Chronic L-dopa treatment in the unilateral 6-OHDA rat: evidence for behavioral sensitization and biochemical tolerance.

Two separate experiments were conducted to assess the behavioral and biochemical effects of chronic L-dihydroxyphenylalanine (L-DOPA) treatment in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. In this animal model, contralateral rotation provides the behavioral indicator response for L-DOPA activation of the dopamine denervated striatum. Following 30 daily L-DOPA treatments, a subthreshold dose (10 mg/kg) for rotation became suprathreshold and the contralateral rotation induced by a suprathreshold dose (20 mg/kg) became exaggerated. This motoric sensitization to L-DOPA was not reversed by a three-day period of L-DOPA withdrawal. In contrast with the emergence of behavioral sensitization to L-DOPA, biochemical measurements showed that the increase of dopamine metabolite concentrations (DOPAC and HVA) induced by acute L-DOPA treatment became attenuated with chronic treatment. This finding suggests that chronic L-DOPA treatment produces a partial tolerance in the conversion of L-DOPA to extracellular dopamine. The emergence of L-DOPA sensitization-over-stimulation effects was hypothesized to reflect the combined effects of dopamine receptor priming and Pavlovian drug conditioning and to contribute to the emergence of dyskinetic effects of L-DOPA therapy. The partial tolerance observed for dopamine metabolites was hypothesized to represent a decreased conversion of L-DOPA to dopamine which with long-term treatment could progress to an eventual wearing-off effect of L-DOPA therapy.     

Sensitization and conditioned rotation: apomorphine, quinpirole and SKF-38393 compared.

Rats lesioned in one substantia nigra were treated on three consecutive days with the nonselective dopamine agonist, apomorphine (0.05 mg kg-1), the selective D2 agonist, quinpirole (0.025, 0.05, or 0.2 mg kg-1) or the selective D1 agonist, SKF-38393 (2.0, 4.0 or 8.0 mg kg-1). Each of these compounds resulted in acute contralateral rotation which increased significantly upon successive administrations. Two weeks after apomorphine treatment rats exhibited rapid contralateral rotation when placed, undrugged, in the drug-associated environment. Similar undrugged rotation was seen ten weeks after the lower doses of SKF-38393. No evidence of undrugged rotation was seen after quinpirole. The results show that sensitization does not necessarily predict development of a placebo effect, and suggest that persistent motor effects of dopamine agonists are associated with D1 receptor stimulation.     

The relationship between loss of dopamine nerve terminals, striatal [H]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 tol-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 tol-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 tol-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 beforel-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.     

Reversal by L-DOPA of the suppression of locomotor activity induced by inhibition of tyrosine-hydroxylase and DA-beta-hydroxylase in mice

In a previous experiment it was shown that the α-methyltyrosine (α-MT)-induced suppression of locomotor activity, but not that induced by reserpine, could be reversed by a low dose ofl-3,4-dihydroxyphenylalanine (l-DOPA)². Reserpine, but not α-MT, interferes with the granular storage of transmitters. It is further known that the nerve impulse-induced release of transmitters is dependent on intact granules²¹. The hypothesis was raised that the functional response tol-DOPA after α-MT is dependent on the nerve impulse-induced release of catecholamines. The present experiments were undertaken to investigate to what extent the poor granular refillment of noradrenaline (NA) byl-DOPA in reserpine-treated animals may account for the failure to restore function byl-DOPA after reserpine. The effects ofl-DOPA, 10 or 50 mg/kg, in combination with an inhibitor of peripheral DOPA decar?ylase (MK-486) was investigated on locomotor activity suppressed by treatment with α-MT or treatment with α-MTplus an inhibitor (FLA-63) of the dopamine (DA)-β-hydroxylase in mice. Treatment with α-MTplus FLA-63, but not treatment with α-MT alone, inhibits the accumulation of brain NA after the administration ofl-DOPA, whereas brain DA increased to the same extent in both cases. The locomotor activity, suppressed by α-MT or α-MTplus FLA-63, increased to the same extent afterl-DOPA, 10 mg.kg. The results obtained are compatible with the view that the granular storage mechanism must be intact and thereby make the release of catecholamines by nerve impulses possible for the maintenance of function.     

