Behavioural and biochemical effects of dopamine and noradrenaline depletion within the medial prefrontal cortex of the rat

The effects of 6-hydroxydopamine (6-OHDA) lesions of catecholamine terminals within the medial prefrontal cortex on spontaneous motor activity, dopamine (DA)-dependent stereotyped behaviour and subcortical dopamine turnover were investigated in the rat. Two types of lesions were examined, bilateral injection of 6-OHDA into the medial prefrontal cortex of untreated rats (6-OHDA alone), and bilateral injection of 6-OHDA into the medial prefrontal cortex of animals pretreated with the noradrenaline (NA) uptake blocking agent desmethylimipramine (6-OHDA/-DMI). Ten days after surgery the 6-OHDA lesions produced no significant change in spontaneous motor activity and had no overall effects on stereotyped behaviour induced by apomorphine or (+)-amphetamine. This lesion caused gross depletion of NA within the medial prefrontal cortex and curiously, elevated DA concentrations within this site. No changes in DA concentration were recorded within subcortical sites, although concentrations of DA metabolites within striatum and nucleus accumbens were reduced. In contrast, the 6-OHDA/DMI lesion of the medial prefrontal cortex significantly enhanced spontaneous motor activity and amphetamine-induced stereotyped behaviour. Apomorphine-induced stereotypy, on the other hand, was significantly reduced. Biochemically the lesion caused a large depletion of DA with relatively little loss of NA within the medial prefrontal cortex. In addition, from this and another study (ref. 33), increases in DA and its metabolite concentrations were measured in striatum and nucleus accumbens, together with an apparent increased in DA turnover within these subcortical sites. It is thus apparent that in the absence of a substantial portion of the DA innervation of the medial prefrontal cortex, with a largely intact NA innvervation, there is an increase in motor activity and amphetamine-induced stereotypy which may be related to functional changes in DA activity within subcortical telecephalic structures. Such a finding might suggest that DA within the frontal cortex has a behaviourally inhibitory role in the rat, although further work is required to substantiate this.     

Amygdalar noradrenergic and dopaminergic mechanisms in the regulation of hunger and thirst-motivated behavior

The feeding behavior of rats was studied after neurochemical damage of the amygdalar terminal fields of mesolimbic dopaminergic (DA) and coerular noradrenergic (NA) pathways. 6-Hydroxydopamine (6-OHDA) or 6-hydroxydopa (6-OHDOPA) were injected bilaterally into the central part of amygdala. 6-OHDA was also injected after desmethylimipramine (DMI) pretreatment in order to study the selective destruction of DA terminals. The body weight increased after 6-OHDA injection and a mild hyperphagia and hyperdipsia developed. The 6-OHDA plus DMI treatment resulted in body weight decrease, hypophagia and hypodipsia. These effects were dose-dependent. While a high dose of 6-OHDOPA (15 mug/mul) decreased the body weight, an increase of weight was observed after a low dose (4 mug/0.5 mul). After 6-OHDA, 6-OHDA plus DMI or the high dose of 6-OHDOPA the DA concentration dropped significantly in the amygdala while low-dose 6-OHDOPA resulted in DA increase. In every case there was a parallel change in striatal DA content. The amygdalar NA concentration decreased after both 6-OHDA and the high dose of 6-OHDOPA. There was no change in NA levels after 6-OHDA plus DMI treatment and the NA concentration increased after the injection of a low dose of 6-OHDOPA. When DA/NA ratio was calculated the results showed that body weight increases were accompanied by a relative deficit in NA while a relative deficit of DA was present if body weight decreased. Our results suggest that the amygdalar balance of these transmitters may play an important role in the regulation of body weight and the contradictions of results with electrolytic lesions in the amygdala can be resolved at transmitter level.     

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.     

Electrophysiological evidence for non-dopaminergic mesocortical and mesolimbic neurons in the rat

The neurons located in the ventromedial tegmentum (VMT) and projecting either to the frontal cortex, to the septum or to the nucleus accumbens were identified by the antidromic activation method in normal rats and in animals whose dopaminergic (DA) system had been previously lesioned by microinjections of 6-hydroxydopamine (6-OHDA). Two groups of VMT neurons innervating each structure could be distinguished. The first group (group S) are slow conducting neurons whose number is reduced in 6-OHDA lesioned rats and which may correspond to A10 DA neurons. The second group (group F) are fast conducting neurons which are resistant to 6-OHDA treatment and therefore probably non-DA VMT cells.     

