Dopamine Lesions Research Articles

Effects of neurotoxic and mechanical lesions of the mesostriatal dopamine pathway on striatal polyamine levels in the rat: Modulation by chronic ganglioside GM1 treatment

In male rats, partial hemitransections but not 6-hydroxydopamine (6-OHDA)-induced lesions of the mesostriatal dopamine (DA) pathway produce after 7 days a marked and a modest increase of striatal putrescine and spermidine levels, respectively, on the lesioned side. Following chronic ganglioside GM1 treatment of partially hemitransected rats, an increase of striatal polyamine levels was observed also on the intact side. It is suggested that retrograde cell body changes produced by hemitransection may induce striatal ornithine decarboxylase activity and in this way increase striatal putrescine levels, favoring regenerative mechanisms. The increase of striatal polyamine levels by GM1 treatment on the intact side of both 6-OHDA and mechanically lesioned rats compared with intact unoperated rats may also reflect an increased synthesis of striatal polyamines.

Mesolimbic dopamine lesions produce an augmented behavioral response to enkephalin

The mesolimbic dopamine (DA) system was lesioned by the injection of 6-hydroxydopamine into the nucleus accumbens or ventral tegmental area of rats. The rats were then examined in a photocell apparatus for their response to injection with the enkephalin analogue, d-Ala 2-Met 5-enkephalinamide (DALA), into the nucleus accumbens. Rats with DA lesions showed a significantly greater increase in photocell counts in response to DALA than did sham-lesioned animals. The potentiated motor response was dose-related, and rats having the greatest depletion of DA in the nucleus accumbens showed the greatest behavioral response to DALA. It was concluded that chronic impairment of dopaminergic innervation to the nucleus accumbens results in an enhanced response to DALA injected directly into the nucleus accumbens.

Tolerance pattern to amphetamine anorexia after selective lesions in the hypothalamic dopaminergic projection

Tolerance to the anorexic effect of d-amphetamine was studied in rats with selective dopamine lesions in the forebrain by means of 6-hydroxy dopamine, and measuring the food intake during two consecutive 2 h periods. Lesions placed in the perifornical hypothalamus (PFH) strongly antagonised the anorexic effect, whereas, lesions produced via intraventricular injections affected the anorexia only marginally. Amphetamine anorexia observed in the first 2 h in control and lesioned groups remained persistently, without any evidence of tolerance, upto 2 weeks of treatment. The second 2 h food intake exhibited a progressive increase which contributed to the apparent tolerance seen in total 4 h food intake in the control and lesioned animals. The onset and completion of this apparent tolerance was markedly delayed in the dopamine depleted group; lesions placed in the relatively medial areas delayed the tolerance development more effectively than that of PFH lesions. The stimulant effect of amphetamine on locomotion was abolished in lesioned animals. The results indicate that an apparent tolerance to amphetamine anorexia still developed in animals with forebrain dopamine loss. Although both the beta adrenergic and dopaminergic systems act together in mediating AMPH anorexia, the onset and the rate of completion of tolerance appear to be under the influence of hypothalamic dopaminergic system.

Differential effects of selective dopamine, norepinephrine or catecholamine depletion on activity and learning in the developing rat

The present experiment investigated the behavioral changes which occurred following neonatal depletion of central catecholamine systems in the rat. The behavioral effects which resulted from selective dopamine (DA) depletion were compared with those resulting from selective norepinephrine (NE) depletion as well as depletion of both catecholamines (CA). Neonatal 6-hydroxydopamine (6-OHDA) was administered intracisternally at 5 days of age following pretreatment with desmethylimipramine in order to selectively deplete DA. NE levels were reduced by intraperitoneal injections of 6-OHDA at 1 and 2 days of age. Depletion of both catecholamines was effected by combining the procedures used for selective depletion of both DA and NE. Activity was time sampled during an hour at 3 preweanling ages. Avoidance and escape learning were measured in a T maze when pups were 20 days of age and in a Shuttlebox apparatus on day 28. Results revealed that DA and CA depleted animals were hyperactive in comparison to controls and displayed severe learning impairments in both T maze and Shuttlebox performance. In contrast, NE depleted animals showed activity levels which were similar to controls but were significantly impaired on both learning paradigms. These results suggest that selective lesions of DA and NE in infancy lead to a constellation of behaviors which are distinctly unique. The implications of these findings is discussed in terms of clinical research into the Attentional Deficit Disorder of childhood.

