Regulatory behaviour, exploration and locomotion following NMDA or 6-OHDA lesions in the rat nucleus accumbens.

The effects of bilateral, N-methyl-D-aspartate (NMDA)-induced lesions of the nucleus accumbens (N.Acc.) on regulatory and behavioural responding were studied in rats and compared with the effects of bilateral 6-hydroxydopamine (6-OHDA) lesions. After postoperative body weight, food and water intake had been monitored for a period of 4 weeks, rats were tested in an exploration-choice box. Spontaneous locomotion and the locomotor and stereotypy responses to different doses of dopaminergic agonists were measured subsequently. Detailed assessment of NMDA-induced lesion volumes showed that on average 81.53% of total N.Acc. area was damaged, depending on excitotoxin dose. Tyrosine hydroxylase immunohistochemistry was used to confirm loss of mesolimbic dopamine neurones following 6-OHDA. Analysis of the behavioural data showed that NMDA N.Acc. lesions significantly enhanced exploratory behaviour, spontaneous locomotor activity and the locomotor response to a low dose of D-amphetamine. By comparison, 6-OHDA lesions did not affect exploration and spontaneous locomotion but significantly attenuated the locomotor response to a low dose of D-amphetamine. Regulatory responses were unaffected 28 days after surgery, although NMDA-lesioned rats took longer to recover from postoperative hypodipsia. The results suggest that NMDA N.Acc. lesions induce a deficit in the control of general locomotor output and are consistent with the hypothesis that the N.Acc. functions as an interface between sensory input and locomotor output and that it is needed to channel activity levels appropriately.     

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.     

Reduction in cholinergic interneuron density in the nucleus accumbens attenuates local extracellular dopamine release in response to stress or amphetamine

Depletion of cholinergic interneurons in the ventral striatum (nucleus accumbens or N.Acc.) in adult rats increases the locomotor activating effects of amphetamine. It also impairs sensorimotor gating processes, an effect reversed by the antipsychotic haloperidol. These behavioral effects are suggestive of pronounced hyper‐responsiveness of the mesolimbic dopamine (DA) projection to the N.Acc. However, it is unclear whether local cholinergic depletion results predominantly in exaggerated presynaptic DA release or a postsynaptic upregulation of DAergic function. The purpose of the present study is to test the former possibility by employing in vivo voltammetry to examine changes in the levels of extracellular DA within the N.Acc. in response to either mild tail pinch stress or amphetamine administration. While both cholinergic‐lesioned and control rats showed reliable stress‐induced increases in extracellular DA on two consecutive test days, those in the lesioned rats were significantly less pronounced. In response to amphetamine, a separate cohort of lesioned rats also exhibited smaller increases in extracellular DA release than controls, despite showing greater locomotor activity. Moreover, the increased behavioral response to amphetamine in lesioned rats coincided temporally with decreasing levels of DA in the N.Acc. The results confirm that cholinergic depletion within the N.Acc. suppresses presynaptic DA release and suggest that lesion‐induced behavioral effects are more likely due to postsynaptic DA receptor upregulation. The results are also discussed in the context of schizophrenia, where post mortem studies have revealed a selective loss of cholinergic interneurons within the ventral striatum. Synapse, 2013. © 2012 Wiley Periodicals, Inc.     

Spontaneous and drug-induced locomotor activity after partial dopamine denervation of the ventral striatum

Spontaneous and drug-induced locomotor behavior was investigated in rats subjected to lesions of the ventral striatum, using the neurotoxin 6-hydroxydopamine to produce selective depletions of dopamine. Locomotor activity changed with time after lesion. At 2 weeks postoperative less spontaneous rearings were observed compared to controls, a reduced response to 1.0 mg/kg amphetamine and an increased response to 0.1 mg/kg apomorphine. These changes were not observed 9 weeks postoperative; that is, spontaneous locomotor activity and the response to amphetamine were not different from those of controls, and the rearing response to apomorphine was now reduced. The neurochemical assays of the lesioned ventral striate showed equivalent dopamine depletions of about 48% in both lesion groups relative to controls.     