Suppression of noradrenergic innervation compensates for behavioral deficits induced by lesion of dopaminergic terminals in the lateral septum

Spontaneous alternation which is disrupted by lesion of septal dopaminergic (DA) afferents was chosen as a behavioral marker for the study of functional interactions between DA and noradrenergic (NA) innervation of the lateral septum. Three groups of rats were studied: a solvent group which received only vehicle injection, and two lesioned groups, one with DA lesion and the second with simultaneous DA + NA lesion of the septal innervation. DA lesion was produced by infusing 6-hydroxydopamine (6-OHDA) into the lateral septum after pretreatment with desmethylimipramine (DMI) injected intraperitoneally. The DA + NA lesion was produced by infusing 6-OHDA without DMI pretreatment. The lesion of DA innervation alone led to a disturbance of alternation behavior in a Y-maze, but performance was not affected by the combined DA + NA lesion. The group with septal DA lesion was then injected with 6-OHDA into the pedunculus cerebellaris superior (PCS) in order to destroy NA efferents from the locus coeruleus. The two other groups were sham-operated. After post-operative recovery, the rats were retested for spontaneous alternation. The rats with the PCS NA lesion subsequent to the DA septal lesion displayed normal alternation behavior. Their performance was not different from that of animals with both NA and DA lesions in the septum. Thus the NA lesion appears to prevent the alternation deficits induced by the DA septal lesion, and also abolishes the deficits induced by the prior DA lesions. These results may have therapeutic implications.     

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.     

Behavioural deficits induced by an electrolytic lesion of the rat ventral mesencephalic tegmentum are corrected by a superimposed lesion of the dorsal noradrenergic system

The bilateral electrolytic lesion of the ventral mesencephalic tegmentum (VMT) induces, in the rat, behavioural deficits such as locomotor hyperactivity and disappearance of spontaneous alternation ('VMT syndrome'). When a specific 6-hydroxy dopamine (6-OHDA) destruction of the dorsal noradrenergic (NA) ascending pathway was superimposed to an electrolytic lesion of the VMT, animals recovered a normal locomotor activity and the possibility to alternate. Since many studies indicate that the development of the 'VMT syndrome' is linked to the disruption of the dopaminergic (DA) meso-cortico-limbic transmission, it is proposed that the recovery observed is due to an interaction between NA and DA ascending systems in cortical and/or subcortical structures; noradrenergic innervation would have a permissive role on the expression of the 'VMT syndrome', possibly via a mechanism of heteroregulation of DA receptors by NA fibers.     

Male rat sexual behavior compared after 6-OHDA and electrolytic lesions in the dorsal NA bundle region of the midbrain

Forebrain catecholamine depletion and midbrain histological damage in adult male rats were investigated as a function of 6-hydroxydopamine dosage in the range 4 μg in 2 μml to 8 μg in 4 μl, stereotaxically injected at 0.43 μl/min bilaterally in the region of the ascending dorsal noradrenaline bundle of the locus coeruleus, without and with a 30–60 min earlier 25 mg/kg intraperitoneal dose of desmethylimipramine (DMI). Sexual behavior of the male rat was compared for treatment with 4 μg in 2 μl 6-OHDA, without and with 25 mg/kg protective dose of DMI, and alternatively for 1 mA 30 sec bilateral electrolytic lesions at the same location. For the behaviorally tested rats receiving 6-OHDA treatment, cortical noradrenaline was depleted to 17% and to 81% of control, without and with DMI, respectively. Hypothalamic NA was depleted to 60% and 102% (no depletion), respectively. Caudate dopamine depletion did not reach significance at P = 0.05. For rats with electrolytic lesions cortical NA was depleted to 46% of control and caudate dopamine was not depleted. For the electrolytically lesioned rats, the first 3 post-ejaculatory intervals decreased by an average of 24%, while the 1 h ejaculatory frequency increased by 17%, which confirms a prior finding. However, no measured sexual behavioural effects were observed with 6-OHDA. Thus, interrupting the dorsal noradrenaline bundle has not been shown to have any effect on sexual behavior in the male rat.     

Microdialysates of amines and metabolites from core nucleus accumbens of freely moving rats are altered by dizocilpine

