Effects of postpuberal castration on dopamine receptor sensitivity in the male rat brain

In order to study the effects of castration of brain dopamine (DA) receptor sensitivity, the effects of apomorphine on locomotor activity and striatal DA synthesis, as assessed by the dihydroxyphenylalanine (DOPA) accumulation after NSD-1015 treatment, were examined in normal and castrated male Sprague-Dawley rats pretreated with reserpine (5 mg/kg-18 hrs). There was an enhanced locomotor response to apomorphine (0.05-0.1 mg/kg) in castrated animals, as compared to sham operated controls. Furthermore, the increase in DOPA accumulation produced by the reserpine treatment was antagonized to a greater extent by apomorphine in the castrated animals. These results indicate an enhanced DA receptor sensitivity at both pre- and post-synaptic sites.     

Striatal dopamine receptor sensitivity after subchronic fencamfamine in the rat

Dopamine (DA) receptor sensitivity was assessed in the rat striatal system following subchronic treatment with fencamfamine or saline for 7 days (10 mg/kg i.p.). Seventy-two hours after the last injection the stereotyped behaviour and general activity induced by apomorphine or saline were evaluated. Apomorphine (2.0 mg/kg s.c.) induced a decrease of the stereotypic response when fencamfamine-pretreated animals were compared to saline-treated ones while apomorphine (0.02 mg/kg s.c.) failed to alter the general activity of animals, treated with fencamfamine or not. In biochemical experiments subchronic fencamfamine did not alter the effects of apomorphine (0.02 mg/kg s.c.) in reducing homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) striatal levels, when compared to saline. In addition we observed a slight but significant reduction in the total dopamine receptor content in the striatum labelled by [3H]spiroperidol. These findings indicate that subchronic fencamfamine treatment leads to a desensitization of postsynaptic DA receptors in rat striatum.     

ι-四氢巴马汀抑制羟考酮引起小鼠行为敏化的实验研究

目的探讨ι-四氢巴马汀(-tetrahydropalmatine,ι-THP)对羟考酮(oxycodone,oxy)行为敏化的影响和作用机制。方法采用连续7d给小鼠注射羟考酮(5mg.kg-1,ip),停药5d,d13用相同剂量的羟考酮(5mg.kg-1,ip)激发致小鼠行为敏化模型,利用红外光束自主活动测定仪测定小鼠自发活动的实验方法。结果ι-THP(6.25,12.5,18.75mg.kg-1,ig)一次或多次给药,对小鼠的自发活动没有影响,但ι-THP(18.75mg.kg-1,ig)能抑制羟考酮(5mg.kg-1,ip)引起的小鼠行为敏化的形成和表达。阿朴吗啡(0.5、1.0mg.kg-1,ip)给药后50min自身不影响小鼠的自发活动,但阿朴吗啡(1.0mg.kg-1,ip)能翻转ι-THP(18.75mg.kg-1,ig)抑制羟考酮小鼠行为敏化形成的作用,但不影响ι-THP抑制羟考酮行为敏化表达的作用。结论ι-THP抑制羟考酮引起的小鼠行为敏化的形成和表达,ι-THP抑制羟考酮行为敏化的形成可能与抑制DA受体相关,而抑制表达可能与抑制DA受体无关。     

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.     

Apomorphine-induced behavioural sensitization in rats: individual differences, role of dopamine and NMDA receptors

