Subsensitivity of striatal and mesolimbic dopamine target cells after repeated treatment with apomorphine dipivaloyl ester

Summary The effects of acute and repeated treatments with the dipivaloyl ester of apomorphine on behaviour and brain dopamine metabolism were compared in rats. A single injection of the ester (50 mg/kg i.p.) induced a stereotyped behaviour lasting for at least 6h and a concomitant decrease in striatal HVA levels. After repeated treatment (twice daily for 7 days) with the drug, both the stereotyped behaviour and the decreases in striatal HVA levels were attenuated as compared to acute treatment; the minimal dose tested which induced this tolerance was found to be 25 mg/kg i.p. The minimal length of treatment with 50 mg/kg of the ester after which tolerance was observed was 3–4 days. The ED₅₀ for haloperidol-induced catalepsy was about 4 times lower in rats treated with apomorphine dipivaloyl ester (50 mg/kg) for 7 days than in naive rats. Similarly, a shift to the left of the haloperidol doseresponse curve for the increase in striatal dopamine metabolite levels was observed in rats treated subacutely with the ester as compared to control rats.Repeated treatment (7 days) with the dipivaloyl ester of apomorphine also attenuated the decrease in NVA levels seen with acute treatment in nucleus accumbens and tuberculum olfactorium; however, the threshold dose inducing tolerance in limbic regions was higher than in striatum.No difference in the brain concentrations of apomorphine was found after acute and repeated treatments with the ester.Thus, the present study provides evidence for the development of subsensitivity of dopamine receptors after repeated administration of apomorphine dipivaloyl ester.     

Behavioral sensitization to beta-phenylethylamine (PEA): enduring modifications of specific dopaminergic neuron systems in the rat

Repeated daily administration of an endogenous trace amine, beta-phenylethylamine (PEA), produces behavioral sensitization such that the intensity of PEA-induced stereotyped behaviors in rats increases gradually during the treatment, and a challenge injection with PEA reinstates the enhanced stereotypy even long after withdrawal. In the present study, we examined the neurochemical changes in the central dopaminergic neuron systems in the rat for 7 drug-free days after repeated treatment with PEA (50 mg/kg, IP day for 14 or 28 days). During withdrawal, a decrease in steady-state levels of tissue dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC), was found in the mesolimbic DA nerve terminal areas of the rat brain receiving repeated PEA treatment. Fifteen minutes after challenge administration of PEA at varying doses from 6.3 to 75 mg/kg, the rats with repeated PEA treatment required smaller doses of PEA challenge than the rats with acute PEA treatment in order to obtain a significant decrease in striatal DOPAC content compared to the saline control in each treatment group. These results imply that the behavioral sensitization to PEA is accompanied by enduring modifications of the specific dopaminergic neuron systems in the rat brain. This suggestion was strongly supported by the results of the study using in vivo intracerebral dialysis, which indicated that 25 mg/kg PEA challenge elicited a remarkable increase in the extracellular DA concentrations in striatal perfusates collected from the PEA-pretreated rats, in accordance with the intensity of stereotyped behaviors. These findings argue that the hyper-responsiveness to PEA of the striatal dopaminergic neuron systems persists long after withdrawal from repeated treatment with PEA.     

Capsaicin decreases B-endorphin hypothalamic concentrations in the rat

Capsaicin has been administered intraventricularly to adult rats and subcutaneously to neonatal rats. Adult rats were killed three, five, seven and fifteen days after capsaicin administration, while rats treated neonatally were killed when six months old. In the adult rats capsaicin induced a decrease in hypothalamic B-endorphin concentrations three, five and seven days after treatment, while they returned to normal values by day fifteen. A decrease in B-endorphin hypothalamic concentrations was also present in rats treated neonatally, while substance P, somatostatin and met-enkephalin concentrations were never affected by capsaicin treatment.     

Elevation of Met5-enkephalin and beta-endorphin hypothalamic content in rats receiving anorectic drugs: differences between D-fenfluramine and D-amphetamine

D-Fenfluramine, an anorectic that releases serotonin (5-HT), repeatedly injected in rats (15 mg/kg per day) enhanced the met5-enkephalin and beta-endorphin content of the hyhpothalamus. The onset of this effect was slow, reaching a peak at 5 days; the increase in beta-endorphin gradually declined toward control level while the drug was still being administered although that of met-enkephalin persisted for 15 days. The elevation of the opioid peptide content of the hypothalamus was temporally associated with a slowing in the rate of body weight increase. A transient, small, increase in striatal met-enkephalin content was also induced by repeated D-fenfluramine injections; however the met-enkephalin content of frontal cortex, hippocampus and brainstem was not affected. A modification of the beta-endorphin content of hypothalamus was not seen after acute injection of D-fenfluramine or D-amphetamine but an increase was observed during repeated treatment with D-fenfluramine. Repeated injections of D-amphetamine for 5 days (4.5 mg/kg per day) failed to increase either the met-enkephalin or the beta-endorphin content of the hypothalamus. These data suggest that the anorexia elicited by repeated injections of D-fenfluramine but not that elicited by D-amphetamine, includes a participation by hypothalamic and beta-endorphin stores.     