In vivo microdialysis combined with high performance liquid chromatography (HPLC) with electrochemical detection, was used to study the effect of MK-801 (0.1 mg/kg i.p.) on extracellular concentrations of dopamine (DA) 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-HT), norepinephrine (NE) and DOPAC/DA ratio in intact, 6-hydroxydopamine (6-OHDA)-lesioned, DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine hydrochloride)-lesioned and reserpine-treated rats. The results revealed high basal DA (0.735+/-0.05 fmol/microl), DOPAC (195.93+/-20.18 fmol/microl) and NE (0.585+/-0.01 fmol/microl), low 5-HT (0.334+/-0.032 fmol/microl) and high DOPAC/DA ratio (265.11+/-20.73) in intact cACC. 6-OHDA alone (8 microg/2 microl) depleted DA (-66%), DOPAC (-65%), and NE (-62%). On the other hand, in desipramine (DMI)-pretreated rats, 6-OHDA induced a large depletion of DA (-94%), DOPAC (-97%) and reduced DOPAC/DA ratio (-73%), but increased NE to 142% of intact and 369% of 6-OHDA-lesioned rats. DSP4 (50 mg/kg) decreased NE (-97%), DOPAC (-75%) and DOPAC/DA ratio (-69%). Reserpine (5 mg/kg s.c.) significantly decreased DOPAC (-84%), DOPAC/DA ratio (-81%), 5-HT (-69%) and NE (-86%), but nonsignificantly increased DA. In the intact rats, MK-801 did not change DA, but increased DOPAC and DOPAC/DA ratio. In 6-OHDA-lesioned rats, MK-801 increased DA, whereas in 6-OHDA+DMI rats MK-801 additionally increased DOPAC and DOPAC/DA ratio. DSP4 and reserpine reduced the ability of MK-801 to increase DOPAC and DOPAC/DA ratio. MK-801 did not change NE concentration in dialysates collected from intact rats, but increased that from 6-OHDA+DMI-lesioned rats. In DSP4-lesioned and reserpine-treated rats, MK-801 increased NE but to a level lower than that observed in the intact rats. These results suggest that systemic administration of a low dose of MK-801, which induces profound locomotor stimulation without stereotypy, increases DOPAC and DOPAC/DA ratio in the cACC of intact rats, whereas it additionally increases the depleted DA and NE concentrations especially in 6-OHDA-lesioned rats pretreated with DMI.     

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.     

Reduction of dopamine utilization in the prefrontal cortex but not in the nucleus accumbens after selective destruction of noradrenergic fibers innervating the ventral tegmental area in the rat

The present study was made to determine the role of the noradrenergic (NA) neurons which innervate the ventral tegmental area (VTA) in the regulation of VTA dopaminergic (DA) neurons projecting to the prefrontal cortex and the nucleus accumbens. For this purpose, a 6-hydroxydopamine lesion was made in benzotropine pretreated rats medially just above the decussatio of the pedunculus cerebellaris superior in order to specifically destroy the NA fibers innervating the VTA without affecting those projecting to the prefrontal cortex. Seven days later the ratio of DOPAC and DA levels was estimated in the prefrontal cortex and the nucleus accumbens and used as an index of DA utilization. In the lesioned rats the DOPAC/DA ratio was significantly decreased in the prefrontal cortex but not in the nucleus accumbens. These results suggest that the NA neurons which innervate the VTA exert a specific tonic excitatory influence on the mesocortico-prefrontal DA neurons.     

Role of ventral mesencephalic reticular formation and related noradrenergic and serotonergic bundles in turning behaviour as investigated by means of kainate, 6-hydroxydopamine and 5,7-Dihydroxytryptamine lesions

A unilateral kainate (KA) infusion (2 × 0.15 μg, 2 × 0.25 μg) in the ventral mesencephalic reticular formation (MRF) resulted in spontaneous contraversive turning lasting only a few days. Upon challenge with apomorphine (0.5 mg/kg s.c) or amphetamine (5 mg/kg i.p.) the contraversive turning could be reinstated. The incidence, as well as the intensity, of the drug-induced response decreased over the 45 days of observation. KA infused in the ventral MRF induced typical lesions after doses of2 × 0.15 μg but resulted in demyelination after2 × 0.25 μg. These lesions failed to reduce noradrenaline (NA), serotonin (5 HT) or dopamine (DA) in various forebrain areas. Unilateral lesion of ascending NA projections by 6-OHDA infusion (4 μg) within the NA bundles coursing in the mesencephalon or near the locus coeruleus, failed to induce motor asymmetries. Unilateral selective lesion of the ventral NA bundle by local 6-OHDA (2 μg) infusion also failed to induce motor asymmetries, either spontaneously or in response to dopaminergic drugs. Unilateral lesion of ascending 5-HT projections by the tegmental infusion of 5,7-dihydroxytryptamine (10 μg) also failed to induce motor asymmetries in response to dopaminergic drugs but resulted in contraversive circling in response to 5-hydroxytryptophan. These data indicate that intrinsic neurones of the ventral MRF play a role in turning behaviour and exclude, in contrast with previous studies, a role of NA or 5-HT projections in the contraversive turning responses to DA receptor agonists obtained after lesions of the ventral MRF.     