Restoration of locomotor activity in mice by low L-DOPA doses after suppression by alpha-methyltyrosine but not by reserpine

The effects of low and high doses ofl-DOPA on locomotor activity in mice were investigated after pretreatment with α-methyltyrosine or with reserpine. After pretreatment with α-methyltyrosine, the administration of low doses ofl-DOPA (10, 25 or 50 mg/kg i.p., after inhibition of the peripherall-DOPA decar?ylase) restored the locomotor activity at 3 and 4 h concomitantly with a normalization of the brain catecholamine concentrations. On the other hand, the same treatments withl-DOPA did not cause any reversal of the reserpine-induced suppression of locomotor activity despite a marked increase in brain dopamine. Both after pretreatment with α-methyltyrosine and with reserpine, high doses ofl-DOPA (200 or 400 mg/kg i.p.) induced a marked increase in locomotor activity, even in comparison to saline-treated controls, and other signs of overstimulation. The difference between the functional effects of the low doses ofl-DOPA after pretreatment with α-methyltyrosine and with reserpine may be explained by a release of the newly formed catecholamines by nerve impulses from the nerve terminals in the former but not in the latter case.     

Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

Methylphenidate (MPD) is used to treat ADHD and as a cognitive enhancement and recreationally. MPD’s effects are not fully understood. One of the sites of psychostimulant action is the ventral tegmental area (VTA). The VTA neuronal activity was recorded from freely behaving rats using a wireless system. 51 animals were divided into groups: saline, 0.6, 2.5, and 10.0 mg/kg MPD. The same repetitive MPD dose can elicit either behavioral sensitization or tolerance; thus the evaluation of the VTA neuronal activity was based on the animals’ behavioral response to chronic MPD exposure: animals exhibiting behavioral tolerance or sensitization. Acute MPD elicits dose-related increases in behavioral activity. About half of the animals exhibited behavioral sensitization or tolerance to each of the MPD doses. 361 units were recorded from the VTA and exhibited similar spike shape on experimental day 1 (ED1) and on ED10. 71, 84, and 79 % of VTA units responded to acute 0.6, 2.5, and 10.0 mg/kg MPD, respectively. The neuronal baseline activity at ED10 was significantly modified in 94, 95, and 100 % of VTA units following 0.6, 2.5 and 10.0 mg/kg MPD, respectively. Following chronic MPD exposure, 91, 98, and 100 % exhibit either electrophysiological tolerance or sensitization of 0.6, 2.6, or 10.0 mg/kg MPD, respectively. In conclusion, the chronic administration of the same dose of MPD caused some animals to exhibit behavioral sensitization and other animals to exhibit tolerance. The VTA units recorded from animals exhibiting behavioral sensitization responded significantly differently to MPD from animals that exhibited behavioral tolerance.     

Antiparkinsonian effects of caffeine depend upon pavlovian drug conditioning processes

Caffeine induces the antiparkinsonian response of contralateral rotation in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions following exposure to the direct-acting dopamine agonist apomorphine. This effect of caffeine has been attributed to a 'priming' effect of apomorphine which enables the supersensitive dopamine receptors to respond to caffeine and other methylxanthines. These studies, however, did not differentiate between conditioning and pharmacological variables. To resolve this issue, a Pavlovian conditioning procedure was employed in which separate groups of 6-OHDA rats were given 0.05 mg/kg (s.c.) apomorphine treatments paired or unpaired with a test environment. The animals in the paired or conditioning treatment groups subsequently exhibited contralateral rotation when tested with caffeine (10 mg/kg, i.p.), whereas animals in the unpaired or 'priming' treatment groups displayed only enhanced ipsilateral rotation. The activation of the conditioned contralateral rotation by caffeine in the paired group occurred even after the response was suppressed by extinction. This preferential activation following extinction of a previously conditioned drug response by caffeine implicates caffeine mechanisms (e.g. adenosine antagonism) in drug conditioning processes.     

Transient amelioration of the sensitization of cocaine-induced behaviors in rats by the induction of tolerance

Intermittent administration of cocaine produced a progressive increase in the stereotypy response of rats to a challenge dose of cocaine (7.5 mg/kg, i.p.). Continuous infusion of cocaine (80 mg/kg per day) via osmotic pumps for 7 days into the sensitized rats produced tolerance to the behavioral responses to the challenge dose of cocaine 1 day after the removal of the pumps. Therefore, tolerance can mask the expression of behavioral sensitization in rats. However, by 10 days after the removal of the pumps, the behavioral tolerance was reversed and the rats again displayed a sensitized response to cocaine. Therefore, the tolerance to cocaine was temporary while the underlying sensitization persisted. The development of tolerance did not alter the underlying sensitization demonstrating that these represent independent phenomena. The relationship between sensitization and tolerance observed in these studies may provide a model relevant to the progress in humans of addiction to psychomotor stimulants.     

