that hyperactivity in ADHD may be due to injury or impairment of both DA and 5-HT neurons.     

Intracranial self-stimulation from the sulcal prefrontal cortex in the rat: The effect of 6-hydroxydopamine or kainic acid lesions at the site of stimulation

An electrode cannula system was used to elicit intracranial self-stimulation (ICSS) from the sulcal prefrontal cortex in rats to test the behavioral effects of local infusions of 6-hydroxydopamine (6-OHDA) or kainic acid (KA) into the brain area surrounding the electrode tip. In experimental I sulcal ICSS animals received injections of 6-OHDA with or without desipramine (DMI) pretreatment to block 6-OHDA uptake into noradrenergic (NA) terminals. Those animals that received DMI pretreatment were subsequently shown to have sustained sulcal cortical dopaminergic (DA) denervation while sulcal molecular layer NA systems were spared as revealed with glyoxylic acid-induced catecholamine histofluorescence. Those animals not receiving DMI pretreatment sustained near-complete denervation of both NA and DA sulcal cortical systems. Neither treatment had a lasting effect on sulcal ICSS suggesting that sulcal ICSS is not dependent on the presynaptic release or DA of NA into that brain area.In experiment II KA injections that lesioned neurons in sulcal cortical layers V and VI resulted in the abolition of sulcal ICSS for the duration of a 21 day postlesion trial period. These results suggest that activation of a descending corticofugal system originating in the sulcal cortex is responsible for the mediation of sulcal prefrontal cortical ICSS. This system was mapped by the selective silver impregnation of degenerating neural elements resulting from effective lesions.     

Hyperactivity and hypoactivity produced by lesions to the mesolimbic dopamine system

Spontaneous locomotor activity and the locomotor response to amphetamine and apomorphine were studied in rats subjected to either radiofrequency (RF), 6-hydroxydopamine (6-OHDA) or both RF and 6-OHDA lesions of the mesolimbic dopamine (DA) system. Large 6-OHDA lesions of the ventral tegmental area (VTA) or of the nucleus accumbens (N.Acc.) produced hypo-activity in the open field, a complete blockade of the locomotor stimulating effects of D-amphetamine and a profound supersensitive response to apomorphine as measured by a significant increase in locomotor activity as compared to sham-operated animals. In contrast, smaller 6-OHDA lesions of the VTA produced significant increases in spontaneous daytime and nocturnal activity with the biggest effect occurring at the lowest dose. RF lesions to the VTA produced even greater hyperactivity which was blocked by the addition of a 6-OHDA lesion to the N.Acc. The rats with RF lesions to VTA alone that were spontaneously hyperactive remained hyperactive after injection of amphetamine, whereas apomorphine produced a significant decrease in this hyperactivity. In contrast, the rats with the combined RF lesion and N.Acc. 6-OHDA lesion showed a blockade of the locomotor stimulating effects of D-amphetamine and a potentiated response to apomorphine identical to that observed with a N.Acc. lesion alone. All lesion groups revealed massive depletion of DA in the N.Acc. and anterior striatum with significantly greater depletions in those groups showing hypoactivity and hypo-responsiveness to amphetamine. All groups except the N.Acc. 6-OHDA alone group showed significant depletions of DA in the posterior striatum. Thus, limited destruction of the mesolimbic DA system can produce hyperactivity, but more extensive destruction of this system in the region of the N.Acc. and anterior striatum can reverse this hyperactivity and produce a hypo-responsiveness to the locomotor stimulating effects of amphetamine. These results suggest an essential role for dopamine in the expression of spontaneous and stimulant-induced activity. Furthermore, the much larger increase in spontaneous activity in the RF-VTA lesion group as compared to the VTA-6-OHDA groups suggests the presence of an, as yet unidentified, powerful inhibitory influence to the mesolimbic DA system within the midbrain tegmentum.     

The effects of norepinephrine depletion on cerebral blood flow in the rat

Cerebral blood flow (CBF) was measured by [14C]butanol indicator fractionation in 10 rats given intraventricular injections of 6-hydroxydopamine (6-OHDA) compared to 8 saline-injected controls. Rats treated with 6-OHDA displayed an 83% reduction in cortical norepinephrine (NE) levels. CBF was significantly increased in 6-OHDA-treated rats compared to controls (average whole brain blood flow of 126.0 +/- 8.3 and 97.1 +/- 10.6 ml.min-1.10(-2)g-1 respectively, P less than 0.05). These studies suggest that noradrenergic innervation of the brain and cerebral microvasculature exerts a moderating effect on resting CBF.     