Effects of subchronic treatment with selegiline on L-DOPA-induced increase in extracellular dopamine level in rat striatum

Selegiline is used an adjunct to L-DOPA therapy. We investigated extracellular striatal dopamine (DA) level in awake rats treated with L-DOPA and/or selegiline using a microdialysis method. Rats given 10 mg/kg, i.p. per day selegiline for 7 days were administered with a single dose of 100 mg/kg, i.p. L-DOPA 0 (3 h), 1, 3, 7, 14, 21, or 28 days after the last selegiline treatment. Carbidopa was administered 0.5 h before L-DOPA administration. The significant increase in basal DA level before L-DOPA treatment persisted until 1 day after the last selegiline treatment, and the significant decrease in basal DOPAC level persisted for more than 28 days. Thus, selegiline affected DA catabolism for more than 28 days. Total monoamine oxidase (MAO) and MAO-B activities at day 0 decreased by 22% and 5.7%, respectively. The significant enhancement of L-DOPA-induced increase in DA level was observed until 3 days after the last selegiline treatment. Next, the effects of reducing L-DOPA dose by 25% were examined 3 h after the last selegiline treatment. A dose-dependent decrease in DA level was observed, indicating that DA level in selegiline-treated rats can be controlled by L-DOPA dose.     

Correlation between catalepsy and dopamine decrease in the rat striatum induced by neuroleptics.

The time-course of the development of catalepsy was well correlated with that of a decrease in dopamine in the corpus striatum in rats after the subcutaneous administration of 10 mg/kg haloperidol. The striatal dopamine was decreased by a subcutaneous injection of haloperidol in the same dose-dependent manner as the catalepsy was intensified with increasing doses of the drug. By repeated administration of haloperidol or trifluperidol, the catalepsy in rats was intensified, and the dopamine decrease in the rat striatum was extended through 10 days treatment. However, by a repeated administration of ID-4708, a new butyrophenone compound, the intensity of catalepsy and the dopamine decrease induced by its initial administration was little altered. An oral administration of 100 mg/kg chlorpromazine produced moderate catalepsy and decreased the striatal dopamine to 80% of the value for control animals. No catalepsy or only slight catalepsy was observed after the administration of thioridazine, clozapine and sulpiride, and a decrease of dopamine in the striatum did not occur.     

Hypophysectomy fails to affect the supersensitivity of striatal dopamine target cells induced by prolonged haloperidol treatment

The influence of hypophysectomy on biochemical indices of striatal dopamine target cell supersensitivity induced by prolonged haloperidol treatment was investigated in the rat. Hypophysectomy itself did not modify dihydroxyphenylacetic acid (DOPAC) levels but slightly enhanced acetylcholine concentrations in the striatum. Hypophysectomy failed to affect the ability of haloperidol, apomorphine and pergolide to alter these biochemical parameters after acute administration. Prolonged administration of haloperidol (by means of osmotic minipumps delivering 2.5 micrograms/h) for 14 days caused a decrease in DOPAC and an increase in acetylcholine levels in the striatum during withdrawal; these effects were of a similar magnitude in sham-operated and hypophysectomized rats. Moreover, there was a similar degree of tolerance to the elevation of DOPAC and to the diminution of acetylcholine concentrations in striatum in response to challenge with haloperidol during withdrawal in sham-operated and hypophysectomized animals. Finally, a similar supersensitive biochemical response to pergolide (decrease in DOPAC and increase in acetylcholine levels) was observed in both hypophysectomized and sham-operated animals after prolonged haloperidol treatment. These data suggest that hypophyseal factors do not affect the development of striatal dopamine target cell supersensitivity caused by prolonged haloperidol treatment.     