Relationship between the locomotor hyperactivity induced by A10 lesions and the destruction of the frontocortical dopaminergic innervation in the rat

Bilateral high frequency lesions of the ventral tegmental area (VTA) in the rat induce a behavioral syndrome characterized by a permanent locomotor hyperactivity and a reduction of attention capacities. The VTA contains the cell bodies of the mesocortical and mesolimbic dopaminergic (DA) systems but is also rich in serotoninergic (5-HT) fibers which originate from the raphe nuclei and innervate the forebrain. In order to establish possible correlation(s) between the destruction of specific aminergic system(s) and some of the behavioral effects of VTA lesions, rat locomotor activities were recorded and DA, 5-HT and norepinephrine (NE) were estimated in discrete areas of the forebrain using specific and sensitive radioenzymatic methods.VTA lesions greatly affected DA and 5-HT levels in the forebrain but only induced minor effects on cortical NE.No significant correlations were found between the changes in locomotor activity and the reduction of 5-HT levels in the parietal and rhinal cortices, the striatum and the hippocampus.On the other hand, a very good correlation was observed between the increase in locomotor activity and the decrease in DA content in the frontal cortex (r= −0.82,n= 20, P < 0.01). Although not as striking, a correlation was also found between the changes in locomotor activity and those of DA levels in the nucleus accumbens, a structure innervated by the mesolimbic DA system (r= −0.47,n= 24, P < 0.05).A comparison between changes in DA levels in the frontal cortex and the nucleus accumbens after VTA lesions suggested that cell bodies of the mesocortical and mesolimbic DA systems, although very close, are not the same.It cannot be excluded that the mesolimbic DA system plays a role in the ‘VTA syndrome’. However, it is clear that the disappearance of DA in the frontal cortex is critical for the development of the non-vicarious locomotor hyperactivity. This suggests that the dopaminergic neurons which innervate the frontal cortex exert an inhibitory role on locomotor behavior.     

Amphetamine and apomorphine responses in the rat following 6-OHDA lesions of the nucleus accumbens septi and corpus striatum.

Eight mug of 6-hydroxydopamine (6-OHDA) injected bilaterally into the nucleus accumbens septi (NAS) or the caudate nucleus of the rat resulted in 79% and 50% depletion of endogenous dopamine (DA) at these respective sites. Fourteen days after the injection a low dose of amphetamine failed to induce the characteristic locomotor response in the NAS-lesioned rats but did so in the caudate-lesioned animals. By contrast the caudate lesion, but not the NAS lesions, abolished intense forms of stereotyped behaviour induced by higher doses of amphetamine. Both lesioned groups exhibited supersensitivity to the dopamine agonist, apomorphine; the NAS group showed enhanced locomotor activity and the caudate group enhanced stereotyped behaviour. The block of amphetamine locomotion and the enhanced response to apomorphine were maximal around 14 days after the operation and gradually attenuated up to 90 days. Theer is evidence that remaining DA levels in the NAS are greater at 90 than at 14 days postoperatively. Thus recovery of behavioural effects correlated with an increase in the remaining levels of DA in the NAS.     

Effect of bilateral 6-OHDA lesions of the substantia nigra on locomotor activity in the rat