The rotational behavior model: asymmetry in the effects of unilateral 6-OHDA lesions of the substantia nigra in rats

A basic assumption of the ‘rotational behavior model’ is that amphetamine (AMPH) produces ipsiversive rotational behavior in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine (DA) system. However, we report here that if the normally ‘dominant’ striatum is partially depleted of DA the majority of rats turn contraversive when given AMPH, i.e. in the opposite direction predicted by the model.

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 hypoactivity 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 relationship between loss of dopamine nerve terminals, striatal [ 3H]spiroperidol binding and rotational behavior in unilaterally 6-hydroxydopamine-lesioned rats

The relationship between the destruction of dopamine-containing nerve terminals, specific binding of [ 3H]spiroperidol and contralateral rotation in response to l-DOPA, was studied in rats with unilateral lesions of the nigrostriatal dopamine (DA) system, induced by intracerebral injections of the neurotoxin 6-hydroxydopamine (6-OHDA). Animals with significant rotational behavior in response to l-DOPA had both a greater amount of specific binding of [ 3H]spiroperidol in the lesioned striatum compared to the non-lesioned striatum, and at least 90% destruction of DA terminals in the lesioned striatum (less than 10% of control uptake). The non-rotators to l-DOPA had considerably less destruction of DA terminals and no significant increase in specific binding on the lesioned side. The data from this study suggest that before l-DOPA is effective as an inducer of contralateral rotational behavior, there must be both unilateral damage to the DA terminals greater than 90%, and increased specific binding.

Effects of specific dopamine lesions and dopamine receptor sensitivity on angiotensin II- and carbachol-induced thirst in rats.

A study was made of the effects of manipulating brain dopaminergic activity upon drinking induced by intracerebroventricular administration of angiotensin II or carbachol. Non-specific lesions induced by injecting 6-hydroxydopamine (6-OHDA) into the cerebroventricles caused a significant reduction in angiotensin-induced thirst without affecting carbachol drinking. specific 6-OHDA-induced lesions of the dopaminergic nigro-striatal pathway also attenuated the angiotensin-induced response, while unilateral lesions reduced and bilateral lesions almost completely abolished the effect. Again, the response to carbachol was unaffected. Chronic haloperidol treatment increased behavioural responses to the dopamine agonist apomorphine and significantly stimulated angiotensin-induced drinking without affecting response to carbachol. These studies provide support for the hypothesis that a dopaminergic event is involved in the angiotensin-induced thirst response and point to the need for a functioning dopaminergic nigro-striatal pathway for the full expression of this response.

Functional reactivation of the deafferented neostriatum by nigral transplants.

Functional deficits following brain lesions can be due not only to the disruption of conduction in specific input and output pathways passing through the site of injury, but also to the loss of important regulatory systems controlling the functional state of neuronal circuitries in areas distant from the lesion. For example, the behavioural disturbances that result from lesions of the nigrostriatal dopamine (DA) pathways can be reversed by administration of dopamine receptor-activating drugs, such as L-dopa or apomorphine. This suggests that the lesioned dopaminergic system, rather than conveying specific input and output signals, is normally acting on neuronal machineries whose activity levels are set by the activity at the dopaminergic synapses. Thus the neurological deficits resulting from these lesions are due to functional inactivation of otherwise intact neostriatal circuitries. Previous studies have shown that intracerebral transplants of embryonic substantia nigra can compensate for drug-induced as well as spontaneous asymmetric motor behaviour (expressed as a tendency to move in circles towards the lesioned side), whereas the sensorimotor asymmetry, which is pronounced in rats with a unilateral lesion of the nigrostriatal DA pathway, was unaffected by the transplant. We report here that restoration of striatal dopaminergic neurotransmission by nigral transplants in animals with bilateral, complete lesions of the nigral transplants in animals with bilateral, complete lesions of the nigrostriatal DA pathways can reinstate not only certain aspects of spontaneous motor behavior, but also sensorimotor orientation and sensory attention on the side of the body contralateral to the graft.