Biperiden (M₁ antagonist) impairs the expression of cocaine conditioned place preference but potentiates the expression of cocaine-induced behavioral sensitization

Cocaine addiction is a public health issue in many countries, stressing the need for more effective treatments. As all drugs of abuse, cocaine acts on the brain reward system, increasing dopamine (DA) levels. Other neurotransmitters such as acetylcholine (ACh) are involved in the mechanisms underlying the development and the maintenance of cocaine addiction. ACh plays an important role in learning and memory processes and also regulates DA in some specific regions of the central nervous system. The present study investigated the effects of biperiden, a muscarinic cholinergic (mACh) antagonist in two animal models: conditioned place preference (CPP) and behavioral sensitization. Male C57BL/6J mice were used in both studies. The CPP protocol was unbiased and carried out in three phases: habituation, conditioning and testing. For conditioning, cocaine was injected at a dose of 10mg/kg in eight 15 min-sessions. The treatment with biperiden (doses of 0.1, 1 and 10 mg/kg) was made 30 min prior to the testing session. For behavioral sensitization development, cocaine was administered at the dose of 10 mg/kg for 10 days. After sensitization, two challenges were performed: saline and cocaine (5 mg/kg). Biperiden (10 mg/kg) was administered 30 min before the cocaine challenge. At the dose of 10 mg/kg, biperiden blocked the cocaine-CPP expression, suggesting an effect on conditioned memory retrieval. However, the same dose potentiated the expression of behavioral sensitization, suggesting an increase in DA release, probably in the NAc. Biperiden, as other mACh antagonists, may be a promising drug for the pharmacologic treatment of cocaine addiction.     

Factors in amphetamine-induced contralateral rotation in the unilateral 6-OHDA lesion rat model during the first-week postoperative: implications for neuropathology and neural grafting

Amphetamine induced ipsilateral rotation in rats with chronic unilateral 6-hydroxydopamine (6-OHDA) lesions is a widely accepted line of evidence supportive of dopaminergic mediation of amphetamine effects on motoric behavior. However, there is literature indicating that amphetamine induces contralateral rotation, in the early postoperative phase of a unilateral 6-OHDA lesion. In an attempt to reconcile these opposite amphetamine effects on rotation in terms of dopaminergic mechanisms, a series of 4 experiments were conducted. These studies showed that amphetamine reliably elicits contralateral rotation for up to 7 days postoperative but only ipsilateral rotation thereafter. The amphetamine induced contralateral rotation differed behaviorally in several respects from subsequent ipsilateral rotation induced by amphetamine. It was comparatively more intense; and, while onset of peak rotation was dose dependent, rate of rotation was independent of dose level (0.5, 1.0 and 2.5 mg/kg). Dopamine and dopamine metabolite analyses by HPLC-EC after 3 postperative intervals (days 3, 6, and 9) indicated a progressive and severe depletion of striatal dopamine in conjunction with elevated dopamine turnover. Importantly, after 6 days postoperative, dopamine was reduced to <0.06% after intact hemisphere but yet, amphetamine (1.0 mg/kg) elicited contralateral rotation. It was proposed that amphetamine could release a small amount of dopamine present in a sparse number of residual degenerating terminals and this dopamine, unrestricted by reuptake, could widely access supersensitive dopamine receptors to elicit contralateral rotation. This possibility calls into question amphetamine tests for neural graft efficacy in animal models which use amphetamine induced contralateral rotation as the criterion response.     

Synergistic interaction between an adenosine antagonist and a D1 dopamine agonist on rotational behavior and striatal c-Fos induction in 6-hydroxydopamine-lesioned rats

The interaction between adenosine and D₁ dopamine systems in regulating motor behavior and striatal c-Fos expression was examined in rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. These results were compared to the synergistic interaction between D₁ and D₂ dopamine systems in 6-OHDA rats. Coadministration of the adenosine antagonist 3,7-dimethyl-1-propargylxanthine (DMPX: 10 mg/kg) and the D₁ dopamine agonist SKF38393 (0.5 mg/kg) to 6-OHDA-lesioned rats produced significant contralateral rotation and c-Fos expression in the ipsilateral striatum compared to 6-OHDA rats treated with either drug alone. However, the regional pattern of striatal c-Fos activation following treatment of 6-OHDA rats with SKF38393 and DMPX was different from the dorsolateral pattern of striatal c-Fos induction observed after coadministration of D₁ and D₂ dopamine agonists (SKF38393: 0.5 mg/kg+quinpirole: 0.05 mg/kg). These data are consistent with a functional interaction between D₁ dopamine and adenosine systems in the striatum, but suggest that activation of different subsets of striatal neurons underlie the behavioral synergy observed following combined adenosine antagonist-D₁ dopamine agonist and combined D₁ dopamine agonist–D₂ dopamine agonist treatment.     