Central noradrenergic involvement in yohimbine excitation of acoustic startle: Effects of DSP4 and 6-OHDA

It was previously shown that i.p. administration of the alpha 2-adrenergic antagonist yohimbine increased the magnitude of the acoustic startle response in rats. The purpose of the present study was to determine possible central noradrenergic involvement in yohimbine's effect on startle. Pretreatment with N-(2-chloroethyl)-N-ethyl-2-bromo-benzylamine (DSP4; 50 mg/kg, i.p.; 1-2 days before testing) completely blocked the excitatory effect of yohimbine on startle. DSP4 reduced forebrain and spinal cord NE levels by 47% and 56%, respectively, without affecting forebrain or spinal serotonin (5-HT), or forebrain dopamine (DA). Pretreatment with the NE reuptake blocker desmethylimipramine (DMI; 20 mg/kg, i.p.; 30 min before DSP4) prevented the ability of DSP4 to block the yohimbine effect. DMI partially reversed the NE-depleting effects of DSP4. Neither bilateral adrenalectomy nor intravenously administered 6-hydroxydopamine (6-OHDA; 20 mg/kg; 1-2 days before testing) altered the excitatory effect of yohimbine, indicating that peripheral NE is not involved. 6-OHDA (2 X 200 micrograms) injected into the lateral ventricles blocked yohimbine's effect, and depleted NE by 95% (spinal cord) and 86% (forebrain), without affecting 5-HT in either region. 6-OHDA also depleted forebrain DA levels by 49%. Finally, intrathecal administration of 6-OHDA (20 micrograms; 14 days before testing) into the subarachnoid space of the lumbar spinal cord blocked the excitatory effect of yohimbine, and produced an extensive (94%) depletion of spinal cord NE. Intrathecal 6-OHDA did not alter spinal levels of 5-HT or forebrain levels of NE, 5-HT or DA. In summary, these data indicate that central descending NE neurons are necessary for yohimbine's excitatory effect on startle.     

DSP-4, a noradrenergic neurotoxin, produces more severe biochemical and functional deficits in aged than young rats

The present study examines the effects of noradrenergic lesions (either DSP-4 i.p. or 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle on biochemical (noradrenaline (NA), dopamine (DA), serotonin (5-HT) and choline acetyltransferase (ChAT) activity) and cortical EEG (quantitative EEG (qEEG) and high-voltage spindle (HVS) activity in young and aged rats. Near complete 6-OHDA NA lesions, but not partial DSP-4 NA lesions, increased HVS activity in young rats. DSP-4 and 6-OHDA lesions produced no significant changes in the 5-HT or DA levels or in the ChAT activity in young rats. In some of the aged rats, DSP-4 produced similar biochemical and HVS effects, as it induced in young rats. In the remainder of the aged rats, NA levels were greatly and 5-HT levels slightly decreased. DA levels and ChAT activity were unaltered in either set of aged rats. HVS activity was increased only in that group of aged rats with the greatly lowered NA content. These results suggest that: (1) some of the aged rats are more sensitive to DSP-4 treatment than young adult rats; and (2) NA depletions have to be complete to produce an increase in HVS activity in young and aged rats.     

Effect of 6-hydroxydopamine-induced lesions to ascending and descending noradrenergic pathways on morphine analgesia

A systematic study of the role of descending, ascending and both aspects of noradrenergic pathways in the analgesic action of morphine was undertaken. The neurotoxin 6-hydroxydopamine (6-OHDA) was microinjected into the medullary A1 region, the dorsal bundle (DB), locus coeruleus (LC) or the cerebral ventricles (i.c.v.) to deplete noradrenaline (NA) in these pathways. The analgesic effect of systemically administered morphine 7-15 mg/kg was generally tested 7-12 days postlesion, and at the end of the experiment, brain and spinal cord regions were extracted and NA and dopamine (DA) measured by HPLC to verify the placement of lesions. Medullary A1 lesions profoundly depleted spinal cord NA with only a modest effect on mesencephalic levels. Such lesions inhibited the effect of morphine in a pressure test, but not in thermal tests (tail flick and hot plate) for nociception. DB lesions reduced NA in the cortex, hippocampus, hypothalamus and midbrain, but not in the spinal cord, and potentiated morphine analgesia in thermal tests for nociception. DA levels in the striatum were normal in this group. In another group where different stereotaxic coordinates were used, the pattern of NA depletion was similar, but DA levels in the striatum were reduced. In this group, potentiation of analgesia was no longer observed. LC lesions depleted NA throughout the neuraxis and potentiated morphine analgesia in both pressure and thermal tests for nociception. I.c.v. 6-OHDA depleted NA to a comparable degree to LC lesions, but striatal DA levels also were reduced and potentiation of morphine analgesia was not observed. These results indicate that central NA pathways are critical to the expression of morphine analgesia. The effect of depletion of NA in both ascending and descending aspects is the same as depletion in ascending pathways only, suggesting that this pathway is an important mediator of morphine analgesia. Simultaneous depletion of DA in the striatum can reverse the potentiating action of NA depletion indicating a critical role for DA with respect to NA pathways and mechanisms of analgesia.     