Previous parkinsonian rat models have utilized stereotactic 6-OHDA injections to completely lesion the dopaminergic mesostriatal system on one side. Recently, hemiparkinsonian rat models in which the mesolimbic system is left intact have been developed. The selective, partial lesion models better mimic the neuropathology of human parkinsonism in which there is usually an incomplete destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and a relative sparing of ventral tegmental area (VTA) cell groups. However, such hemiparkinsonian models which possess dopaminergic asymmetry cannot demonstrate bradykinesia, one of the main symptoms in human parkinsonism. Meanwhile, bilateral lesions of the ascending forebrain dopaminergic system have been reported to induce severe aphagia, adipsia and akinesia. We, therefore, undertook development of a bilateral partial SNpc lesion model which also spares the VTA on both sides. We have investigated spontaneous locomotor activities as well as amphetamine, apomorphine and levodopa induced activities during a subchronic period of up to 27 days after the bilateral lesion. Three activity parameters, i.e. horizontal activity, vertical activity and distance traveled, were measured. The relationship between dopamine neuron loss in the SNpc and changes in the locomotor activity was analyzed. Spontaneous activity was significantly decreased in animals with extensive (80%) SNpc lesions on both sides. Animals with a 95% lesion were severely aphagia and adipsia. Responses to amphetamine and apomorphine were variable. It is possible that in some cases the bilateral SNpc neurons were not equally damaged, which could cause the enhanced rotational behavior. Bradykinetic rats displayed on the average, a 20% decline in horizontal activity, a 40% decline in vertical activity and a 30% decline in distance traveled after the lesion. These bradykinetic rats consistently showed a marked increase in activity in response to levodopa therapy as observed in human parkinsonian patients. The results indicate that rats with bilateral partial lesions of the SNpc may be useful for the evaluation of new therapeutic approaches for treating Parkinson's disease.     

Neuroleptic-like distruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems

An examination of the ability to learn an active avoidance response was made in rats subjected to 6-hydroxydopamine (6-OHDA) lesions of the individual terminal areas of the midbrain dopamine (DA) system or a lesion to all these terminal regions in one group. Lesions were made by infusing 8 μg (base) of 6-OHDA in 2 μl of vehicle into the following forebrain regions (each region representing a separate group of rats); frontal cortex, nucleus accumbens, corpus striatum and a double lesion of nucleus accumbensand corpus striatum. A separate group of rats received a smaller 6-OHDA lesion of the ventral substantia nigra. Only those rats with the combined double lesion of both the nucleus accumbens and corpus striatum (90% total depletion of dopamine) showed a severe deficit in acquisition of active avoidance. However, the rats with the separate 6-OHDA lesions to the mesolimbic or nigrostriatal DA systems did show the appropriate blockade of the amphetamine-induced locomotion or stereotyped behavior, respectively. In contrast, the rats with the double lesion showed no response to a low or high dose of amphetamine, remained cataleptic for the duration of the experiment but rapidly recovered from transient aphagia and adipsia (< 10days post lesion). Results suggest that a severe deficit in acquisition of an active avoidance response, similar to that observed with high doses of neuroleptics, requires destruction of all of the dopamine innervation of nucleus accumbens and corpus striatum. Results also suggest that both the mesolimbic and nigrostriatal dopamine systems act in concert to produce response enabling to important environmental events, and that the severe response enabling deficits observed in Parkinson's disease involves not only degeneration of the nigrostriatal dopamine system, but of the mesolimbic dopamine system as well.     

Neuroleptic-like disruption of the conditioned avoidance response requires destruction of both the mesolimbic and nigrostriatal dopamine systems

An examination of the ability to learn an active avoidance response was made in rats subjected to 6-hydroxydopamine (6-OHDA) lesions of the individual terminal areas of the midbrain dopamine (DA) system or a lesion to all these terminal regions in one group. Lesions were made by infusing 8 micrograms (base) of 6-OHDA in 2 microliter of vehicle into the following forebrain regions (each region representing a separate group of rats); frontal cortex, nucleus accumbens, corpus striatum and a double lesion of nucleus accumbens and corpus striatum. A separate group of rats received a smaller 6-OHDA lesion of the ventral substantia nigra. Only those rats with the combined double lesion of both the nucleus accumbens and corpus striatum (90% total depletion of dopamine) showed a severe deficit in acquisition of active avoidance. However, the rats with the separate 6-OHDA lesions to the mesolimbic or nigrostriatal DA systems did show the appropriate blockade of the amphetamine-induced locomotion or stereotyped behavior, respectively. In contrast, the rats with the double lesion showed no response to a low or high dose of amphetamine, remained cataleptic for the duration of the experiment but rapidly recovered from transient aphagia and adipsia (less than 10 days post lesion). Results suggest that a severe deficit in acquisition of an active avoidance response, similar to that observed with high doses of neuroleptics, requires destruction of all of the dopamine innervation of nucleus accumbens and corpus striatum. Results also suggest that both the mesolimbic and nigrostriatal dopamine systems act in concert to produce response enabling to important environmental events, and that the severe response enabling deficits observed in Parkinson's disease involves not only degeneration of the nigrostriatal dopamine system, but of the mesolimbic dopamine system as well.     