In vivo changes in responsiveness of the caudate nucleus tol-DOPA infusion as a function of the estrous cycle

In the present experiment we measured changes in the responsiveness of the nigrostriatal dopaminergic system tol-DOPA as a function of the estrous cycle in the freely behaving animal with push-pull perfusion. Intact female rats were implanted with a push-pull cannula directed at the caudate nucleus and perfused repetitively on each day of their estrous cycle. During the perfusion, the response of the caudate nucleus was tested with two successive increasing doses ofl-DOPA (1.0 and 10 μM) infused directly through the push side of the cannula. In response to 1.0 μMl-DOPA, significantly greater dopamine release was obtained for female rats perfused on proestrus, with all 6 females showing maximal responsiveness at this estrous cycle stage. There was an overall 3–4 fold greater increase in dopamine release to the 10 μMl-DOPA infusion, regardless of estrous cycle day. However, with the use of this 10 μMl_DOPA dose, the significant effect at proestrus was maintained. These results demonstrate that the responsiveness of the caudate nucleus tol-DOPA is maximal at proestrus. These data together with previous work from our laboratory indicate that the natural physiological changes which occur in hormone levels, in particular changes in progesterone during proestrus, exert a substantial influence upon this extra-hypothalamic central nervous system site.     

Apparent synaptic dopamine deficiency induced by withdrawal from chronic cocaine treatment

The effects on motor behavior and forebrain dopamine (DA) synaptic function of withdrawal from chronic cocaine treatment were examined with simultaneous activity monitoring and microdialysis in nucleus accumbens. Rats exhibited behavioral sensitization to daily 30 mg/kg i.p. cocaine. After 18 days of daily cocaine and 7 days of withdrawal, dialysate DA and homovanillic acid (HVA) levels were reduced 36-38%, consistent with a synaptic DA deficiency.     

Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment

Several studies indicate that blockade of stress-induced corticosterone secretion prevents the development of stress-induced sensitization to the behavioral effects of stimulants. The present study examined whether chronic blockade of corticosterone synthesis with metyrapone could reverse stress-induced amphetamine sensitization in rats. Restraint stress in cylindrical chambers, 2 times 30 min/day for 5 days over an 8-day schedule, was used as the stressor. Following completion of the stress protocol, animals were cannulated with microdialysis guide cannulae over the nucleus accumbens, and then treated with either metyrapone (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh day, animals were implanted with microdialysis probes in the nucleus accumbens, and on the following day, all animals were tested for their locomotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by d-amphetamine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. However, amphetamine-stimulated locomotion and stereotypy were strongly enhanced, while amphetamine-stimulated dopamine release response was slightly enhanced (significant only by drug×time interaction), in stressed animals. Metyrapone treatment reduced the stress-induced increase in the locomotor, but not stereotypy, response to amphetamine. In contrast, the dopamine release response to amphetamine was enhanced in metyrapone-treated animals, in both stressed and non-stressed groups, while DOPAC levels were unaffected by treatment group. This augmentation was particularly evident in the stressed-metyrapone-treated animals. Furthermore, non-stressed animals showed an increased locomotor and stereotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit the expression of, stress-induced sensitization to the behavioral effects of amphetamine. However, the ability of metyrapone treatment to enhance the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate that chronic metyrapone treatment will produce stimulant sensitization when given alone.     

Fear conditioning-related changes in cerebellar Purkinje cell activities in goldfish

Background

Repeated morphine exposure can induce behavioral sensitization. There are evidences have shown that central gamma-aminobutyric acid (GABA) system is involved in morphine dependence. However, the effect of a GABA_B receptor agonist baclofen on morphine-induced behavioral sensitization in rats is unclear.

Methods

We used morphine-induced behavioral sensitization model in rat to investigate the effects of baclofen on behavioral sensitization. Moreover, dopamine release in the shell of the nucleus accumbens was evaluated using microdialysis assay in vivo.