Neonatal and adult forebrain norepinephrine depletion and the behavioral and cortical thickening effects of enriched/impoverished environment

Two experiments examined the effects of neonatal or adult intracerebral injections of 6-hydroxydopamine (6-OHDA) on the effects of enriched (ENR) vs. impoverished (IMP) housing conditions. In Expt. 1, neonatal rats received intraventricular injections of 6-OHDA after pretreatment with buproprion to destroy norepinephrine (NE) terminals while lessening damage to dopamine (DA) terminals. The rats were subsequently raised in either enriched or impoverished environments and then tested for their spatial problem-solving ability in an automated Hebb-Williams maze. Littermates did not undergo this testing but were instead assessed for cortical thickness. Despite the substantial depletion of NE in the forebrains of the 6-OHDA-treated rats, they responded to enriched rearing as did the control rats, i.e., they solved the Hebb-Williams problems more efficiently than their impoverished reared counterparts and they showed thicker cortices. In Expt. 2, adult rats received 6-OHDA lesions of the dorsal noradrenergic bundle and were then relegated to enriched or impoverished housing for 42 days. Subsequently, the enriched-housed rats solved the Hebb-Williams mazes more efficiently than their impoverished-housed counterparts and this effect of housing was not altered by the dorsal bundle lesion which severely depleted forebrain NE. These two experiments do not support a role for forebrain NE in the alteration of the rat cortex and behavior by environmental enrichment. It was concluded that the cognitive effects of enriched rearing do not require intact forebrain NE but that they may be influenced by the peripheral sympathectomy that is one consequence of neonatal systemic 6-OHDA injections.     

Partial protection by desmethylimipramine of the mesocortical dopamine neurones from the neurotoxic effect of 6-hydroxydopamine injected in ventral mesencephalic tegmentum. The role of noradrenergic innervation

As shown in the rat by estimation of dopamine (DA) and noradrenaline (NA) levels, bilateral 6-hydroxydopamine (6-OHDA, 4 micrograms/microliter) lesions made in the ventral mesencephalic tegmentum (VMT) destroy both ascending DA and NA neurones. Pretreatment of rats with desmethylimipramine (DMI, 30 mg/kg, i.p.), 30 min before microinjection of 6-OHDA into the VMT partially prevented the destruction of the DA neurones innervating the prefrontal and cingulate cortices but not those innervating subcortical structures (nucleus accumbens, olfactory tubercles, septum). Results obtained from the prefrontal cortex of rats with extensive lesions of the ascending NA neurones performed 15 days prior to the 6-OHDA lesions of the VMT in the presence of DMI, imply that NA innervation of the VMT seems to be required for DMI to protect the cortical DA neurons from the neurotoxic effect of 6-OHDA.     

Elevated serotonin is involved in hyperactivity but not in the paradoxical effect of amphetamine in mice neonatally lesioned with 6-hydroxydopamine

The neonatal lesion with 6-hydroxydopamine (6-OHDA) in rodents induces juvenile hyperactivity and paradoxical hypolocomotor response to psychostimulants, in striking contrast to what is observed when similar lesions are carried out in adults. The early disruption of central dopaminergic pathways is followed by increased striatal serotonin (5-HT) contents although the functional role of this neurodevelopmental adaptation remains unclear. The aim of the present study is to investigate the participation of this neurochemical imbalance in the main behavioral phenotypes of this model. To this end, mice received a neonatal administration of 6-OHDA that induced an 80% striatal dopamine depletion together with 70% increase in 5-HT. Serotoninergic hyperinnervation was evidenced further by increased [(3)H] citalopram autoradiographic binding and 5-HT transporter immunohistochemistry in striatal sections. To investigate whether elevated 5-HT was implicated in hyperactivity, we treated control and 6-OHDA neonatally lesioned mice with the selective irreversible tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA) to induce 5-HT depletion. Normalization of striatal 5-HT in 6-OHDA neonatally lesioned mice to control levels reversed hyperactivity to normal locomotor scores, whereas the same extent of 5-HT depletion did not affect spontaneous locomotor activity of control mice. In turn, the paradoxical response to amphetamine in neonatal DA-depleted mice was not prevented by PCPA treatment. Taken together, our results suggest that the increased striatal 5-HT that follows neonatal DA depletion is involved in hyperlocomotor behavior but not in the paradoxical calming response to amphetamine observed in this mouse model.     