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.     

Effects of locally applied D1 and D2 agonists on striatal neurons with 6-OHDA and pertussis toxin lesions.

Electrophysiological recordings were performed on caudate neurons in rats with dopamine (DA) depleted striatum in combination with pertussis toxin (PT) lesions. Pertussis toxin inactivates the G protein coupled to D2 receptors. DA depletions were performed by unilateral injections of 6-hydroxydopamine (6-OHDA). After the 6-OHDA lesion, rats were challenged with low doses of apomorphine. When a double peak rotational pattern was stable over repeated rotational tests, PT was injected into striatum ipsilateral to the DA depleted side. Two days after the PT injections extracellular recordings with local applications of the D1 agonist SKF 38393 and the D2 agonist N-0437 were performed. Spontaneous firing rates, measured before drug application, were elevated in animals with both 6-OHDA and 6-OHDA/PT combination of lesions. In rats with only 6-OHDA lesions, a supersensitivity to N-0437 was observed, while no significant change in response to the D1 agonist was detected. Recordings from caudate neurons in rats with a combination of 6-OHDA and PT resulted in no response to the D2 agonist. However, a subsensitivity to the D1 agonist was detected and only 60% of neurons were inhibited by SKF 38393. Taken together, these data suggest an interaction between the D1 and D2 receptors, which is revealed only after an upregulation of the D2 receptors and subsequent blockade of D2 mediated effects.     

The pharmacological and anatomical substrates of the amphetamine response in the rat.

Bilateral 6-hydroxydopamine microinjections into the substantia nigra abolished both the locomotor and stereotyped responses to d-amphetamine in adult rats. The lesions resulted in a depletion of over 99 per cent of striatal tyrosine hydroxylase activity (indicating a near total lesion of the nigro-striatal dopamine pathway) as well as severe noradrenaline depletions. However, lesion of the dorsal or ventral noradrenergic pathways resulted in similar noradrenaline depletions but with no effect on striatal tyrosine hydroxylase levels and without the concomitant blockage of the amphetamine response. The substantia nigra lesioned rats were behaviourally supersensitive to apomorphine and L-DOPA and did not show a locomotor response to cocaine. The substantia nigra lesioned rats were not aphagic or adipsic. It was concluded that both the locomotor and stereotyped responses induced by amphetamine are dependent on the functional integrity of the nigro-striatal dopamine pathway.     

Nociceptin/orphanin FQ and opioid receptor-like receptor mRNA expression in dopamine systems