Results

The present study demonstrated that morphine challenge (3?mg/kg, s.c.) obviously enhanced the locomotor activity following 4-day consecutive morphine administration and 3-day withdrawal period, which indicated the expression of morphine sensitization. In addition, chronic treatment with baclofen (2.5, 5?mg/kg) significantly inhibited the development of morphine sensitization. It was also found that morphine challenge 3?days after repeated morphine administration produced a significant increase of extracellular dopamine release in nucleus accumbens. Furthermore, chronic treatment with baclofen decreased the dopamine release induced by morphine challenge.

Conclusions

Our results indicated that gamma-aminobutyric acid system plays an important role in the morphine sensitization in rat and suggested that behavioral sensitization is a promising model to study the mechanism underlying drug abuse.     

Sensitization to cocaine and dopamine autoreceptor subsensitivity in the nucleus accumbens

It has been suggested that dopamine autoreceptor subsensitivity may play a role in cocaine-induced behavioral sensitization. In order to evaluate this hypothesis, we administered cocaine to rats daily (15 mg/kg ip × 2 days, 30 mg/kg ip × 5 days) and then monitored nucleus accumbens dopamine during the local administration (through the dialysis probe) of the D₂/D₃ agonist, quinpirole (0, 0.1, 1, and 10 μM). Our results indicate that, relative to saline-pretreated control animals, repeated cocaine administration impaired the ability of quinpirole to decrease extracellular dopamine 1–2 days after the last drug injection. However, quinpirole was equipotent at reducing accumbal dopamine in cocaine- and saline-treated animals following a 21–22 day withdrawal period. These results demonstrate that repeated cocaine produces a short duration functional tolerance in the capacity of autoreceptor stimulation to inhibit accumbal dopamine release. © 1995 Wiley-Liss, Inc.     

Chronicl-DOPA-pretreatment of rats: an electrophysiological and biochemical study in the basal ganglia

Treatment of rats withl-DOPA (251.25 mg as the methyl ester HCl/kg) plus benserazide (B, 50 mg/kg) (l-DOPA+B), twice daily (i.p.) for 5 days or 12 days resulted in the dopamine (DA) neurons ofthe substantia nigra pars compacta becoming subsensitive to the rate-depressing effects ofd-amphetamine (i.v.) 16 to 24 h after the last chronic drug dose. In contrast, pretreated rats were significantly less sensitive than control rats to the rate depressant effects of apomorphine (i.v.) after 12, but not 5 days ofl-DOPA+B-pretreatment. After 5, but not 12 days ofl-DOPA+B-pretreatment, a significant increase in the number of spontaneously active DA neurons was noted in the substantia nigra pars compacta. Caudate tyrosine hydroxylase was examined and a significant increase in apparent V_max was noted after 5 days ofl-DOPA+B, with no apparent change being noted in K_m for cofactor. At this time, no change was noted in caudate DA or HVA concentrations. Several distinct processes may be occuring in response to thel-DOPA+B-pretreatment: (1) the DA autoreceptors located on cell bodies in the substantia nigra have become subsensitive after 12 days ofl-DOPA+B-pretreatment; (2) the subsensitivity tod-amphetamine seen after both chronic schedules is probably unrelated to the subsensitive DA autoreceptors and may depend upon homeostatic alterations in neurotransmitter systems other than those utilising DA; (3) the activation of tyrosine hydroxylase may be a reflection of the increase in the number of spontaneously active units.     

Behavioral and dorsal raphe neuronal activity following acute and chronic methylphenidate in freely behaving rats