Involvement of dopamine in circling responses to muscimol depends on intranigral site of injection

The intensity, direction and dopamine dependence of circling behaviour were determined following stereotaxic injections of 40 ng muscimol (in 0.2 μl over 3 min) into different regions of the rat's substantia nigra (SN). Weak, haloperidol-sensitive ipsilateral postural or locomotor asymmetries were invariably obtained from the rostral SN zona compacta (SNC), whilst robust contraversive rotational behaviour was always initiated from the SN zona reticulata (SNR) and caudal SNC. This was most rapid from the central SNR and was markedly attenuated by i.p. pretreatment with haloperidol (0.1 mg/kg) or pimozide (0.25 mg/kg), or by week-old 6-OHDA lesions of the nigrostriatal dopamine (DA) tract. Turning was significantly weaker from the lateral and ventral areas of the SNR, where it was not susceptible to DAergic blockade. Lower circling rates were also obtained if the SNR injections were made rapidly (in 30 sec), in a large volume (0.5 μl) or at a supramaximal dose level (400 ng), possibly due to increased spread of the drug to remote neurones having an opposite effect on directional behaviour, or to exaggerated stereotypy. The variable action of muscimol at multiple sites in the SN is suggested to account for the earlier conflicting data in the literature.

The influence of unilateral 6-OH-dopamine lesions of the substantia nigra in the absence of the telencephalon

Rats were injected unilaterally into the rostral substantia nigra pars compacta with 8 micron of 6-OHDA. Those animals that conformed to be behavioral criteria for an effective nigrostriatal dopamine lesion by turning ipsilaterally to the injected side upon IP amphetamine, and contralaterally upon apomorphine injection were bilaterally detelencephalized (neocrotex, hippocampus, striatum, septum, amygdaloid complex were removed). Most detelencephalized animals exhibited spontaneous turning to the contralateral side, i.e. no longer behaved like 6-OHDA-lesioned rats, but instead, acted like animals with nigral kainic acid or electrolytic lesions. Amphetamine (2-3 mg/kg) increased general activity but no longer influenced turning. Apomorphine in doses of 2-3 mg/kg completely suppressed all motility. In small doses (0.1-0.2 mg/kg) it reversed the spontaneous contraversive turning. This effect could be blocked by haloperidol (0.1 mg/kg) pretreatment. High doses of haloperidol (5.0-7.5 mg/kg) reversed the direction of circling from contraversive to ipsiversive. Arecoline (10-12 mg/kg) induced tremor as in normal animals. Atropine (50-100 mg/kg) did not affect turning, but increased activity level in the thalamic rats.

Relationships between selective denervation of dopamine terminal fields in the anterior forebrain and behavioral responses to amphetamine and apomorphine

To investigate the relationship between denervation of dopamine (DA) terminal fields in the anterior forebrain and the behavioral responses to amphetamine (1.5 mg/kg) and apomorphine (1 mg/kg), we injected 6-hydroxydopamine (6-OHDA) bilaterally into the anterolateral hypothalamus (ALH) or into specific mesolimbic and anterior striatal terminal fields after pretreatment with desmethylimipramine to protect noradrenergic axons and terminals from 6-OHDA toxicity. After drug testing was completed, the extent of denervation was determined by fluorescent histochemical analysis. When nearly all of the mesolimbicocortical and anteroventral striatal DA terminal fields were denervated by bilateral ALH 6-OHDA, the locomotor response to amphetamine was abolished, and the locomotor and stereotyped sniffing responses to apomorphine were increased. When fewer DA terminal fields were denervated, different results were obtained: the locomotor response to amphetamine decreased or did not change; stereotyped sniffing elicited by apomorphine did not increase or sniffing was replaced by stereotyped licking and biting. The results suggest a mass action relationship between DA terminal fields in the anterior forebrain and the locomotor response to amphetamine. The relationship between the same DA lesions and responses to apomorphine appears to be more complex.