Although nociceptin/orphanin FQ (N/OFQ) influences dopamine (DA) neuronal activity, it is not known whether N/OFQ acts directly on DA neurons, indirectly by means of local circuitry, or both. We used two parallel approaches, dual in situ hybridization (ISH) and neurotoxic lesions of DA neurons by using 6-hydroxydopamine (6-OHDA), to ascertain whether N/OFQ and the N/OFQ receptor (NOP) mRNA are expressed in DA neurons in the ventral tegmental area (VTA) and substantia nigra compacta (SNc). In the VTA and SNc, small populations (approximately 6-10%) of N/OFQ-containing neurons coexpressed mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme for DA synthesis. Similarly, very few (1-2%) TH-positive neurons contained N/OFQ mRNA signal. A majority of NOP-positive neurons (approximately 75%) expressed TH mRNA and roughly half of the TH-containing neurons expressed NOP mRNA. Many N/OFQ neurons (approximately 50-60%) expressed glutamic acid decarboxylase 65 and 67 mRNAs, markers for gamma-aminobutyric acid (GABA) neurons. In the 6-OHDA lesion studies, NOP mRNA levels were nearly 80 and 85% lower in the VTA and SNc, respectively, on the lesioned side. These lesions appear to lead to compensatory changes, with N/OFQ mRNA levels approximately 60% and 300% higher in the VTA and SNc, respectively, after 6-OHDA lesions. Finally, N/OFQ-stimulated [(35)S]guanylyl-5'-O-(gamma-thio)-triphosphate levels were decreased in the VTA and SNc but not the prefrontal cortex after 6-OHDA lesions. Accordingly, it appears that N/OFQ mRNA was found largely on nondopaminergic (i.e., GABA) neurons, whereas NOP mRNA was located on DA neurons. N/OFQ is in a position to influence DA neuronal activity by means of the NOP located on DA neurons.     

Parkinsonian Motor Deficits Are Reflected by Proportional A9/A10 Dopamine Neuron Degeneration in the Rat

In a model of Parkinson's disease (PD), amphetamine, a dopamine (DA)-releasing drug, fails to induce ipsilateral drug rotations in a proportion of rats with complete unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle and DA neurons of the substantia nigra. To investigate this phenomenon, individual 6-OHDA lesions (measured by tyrosine hydroxylase immunohistochemistry) in the substantia nigra pars compacta (A9), ventral tegmental area (A10), and striatum were examined in conjunction with outcomes of four behavioral tests. The behavioral tests were skilled paw reaching, a head-turning test, and apomorphine (0.05 mg/kg) and amphetamine (4 mg/kg) drug-induced rotations. Four weeks postlesion, ipsilateral side bias measured by the head-turning test correlated strongly with extent of A9 DA neuronal lesion. Additional A10 neuronal DA lesions did not substantially improve the model fit, indicating that the head-turning bias was primarily A9 dependent. In contrast, total head-turning activity increased monotonically with lesions of A10 striatal DA fibers. Skilled paw-reaching accuracy decreased with increased lesion of both A9 and A10 DA neuronal systems. Associating amphetamine-induced rotations with extent of A9 DA lesion generated a second-order polynomial model, y = -11.1x + 0.20 x(2) + 208.7 (R(2) = 0.73), with an overall F ratio (df = 2,21) of 28.4 (P < 0.0001). This model predicts that an A9 DA lesion of about 50% is required to induce an ipsilateral turning bias, after which rotations increase with the degree of A9 DA neuronal lesion. No further change in rotational behavior was seen until an additional A10 DA lesion reached 60%, after which the rotational response decreased. This analysis provides tests that differentiate between A9 DA degeneration and combined A9/A10 lesions in animal models and in addition allows predictive testing of PD therapeutic intervention at a preclinical level.     

The response of non-dopamine neurons in substantia nigra and ventral tegmental area to amphetamine and apomorphine during hypermotility: the striatal influence