Subsensitivity of the rat striatal dopaminergic system after treatment with bromocriptine: effects on [3H]spiperone binding and dopamine-stimulated cyclic AMP formation

Summary Repeated daily administration of the dopamine (DA) agonist bromocriptine (15 mg/kg; s. cut.) to rats led to a time dependent decrease in the in vitro binding of [³H] spiperone to striatal membranes. Kinetic analysis of [³H]spiperone binding after 2 and 7 days of bromocriptine treatment showed a 25–50% reduction in the total number of binding sites with no change in their affinity for spiperone. These was also a decreased accumulation of cyclic AMP (cAMP) in striatal slices in response to DA after bromocriptine treatment. The DA-sensitive adenylate cyclase in striatal homogenates, however, remained unchanged in bromocriptine treated rats. There was also no change in cyclic nucleotide phosphodiesterase activity in striatal tissue after bromocriptine treatment. Furthermore, incubation of striatal slices in the presence of the phosphodiesterase inhibitor isobutylmethylxanthine did not alter the decreased cAMP response to DA after 2 days of bromocriptine treatment. These results suggest that a decreased number of DA receptor sites may be responsible for the reduced cAMP response to DA in striatal slices after bromocriptine treatment.M. Q. was supported by a fellowship from the Canadian Medical Research Council     

Effects of naftidrofuryl oxalate on microsphere embolism-induced decrease in regional blood flow of rat brain.

1. The purpose of the present study was to determine whether naftidrofuryl oxalate (naftidrofuryl), a vasodilator, is capable of improving brain regional blood flow of animals in sustained ischaemia. 2. Cerebral ischaemia was induced by injecting 900 microspheres (48 microns in diameter) into the right internal carotid artery of rats. Cerebral blood flow of brain regions was measured by a hydrogen clearance method on the 3rd, 7th and 28th days after the onset of ischaemia. Ischaemic animals were treated with naftidrofuryl, 15 mg kg-1 day-1 i.p., from the first to 28th day. 3. Microsphere-embolism caused a sustained decrease in cortical and striatal blood flow over a period of 28 days, whereas hippocampal blood flow was decreased on the 3rd day but not on the 7th or 28th day. On the 3rd day, the striatal and hippocampal but not cortical blood flow of naftidrofuryl-treated, microsphere-embolized rats was higher than untreated rats. On the 7th and 28th days, the cortical and striatal blood flow of the treated and untreated animals did not differ. 4. Brain slices from microsphere-embolized rats contained areas, which were not stained with triphenyltetrazolium chloride (TTC), to a similar degree on the 3rd, 7th and 28th days, indicating the genesis of cerebral infarction. TTC-unstained areas of microsphere-embolized rats that had received naftidrofuryl treatment were smaller than those of untreated rats on the 3rd and 7th days, but not on the 28th day.(ABSTRACT TRUNCATED AT 250 WORDS)     

GABAergic influences on barbital withdrawal induced convulsions

Animals which had been long-term treated with increasing concentrations of sodium barbital in the drinking water were killed 30 min or 72 hr after the last day of treatment, to determine striatal GABA levels and turnover rate. The effects of pentobarbital administration on GABA metabolism of rats withdrawn or not withdrawn from barbital were also studied. Barbital withdrawal induced a significant decrease in striatal GABA levels and also in the turnover rate after pentobarbital treatment. The latter effect was greater in rats killed 72 hr after drug removal. In control animals, pentobarbital treatment increased striatal GABA levels but did not affect the turnover rate. Barbital removal also made the rats less responsive to the effects of pentobarbital on striatal GABA levels. These results suggest the participation of a central GABAergic system in barbital withdrawal convulsions.     

Acute and chronic effects of lithium chloride on GABA-ergic function in the rat corpus striatum and frontal cerebral cortex

Summary The acute (1 h, i. p.) and chronic (14 days, p. o.) effects of LiCl treatment upon GABA-ergic neurons were studied in the rat corpus striatum and frontal cerebral cortex.One hour after a single injection of LiCl the activity of glutamic acid decarboxylase (GAD) was reduced by 29% in the striatum (2 meq/kg LiCl) and by 38% in the cerebral cortex (10 meq/kg LiCl). In contrast, striatal GAD was activated by 34% 1 h after the injection of 10 meq/kg of LiCl; this dose also reduced the endogenous striatal GABA level by 24%.After 14 days of oral LiCl administration (2 meq/kg/day): a) cortical GAD activity was enhanced by 50% and GABA concentration was decreased by 28%; b) no changes were observed in the striatum.These findings suggest that: LiCl administration stimulates GABA-ergic function in specific areas (depending on the dose and length of treatment) increasing both GAD activity and probably GABA release. This occurs in the striatum after acute treatment only with a high dose, and in the frontal cerebral cortex after chronic treatment with a low dose.     