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.     

Opposite changes in dopamine utilization in the nucleus accumbens and the frontal cortex after electrolytic lesion of the median raphe in the rat

As revealed by the changes in dihydroxyphenylacetic acid (DOPAC) levels and in the DOPAC/Dopamine (DA) ratio, DA utilization was markedly enhanced in the nucleus accumbens and reduced in the prefrontal cortex of rats five days after the electrolytic lesion of the median raphe. These opposite effects were not seen any more seventeen days after the lesion. These results suggest that neurones originating from the median raphe and projecting to the ventral tegmental area exert an opposite effect on the activity of DA cells innervating the nucleus accumbens and on those projecting to the prefrontal cortex.     

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.     

Left and right 6-hydroxydopamine lesions of the medial prefrontal cortex differentially affect voluntary ethanol consumption

Dopaminergic projections to the medial prefrontal cortex (mPFC) were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) to examine how dopamine (DA) asymmetry in the mPFC influences voluntary ethanol consumption. Differences in nucleus accumbens (NAS) DA neurotransmission have been related to individual differences in locomotor activity and in the rewarding efficacy of ethanol. Therefore, differences in locomotor activity were used to further characterize the effects of unilateral mPFC 6-OHDA lesions on ethanol consumption. Male Long Evans rats were assessed for high versus low levels of spontaneous locomotor activity. DA terminals in the left or right mPFC were unilaterally lesioned with 6-OHDA, resulting in an average DA depletion of 54% and 50%, respectively. After a minimum seven-day recovery period, preference for a 10% ethanol solution vs. water was determined in a 24-h 2-bottle home-cage free-choice paradigm. Left mPFC 6-OHDA lesions increased and right lesions decreased ethanol consumption. These differential effects of left and right lesions were primarily attributable to rats exhibiting low locomotor activity prior to surgery. The present data suggest that right greater than left cortical DA asymmetry in combination with low endogenous NAS DA (predicted by low locomotor activity levels) may increase the vulnerability to abuse ethanol.     

Role of ascending and descending noradrenergic pathways in the antinociceptive effect of baclofen and clonidine

Baclofen and clonidine interact with central noradrenaline (NA) pathways by a variety of mechanisms. The specific role of ascending and descending pathways in antinociception produced by these agents was examined by lesioning the dorsal bundle (DB), locus coeruleus (LC) and descending NA pathways by the microinjection of the neurotoxin 6-hydroxydopamine (6-OHDA). Lesions were verified using high-performance liquid chromatography analysis of NA. Both baclofen and clonidine were injected intraperitoneally in all experiments. The antinociceptive effect of baclofen in the tail-flick test was inhibited 7–21 days after DB lesions. This manipulation decreased NA levels in cortex, hippocampus and hypothalamus but did not alter spinal cord levels. Lesions of the LC potentiated the effect of baclofen 12–16 days postlesion. NA levels were reduced in all the regions just mentioned. DB lesions produced a transient decrease in the effect of clonidine, being observed 7 but not 12–16 days postlesion. Neither acute depletion of NA levels with-methyl-p-tyrosine (-MPT), nor LC lesions significantly affected antinociception produced by clonidine. Intraspinal 6-OHDA potentiated the antinociceptive action of clonidine in the tail-flick test. This treatment markedly reduced spinal cord NA levels, but had minimal effects on brain NA. The results of this and previous studies in this laboratory suggest that the antinociceptive effect of baclofen is mediated by interactions with both ascending and descending NA pathways. These pathways appear to interact in a complex manner. Interpretation of data for clonidine is complicated because lesions can both deplete endogenous NA as well as inducing postsynaptic supersensitivity of₂-receptors. Clonidine does not depend on endogenous NA pathways for producing antinociception because acute depletion of NA with -MPT does not alter its action. Spinal sites of action are of importance following systemic clonidine because intraspinal 6-OHDA produces supersensitivity. Altering NA activity in ascending pathways alone produces a transient inhibition of the effect of clonidine, but supersensitivity is not apparent. Simultaneous lesions of both ascending and descending pathways do not produce supersensitivity, again suggesting important interactions between such pathways can occur.