The effects of haloperidol pretreatment in striatum on the motor response, and on concurrently recorded unit responses of nondopamine (DA) neurons in substantia nigra (SN) and ventral tegmental area (VTA) to systemic amphetamine and apomorphine, were investigated with the objective of determining the role of the striatum in the output of putative DA output neurons. Unit and motor activity were recorded in the male rat, chronically implanted with 9 electrodes in SN and VTA and with two cannulae for bilateral injections into striatum. The recording electrodes were 3 bundles of 3 wires, each wire in the bundle of a different length, but all 3 aimed at SN, pars reticulata, or VTA. In each recording session, unit activity was derived from 7 wires while gross motor activity was recorded with the open-ended wire technique. The subjects were tested under two conditions. In the first, the vehicle was injected bilaterally into striatum 90 min before one of the DA agonists was injected by the intraperitoneal route. In the second, the DA antagonist haloperidol was injected bilaterally into striatum before the systemic treatment with the DA agonist. In subjects which received injections of the vehicle into striatum, amphetamine induced a large motor response, and concurrently, a large increase in the rate of discharge of a portion of the identified non-DA neurons in SN and VTA. In subjects which received injections of haloperidol into striatum, amphetamine induced a smaller behavioral response, a smaller increase in the rate of discharge of these neurons in SN but not in VTA where the increase was of the same magnitude as controls. In control subjects, apomorphine induced an increase in motor activity and concurrently, an increase in the rate of firing of the identified non-DA neurons in SN and VTA. But the increases were of somewhate smaller magnitude and much shorter duration than the increases induced by amphetamine. In subjects which had been pretreated with haloperidol in striatum, apomorphine induced an increase in motor activity that was of the same magnitude as the insion that the striatum has the capacity to influence the output of non-DA neurons only in SN but also in VTA, indicating that, if there is a specialization of function, it is only relative.(ABSTRACT TRUNCATED AT 400 WORDS)     

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.     

Cocaine-induced place preference conditioning: Lack of effects of neuroleptics and 6-hydroxydopamine lesions

The conditioned place preference paradigm was used to study the reinforcing properties of D-amphetamine. Rats were injected (i.p.) with D-amphetamine sulphate (0.5, 1.0 or 5.0 mg/kg) and 10 min later confined for 30 min to one side of a shuttle box in which each of the two compartments had distinctive features. On alternate (control) days they received saline injections and were confined for 30 min to the opposite side. At all doses D-amphetamine produced place preference for the distinctive compartment that previously had been associated with the drug. Pretreatment with haloperidol (0.15 or 1.0 mg/kg) antagonized the place preference produced by amphetamine (1.5 mg/kg). By itself, haloperidol (0.15 or 1.0 mg/kg) did not produce place aversion. In separate experiments the D-amphetamine-induced place preference was examined in rats that had received 6-hydroxydopamine (6-OHDA) lesions of the nucleus accumbens. Animals with the greatest depletion of dopamine did not show preference for the compartment associated with D-amphetamine. Furthermore, the time spent on the amphetamine-reinforced side correlated significantly with the levels of dopamine remaining in the nucleus accumbens but not with the dopamine content in the striatum. Depletion of peripheral catecholamines by systemic injections of 6-OHDA did not affect D-amphetamine-induced place preference conditioning. Other groups of animals that received the dopamine receptor agonist, apomorphine, also developed a conditioned preference for the compartment that had been associated with the drug treatment. These findings support the view that the reinforcing effects of D-amphetamine are mediated by central dopamine-containing neurons, and in particular those of the mesolimbic system.     

Amphetamine regulation of mesolimbic dopamine/cholecystokinin neurotransmission.

The effects of acute and repeated amphetamine administration on mesolimbic dopamine (DA) neurons was assessed by studying DA and cholecystokinin (CCK) release in the nucleus accumbens (Acc), as well as effects on mRNA genes regulating DA and CCK synthesis in ventral tegmental area (VTA) cells in rats. Amphetamine (1.5 mg/kg) markedly increased extracellular levels of DA in the medial Acc (assessed by in vivo microdialysis) in drug-naive animals, about twice the amount released in animals repeatedly administered the drug for the previous 7 days (twice daily). CCK overflow was found to mirror the DA responses in that the very transient elevation of CCK monitored in drug-naive animals was attenuated in those with prior amphetamine use. The attenuation of both DA and CCK overflow in the medial Acc was found to be associated with a decrease in the number of CCK mRNA-positive VTA neurons (assessed by in situ hybridization histochemistry). Although the number of cells expressing CCK mRNA were decreased, the gene expression in those positive CCK and tyrosine hydroxylase mRNA cells in the VTA was significantly increased. The CCK mRNA neurons in the VTA were positively identified as those projecting to the medial Acc by the local perfusion of Fluoro-gold retrograde tracer via microdialysis probes located in the Acc.     