Concomitant behavioral and dorsal raphe (DR) neuronal activity were recorded following acute and chronic dose response of methylphenidate (MPD) in freely moving rats previously implanted with permanent semi-microelectrodes using telemetric (wireless) technology. On experimental day (ED) 1, the neuronal and locomotor activity were recorded after saline (baseline) and MPD (0.6, 2.5 or 10.0 mg/kg) injection (i.p.). Animals were injected daily with a single dose of MPD for five consecutive days (ED 2–6) to elicit behavioral sensitization or tolerance. After three washout days, the neuronal and locomotor activity recording was resumed on ED 10 followed by saline and MPD rechallenge injection. The main findings were: (1) the same dose of chronic MPD administration elicited behavioral sensitization in some animals and behavioral tolerance in others. (2) 46%, 56% and 73% of DR units responded to acute 0.6, 2.5 and 10.0 mg/kg MPD respectively. (3) 89%, 70% and 86% of DR units changed their baseline activity on ED 10 compared to that on ED 1 in the 0.6, 2.5 and 10.0 mg/kg MPD groups respectively. (4) A significant difference in ED 10 baseline activity was observed in the DR neuronal population recording from animals expressing behavioral sensitization compared to that of animals expressing behavioral tolerance. (5) 89%, 78% and 88% of DR units responded to chronic 0.6, 2.5 and 10.0 mg/kg MPD respectively. (6) The DR neuronal population recording following acute MPD on ED 1 and rechallenge MPD on ED 10 from animals expressing behavioral sensitization was significantly different from the neuronal population recorded from animals exhibited behavioral tolerance. The correlation between the DR neuronal activity and animal's behavior following chronic MPD exposure suggested that the DR neuronal activity may play an important role in the expression of behavioral sensitization and tolerance induced by chronic MPD administration.     

Effects of repeated injections of cocaine on catecholamine receptor binding sites, dopamine transporter binding sites and behavior in rhesus monkey.

In order to determine if repeated injections of cocaine produced long-lasting alterations in catecholaminergic binding sites, rhesus monkeys were treated with saline (1.0 ml/15 kg) or cocaine (3.0-4.0 mg/kg) four times daily for 14 consecutive days and sacrificed two weeks after the last injection. The densities of dopamine D1 receptor binding sites, dopamine transporter binding sites and beta adrenergic receptor binding sites were significantly decreased in caudate nucleus to 51%, 17% and 61% of control, respectively, two weeks after repeated cocaine injections. There were no differences in D2 receptor binding site densities in the caudate, nor were there differences in binding sites between groups in the other brain regions examined: prefrontal cortex (D1, D2, dopamine transporter, beta), nucleus accumbens (D1, D2, dopamine transporter) and substantia nigra (D2). Behavioral observation showed that the cocaine-treated monkeys became sensitized to the repeated injections. Early in the regimen, these animals displayed stereotypic grooming, buccal movements and visual checking after each injection that differed significantly from the saline-treated animals. As the regimen progressed, the frequency of grooming decreased while the frequencies of visual tracking and splayed legs increased in a manner consistent with the development of behavioral sensitization. Together, these findings suggest that the caudate nucleus may be more sensitive than other dopamine-containing brain regions to long-lasting pre- and post-synaptic effects of repeated cocaine administration, and that the changes seen in dopaminergic neurons may be related to behavioral sensitization.     

Dose-related effects of continuous levodopa infusion in rats with unilateral lesions of the substantia nigra

Preclinical studies in rats have demonstrated markedly different effects of intermittent and continuous levodopa administration on many biochemical and functional parameters yet the dose regimens employed have not been fully evaluated. In this study, rats with unilateral 6-hydroxydopamine nigral lesions were administered levodopa (0–1200 mg/kg/day) and benserazide (25 mg/kg/day) subcutaneously via osmotic minipump and studied 20–22 h later for rotational behavior, striatal dopamine concentration, and regional cerebral glucose utilization (RCGU). Levodopa infusion at 100 mg/kg/day resulted in minimal rotation and minimal striatal dopamine replacement but did increase RCGU in the subthalamic nucleus and decrease RCGU in the lateral habenula, consistent with a selective inhibition of the striatopallidal GABAergic (indirect striatal output) pathway. Levodopa infusion at 100 mg/kg/day did not significantly increase RCGU in the entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), as does the acute injection of levodopa (25–50 mg/kg), indicating that this levodopa dose elicits only part of the spectrum of metabolic effects elicited by acute levodopa injection. Higher doses of levodopa (400–1200 mg/kg/day) resulted in moderate rates of rotation, dose-dependent increases in striatal dopamine, and increased RCGU in the EP and SNr, consistent with activation of the striatonigral GABAergic (direct striatal output) pathway. In the EP and SNr, the two major output nuclei of the basal ganglia, levodopa infusion at 800 and 1200 mg/kg/day reproduced the metabolic effects elicited by acute injection of levodopa. These results demonstrate, for the first time, dose-dependent effects of levodopa on distinct populations of striatal output neurons which may be relevant to the pathogenesis of levodopa-induced dyskinesias in Parkinson's disease. The minimal dopamine replacement and partial functional effects elicited by levodopa infusion at 100 mg/kg/day indicate the need for caution in the interpretation of prior studies of continuous levodopa infusion which employed this dose.