Effect of repeated methylphenidate administration on presynaptic dopamine and behaviour in young adult rats.

Methylphenidate, a dopamine reuptake inhibitor, is the most common treatment for attention-deficit hyperactivity disorder and may be prescribed for years, despite little evidence of any long-term benefit, nor knowledge of potential chronic side-effects. Therefore, this study examined the acute and longer-term behavioural effects and assessed striatal dopamine function following subchronic methylphenidate administration to adolescent rats. Male hooded Lister rats received methylphenidate (4 mg/kg i.p. twice daily for 4 days) or saline (1 ml/kg) and the acute locomotor and stereotype behaviour was monitored on days 1 and 4, novel object exploration on day 2 and, following 12 days drug withdrawal, the long-term effect examined on social interaction on day 16. Ex-vivo K+ (20 mM)- and methylphenidate (0.1 mM)-induced [3H]dopamine release from striatal slices and striatal monoamine content were measured on day 18. Compared with saline, methylphenidate induced mild hyperactivity without stereotypy but did not alter novel object exploration and, following withdrawal, had no long-term effect on social interaction. In striatal slices from controls, both K+ and methylphenidate elevated [3H]dopamine release (p < 0.01) while only combined treatment elevated release in methylphenidate pretreated rats, although striatal monoamine content was unaltered compared with control rats. In summary, a repeated dose of methylphenidate that had acute behavioural effects produced no long-term alteration in social interaction but attenuated presynaptic striatal dopamine function.     

Repeated paroxetine treatment reverses anhedonia induced in rats by chronic mild stress or dexamethasone.

The present study was designed to assess the effect of dexamethasone, a synthetic glucocorticoid receptor agonist, in the sucrose preference test in rats. Rats treated acutely with dexamethasone (5-10 mg/kg) showed a significant decrease in sucrose preference (anhedonia) in comparison to vehicle treated rats, although 1 mg/kg dexamethasone did not alter the sucrose preference. Daily paroxetine treatment (10 g/kg, i.p., 14 days) reversed the anhedonic effect of acute dexamethasone (5 mg/kg), while causing no increased sucrose preference in rats that received dexamethasone vehicle. The paroxetine vehicle treated rats showed anhedonia even 14 days after acute dexamethasone administration. Paroxetine (10 mk/kg, i.p. for 28 days) also reversed anhedonia induced by chronic mild stress (8 weeks). In conclusion, acute dexamethasone induced an enduring anhedonic state that was reversed by repeated paroxetine treatment. Thus, the present study adds new data to the evidence supporting an important role for glucocorticoid in depression.     

Effects of acute and chronic bupropion on locomotor activity and dopaminergic neurons

Acute administration of bupropion (10 or 30 mg/kg) to rats increased locomotor activity in a dose-related manner. The highest dose increased the dopamine (DA) concentration while both doses reduced the concentration of dihydroxyphenylacetic acid (DOPAC) in the striatum. The enhancement of locomotor activity and the decrease of striatal DOPAC concentrations were increased with chronic administration (up to 40 days) of bupropion. The rate of DA synthesis in the striatum was increased by the acute administration of d-amphetamine but was not altered by acute or chronic administration of bupropion.     

The effect of a single temazepam administration on enkephalin content in the striatum and hypothalamus of the rat

Temazepam, a benzodiazepine ataractic, given in a dose of 10 mg/kg ip to rats depressed the striatal contents of met-enkephalin and leu-enkephalin by 60 and 35% resp. The changes were most pronounced 30 min after the treatment. In the hypothalamus temazepam produced a short-lasting elevation of met-enkephalin content (225% of the control value). The pattern of changes produced by temazepam resembles that described for diazepam. This suggests that enkephalins participate in the pharmacological effects of benzodiazepine ataractics on the central nervous system.     

Catalepsy, hypermotility, increase of striatal acetylcholine release induced by morphine and Met-enkephalin as affected by prolonged hydrocortisone and ACTH treatment

In the rats treated with ACTH or hydrocortisone for 14 days the catalepsy induced by morphine was almost completely inhibited, while the haloperidol induced catalepsy remained unchanged. The morphine induced hypermotility was altered neither by prolonged treatment with ACTH nor by an acute glucocorticoid administration. Inhibition of Na/K ATPase by ouabain led to an increase of striatal acetylcholine (Ach) release, which was enhanced by Met-enkephalin. This effect of the opioid peptide was not demonstrable in the striata of ACTH or hydrocortisone pretreated rats. It is concluded that glucocorticoids are regulatory factors of the striatal opiate neurotransmission possibly via altered receptorial mechanisms.     