Apomorphine-induced rotation in the unilateral 6-ohda-lesioned rat: Relationship to changes in striatal adenylate cyclase activity and 3H-spiperone binding

Rotational responses to apomorphine in rats with unilateral 6-hydroxydopamine lesions were significantly correlated with increases in 3H-spiperone binding but not with increases in DA-stimulated adenylate cyclase activity in lesioned striata. This behavioural index of DA receptor supersensitivity may be mediated by proliferation of those DA receptors that bind 3H-spiperone but are not linked to adenylate cyclase. Rats with unilateral 6-hydroxydopamine (6-OHDA) lesions of the nigrostriatal dopamine (DA) pathway exhibit contralateral rotational behaviour when challenged with DA agonists Such as apomorphine. This behavioural supersensitivity has been shown to be accompanied by an increase in striatal 3H-haloperidol binding sites (Creese et al., 1977; Seeman et al., 1978). However, studies of the activity of striatal DA-sensitive adenylate cyclase (AC) after such lesions have produced conflicting results (Iversen, 1975; Krueger et al., 1976). While both of these biochemical measures have been proposed as in vitro indices of the DA receptor, recent data suggest they may reflect different types of receptor (Kebabian and Calne, 1979)- The behavioural significance of these two in vitro measures is at present unclear. In the present study we have used rotational response to apomorphine as a behavioural index of DA receptor supersensitivity after unilateral 6-OHDA lesion. In an attempt to determine the functional significance of the in vitro measures of DA receptor sites we have correlated changes in both DA-stimulated AC activity and 3H-spiperone binding in lesioned striata with their associated rotational responses to apomorphine.

Baclofen and muscimol: behavioural and neurochemical sequelae of unilateral intranigral administration and effects on 3H-GABA receptor binding.

Log dose-response curves for induction of contralateral rotational behaviour in the rat by unilateral intranigral injections of the GABA agonist muscimol and the GABA analogue baclofen have been compared. Baclofen, 5--1000 ng, produced a maximal rotational response that was only 40% of that produced by 0.25--100 ng muscimol, and log dose-response curves failed to show parallelism. The behavioural effects of both drugs were only weakly antagonised by haloperidol and were not antagonised by 6-hydroxydopamine lesions of ipsilateral dopamine (DA) neurons, indicating that these responses were independent of DAergic mechanisms. The effects of baclofen were weakly antagonised by picrotoxin. Intranigral muscimol and baclofen substantially elevated striatal DA concentrations. While muscimol also substantially elevated striatal dihydroxyphenylacetic acid (DOPAC) but not homovanillic acid (HVA), bactofen did not significantly effect either DOPAC or HVA. Baclofein, GABA and muscimol displaced specific 3H-GABA binding in vitro with IC50's of 40 micron, 400 nM and 40 nM respectively. These results indicate that muscimol and baclofen do not act via a unitary GABAergic mechanism, but suggest that baclofen may be a partial GABA agonist, at least at nigral GABA receptors.

Striatal cell supersensitivity to apomorphine in dopamine-lesioned rats correlated to behaviour

The sensitivity of glutamate-excited striatal cells to subcutaneous, systemic injections of apomorphine was measured in unlesioned rats and rats with 3–17 months old unilateral lesions of the nigro-striatal dopamine system resulting from a stereotaxic injection of 6-OH-DA into the ascending bundle of dopamine axons. The lowest doses effective in depressing striatal cell activity were used to determine the sensitivity to apomorphine: 0.1–0.4 mg/kg in unlesioned animals; 0.005 and 0.01 mg/kg in denervated animals. Thus, there is a 10–80-fold increase in striatal cell sensitivity to apomorphine after dopamine lesions. The cellular effects were comparable in sensitivity and time course to the rotational behaviour of the animals as recorded in a rotometer.

Lesions of the striatopetal dopamine and serotonin pathways: Anatomy and chemistry

Lesions of the striatopetal dopamine and serotonin pathways: Anatomy and chemistry