Relationship between asymmetries in striatal dopamine release and the direction of amphetamine-induced rotation during. The first week following a unilateral 6-OHDA lesion of the substantia nigra

In animals with a large unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal dopamine (DA) system the traditional “rotational behavior model” states that amphetamine will induce circling behavior towards the denervated striatum (ipsiversive), that is, away from the side where there is greater amphetamine-stimulated DA release and greater DA receptor stimulation. It is puzzling, therefore, why amphetamine induces contraversive rotation in rats tested 4 days after a unilateral 6-OHDA lesion, despite a 90-95% loss of the dopaminergic input to the striatum by this time. Rats reverse their direction of amphetamine-induced rotation by 8 days post-lesion and turn in the ipsiversive direction thereafter. To try and resolve this paradox, bilateral striatal microdialysis was used to estimate the effects of amphetamine on DA neurotransmission on Day 4 and Day 8 following a large unilateral 6-OHDA lesion of the substantia nigra. On Day 4 post-lesion, amphetamine produced a moderate (around 50% of control) increase in the extracellular concentration of DA in the denervated striatum. This amphetamine-releasable pool of DA was exhausted by a single amphetamine challenge, because a second injection of amphetamine given 3 h after the first did not produce a comparable increase in DA. It is suggested that on Day 4 post-lesion the amount of DA released by amphetamine in the denervated striatum is sufficient to produce greater DA receptor stimulation on that side, because of DA receptor supersensitivity, and this leads to contraversive rotation. On Day 8 post-lesion, amphetamine induced DA release in the intact striatum but had no effect on extracellular DA in the denervated striatum (DA was nondetectable). On Day 8, therefore, DA receptor stimulation would be greatest in the intact striatum, leading to ipsiversive rotation. In conclusion, it is suggested that the seemingly paradoxical reversal in the direction of amphetamine-induced rotation that occurs over the first week following a unilateral 6-OHDA lesion is consistent with the traditional rotational model, and is due to time-dependent changes in the ability of amphetamine to release DA in the denervated striatum. © 1994 Wiley-Liss, Inc.     

MK-801 increases locomotor activity without elevating extracellular dopamine levels in the nucleus accumbens

In vivo microdialysis was used in freely moving rats to determine whether the locomotor stimulant effects of dizocilpine maleate (MK-801) were related to increased dopamine (DA) release within the nucleus accumbens (N. Acc.). Each experiment began with a baseline period of at least 2 h (starting 15–20 h after insertion of concentric, removable dialysis probes), during which activity records and dialysate samples were collected every 20 min. Rats in the first experiment then were injected with MK-801 (0.125, 0.25, or 0.50 mg/kg, i.p.) or saline, and activity and extracellular levels of DA, dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) were measured for a further 160 min post-injection. In a second experiment, rats were given 1.5 mg/kg d-amphetamine sulphate 40 min after receiving the same doses of MK-801, and testing was continued for 120 min. Rats in a third experiment were given low, autoreceptor-preferring doses of apomorphine hydrochloride (25 or 50 μg/kg, s.c.) or its vehicle 40 min after injection of 0.25 mg/kg MK-801 and then monitored for 120 min. MK-801 produced strong and consistent increases in locomotor activity that were augmented by amphetamine and greatly reduced by the low doses of apomorphine. MK-801 did not increase extracellular DA levels within the N. Acc. when given alone, and it failed to influence the changes in extracellular DA produced by d-amphetamine and apomorphine. MK-801 did produce consistent, dose-related increases in DOPAC and HVA that were probably not related to transmitter release. These results indicate that the increases in locomotor activity seen following MK-801 do not arise from a drug-induced increase in DA levels within the N. Acc. © 1996 Wiley-Liss, Inc.