Neurochemical and behavioral effects of systemic and intranigral administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the rat

At doses of 5-10 mg kg-1, N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) produces in rats acute immobility, retropulsion, straub tail, piloerection, exophthalmos, salivation and clonic movements of the forepaws. It does not produce analgesia as measured by the tail test, nor does it produce permanent motor impairment after chronic or intranigral administration. The acute retropulsion and immobilizing effects can be blocked by methysergide. Administered acutely, NMPTP doubles levels of serotonin in the raphe nucleus and substantia nigra. At the same time, levels of dopamine increase in the caudate nucleus and decrease in the substantia nigra. The NMPTP-induced decrease in dopamine content of the substantia nigra persists in chronically treated rats, but there is no significant decrease in striatal dopamine. After chronic administration of NMPTP, striatal levels of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased by about 50%. Intranigral administrations of NMPTP (10 micrograms daily for 5 days) failed to produce a 6-hydroxydopamine-like lesion in the nigrostriatal system. These results indicate that NMPTP in the rat does not cause selective destruction of dopaminergic neurons, but it does produce acute tryptamine-like effects.     

Alterations in dopamine release from striatal slices of rats after chronic treatment with haloperidol

The effects of chronic treatment with haloperidol on spontaneous and electrically evoked dopamine (DA) release from striatal slices of rats were investigated in vitro. DA was measured by high-performance liquid chromatography coupled to an electrochemical detector. The superfusion with haloperidol caused a dose-dependent (100 nM-100 microM) reduction in the electrically evoked DA release from striatal slices of rats, which was not antagonized by the superfusion with apomorphine. Chronic administration of haloperidol (1 mg/kg per day for 21 days) caused a significant reduction in electrically evoked DA release as well as in spontaneous DA release from striatal slices 24 h after the last injection. Moreover, pretreatment with haloperidol prevented the reduction of the DA release evoked in response to haloperidol superfusion (1 microM). These results indicated that chronic administration of haloperidol reduced DA release from striatal slices of rats, accompanied by tolerance for the inhibitory effect of drug superfusion on evoked DA release.     

Effect of chronic nicotine treatment and withdrawal on rat striatal D1 and D2 dopamine receptors.

The effects on rat striatal dopamine receptors after chronic nicotine administration (3 and 12 mg kg-1 day-1), and after withdrawal from chronic nicotine (12 mg kg-1 day-1), were studied. After 21 days of continuous minipump infusion, the control (saline) and nicotine-treated rats were killed. The nicotine-withdrawal rats were killed on day 28, 7 days after pump removal. Radioligand studies were performed to determine D1 ([3H]SCH23390) and D2 ([3H]spiperone) striatal dopamine receptor affinity (Kd) and maximum binding (Bmax). Dopamine inhibition of antagonist binding at 3 concentrations and the effect of 0.3 mM GTP on binding affinity were examined. No statistically significant differences between control and nicotine treatment or withdrawal groups were noted in either D1 or D2 receptor Kd or Bmax. Although nicotine has been shown to affect nigrostriatal dopamine release, chronic treatment does not appear to alter overall striatal dopaminergic receptor binding parameters.     

Differences in the time course of dopaminergic supersensitivity following chronic administration of haloperidol,molindone, or sulpiride

The onset and persistence of changes in 3H-spiroperidol binding to dopamine (DA) D2 receptors were examined in rat mesolimbic and striatal regions following daily administration of haloperidol, molindone, or sulpiride for 3, 7, 14, or 28 days. Neuroleptic dose equivalencies were determined by inhibition of 3H-spiroperidol in vivo binding in several rat brain regions. Changes in locomotor and stereotyped responses to the specific DA D2 agonist quinpirole were examined 3 days after the last treatment dose. Haloperidol or molindone administration increased mean stereotypy scores and striatal DA D2 receptor densities throughout the 28-day treatment period. In contrast, mesolimbic DA D2 receptor densities were transiently increased and returned to control values after 28 days of haloperidol or molindone treatment. Sulpiride treatment increased mean stereotypy scores and striatal B_max values, but had no effect on locomotion or mesolimbic dopamine receptor density. Additionally, the magnitude of change in the various measures of brain DA function varied among the three neuroleptic treatment groups. Results from this study suggest that mesolimbic and striatal brain regions differ in their response to long-term neuroleptic administration and that drug choice may influence the magnitude of neuroleptic-induced dopaminergic supersensitivity.