Potentiation of amygdaloid kindling and metrazol-induced seizures by 6-hydroxydopamine in rats

Intact control rats and rats pretreated with an intraventricular injection of 6-hydroxydopamine (6-0HDA) received a convulsive dose of pentylenetetrazol (Metrazol). The control rats responded to the subcutaneous injection of Metrazol with one or more brief intermittent clonic convulsions. In contrast, the rats pretreated with 6-OHDA displayed significantly longer episodes of generalized seizures, nearly all of which contained episodes of tonic extension of the hindlimbs. The severity of the seizure syndrome in rats with substantial depletion of both norepinephrine (NE) and dopamine (DA) did not differ markedly from that in rats with preferential depletion of NE, suggesting that depletion of NE and not DA is the mechanism of the exacerbated convulsive response to Metrazol produced by 6-OHDA. In a second experiment, intact and 6-OHDA-treated rats were subjected to a kindling procedure, wherein daily electrical stimulation of the amygdala that was initially subconvulsive eventually came to elicit bilateral clonic convulsions. Rats with substantial depletion of both NE and DA required less than half as many stimulations to kindle seizures as did intact rats or rats with preferential depletion of NE, and they continued to display significantly longer afterdischarges for nearly 15 days after the first kindled seizure. These data suggest that combined destruction of noradrenergic and dopaminergic neurons, or destruction of the latter alone, is necessary to facilitate the development of kindled seizures. Together, the two experiments confirm earlier observations that central catecholaminergic systems tend to inhibit a variety of seizure phenomena.     

Reductions in spontaneous locomotor activity in aged male, but not female, rats in a model of early Parkinson's disease

The excessive loss of dopamine (DA) neurons that occurs with Parkinson's disease is usually confined to older individuals. While 6-hydroxydopamine (6-OHDA) is often used in animal models of DA neuron degeneration, there have been relatively few studies that have examined the effects of 6-OHDA in older animals. In the present study, we compared the effects of a bilateral, partial lesion with 6-OHDA in young (4 months), middle-aged (14 months), and aged (24 months) Fischer-344 rats of both sexes. Animals were given a single injection of vehicle or 100 mug 6-OHDA into the right lateral ventricle. Four weeks later, spontaneous locomotor activity was monitored. Microdialysis experiments were carried out 1 to 3 days later. The 6-OHDA treatments had no effect on horizontal activity or total distance traveled in young adults. However, with aged rats, there was a decrease in both measures in the vehicle-treated control rats compared to young adult controls, and a further decrease in the lesioned aged male rats. The 6-OHDA treatments led to significant decreases in both potassium- and amphetamine-evoked overflow of DA from the striatum in all groups. Thus, partial bilateral lesions of the nigrostriatal DA system led to decreases in evoked release of DA in the striatum of male and female rats of all three ages, but to changes in spontaneous activity only in the aged males. These results indicate that there are both age and sex differences in the brain's response to 6-OHDA, and imply that compensatory or neuroprotective mechanisms in the young brain and aged female brain are more efficient than in the aged male brain.     

Long-term effects of dopamine-depleting brain lesions on spontaneous activity of type II striatal neurons: Relation to behavioral recovery

The long-term effects of dopamine (DA)-depleting brain lesions on behavior and spontaneous activity of Type II striatal neurons were measured in rats after intraventricular injection of the neurotoxin 6-hydroxydopamine (6-OHDA). Spontaneous firing rates were increased relative to control values when recorded 4-8 days or 4-6 weeks postlesion in animals displaying aphagia, adipsia and akinesia. In contrast, spontaneous activity was not increased when recorded 4-6 weeks after the lesion in animals that had recovered from behavioral deficits. Other animals that had recovered from the effects of an earlier 6-OHDA treatment were given either a second injection of 6-OHDA or a systemic injection of haloperidol, a DA receptor antagonist. In both groups, discharge rates were elevated relative to control levels in association with a reinstatement of behavioral deficits. These results demonstrate that behavioral recovery after large DA-depleting brain lesions is associated with a return of spontaneous activity of striatal neurons to normal levels, and suggest that both behavioral and electrophysiological measures are dependent on the functioning of residual elements of the DA system.