Apomorphine-induced behavioural sensitization was studied in male Wistar rats. The acute administration of apomorphine (0.5 mg/kg s.c.), a dopamine agonist, did not affect the locomotor activity of rats, but it caused stereotyped behaviour characterized by repeated gnawing, licking and sniffing. A significant increase in the locomotor activity became evident after repeated treatments with apomorphine (0.5 mg/kg twice daily for 14 days). However, there were marked individual differences in the sensitization of rats to apomorphine. One third of animals did not react with increased locomotor activity even after the 2-week administration of apomorphine, whereas the other one third needed only a few injections to display increased behavioural response to apomorphine. The behavioural response of the remaining one third of rats was between weak and strong responders. Simultaneously, the stereotyped behaviour occurred earlier and its intensity tended to be lower after repeated treatment with apomorphine. Nevertheless, the established changes of stereotyped behaviour did not correlate with the increase of locomotor activity. The administration of amphetamine (2.5 mg/kg, s.c.), an indirect dopamine agonist, but not a non-competitive NMDA antagonist dizocilpine (0.25 mg/kg i.p.), tended to cause a similar response profile with apomorphine in sensitized rats. The ED₅₀ values of the dopamine antagonists blocking apomorphine-induced increase in the locomotor activity were the following: 0.09 mg/kg for raclopride (dopamine D₂ antagonist), 0.023 mg/kg for SCH 23390 (dopamine D₁ antagonist), 6.42 mg/kg for clozapine (dopamine D₄ antagonist). This supports the involvement of D₁ and D₂ receptors in the expression of apomorphine-induced behavioural sensitization. The concomitant administration of dizocilpine (0.5 mg/kg), SCH 23390 (0.05 mg/kg), raclopride (0.1 mg/kg) and clozapine (20 mg/kg) with apomorphine (0.5 mg/kg twice daily for 2 weeks) antagonized the development of behavioural sensitization to apomorphine. Accordingly, at least three different molecular targets, namely dopamine D₁ and D₂, and NMDA receptors, are involved in the development of apomorphine-induced behavioural sensitization.     

Effect of acute and chronic tri-iodothyronine (T3) administration to rats on central 5-HT and dopamine-mediated behavioural responses and related brain biochemistry

The effects of both acute and chronic T₃ administration (100 μg/kg, s.c.) on behavioural responses in the rat mediated by 5-hydroxytryptamine (5-HT) and dopamine (DA) were examined 24 hr after the last injection of hormone at a time when serum T3 levels had almost returned to control values. Concomitant changes in the biochemistry of the 5-HT and DA systems were also examined.Administration of T₃ produced complex changes in both central DA and 5-HT systems. Both acute and chronic T₃ treatment enhanced the hyperactivity response to tranylcypromine (TCP) plus L-DOPA, with chronic treatment giving a much greater enhancement. Paradoxically, the accumulation of brain DA at 20 and 30 min after L-DOPA in chronically treated rats was less than in the controls. In order to study possible T₃ effects at the DA postsynaptic receptor, behavioural responses to the DA agonist apomorphine were measured. The activity responses were slightly attenuated in chronically treated rats only. Furthermore, the cataleptogenic effect of haloperidol (0.3 mg/kg) was significantly potentiated in chronically T3-treated rats only. Because striatal [³H]-spiroperidol binding was unaltered in chronically treated rats, it is thought that T₃ may produce an altered sensitivity postsynaptic to striatal DA receptors, or a change in activity of a modulatory neuronal system.It was found that 24 hr after either acute or chronic T₃ injection, the hyperactivity response to TCP + L-tryptophan (L-TP) was markedly enhanced [350% (chronic) and 220% (acute) increase above control activity]. A similar result was obtained for the 5-HT agonists (quipazine and 5-MeODMT).There was no change in whole brain 5-HT or TP accumulation measured 75 min following TP injection in the chronically-treated animals. This, together with enhanced 5-HT postsynaptic agonist responses, may be due to primary changes occurring at or beyond DA neurones, which appear to be interposed between 5-HT neurones and the site expressing the behavioural response.     

Acute effect of nicotine on the striatal dopaminergic system in the rat

The acute effects of nicotine (1.5 mg kg-1 day-1) on the striatal dopaminergic system have been examined in the rat. Twenty-four hours after nicotine treatment, spontaneous locomotor activity in response to apomorphine or (+)-amphetamine and the binding of [3H]spiperone to striatal particulates were determined. Pretreatment of nicotine did not alter the characteristics of [3H]spiperone binding to striatal dopamine receptors. The nicotine treatment did not affect the apomorphine-induced locomotor activity, however, the (+)-amphetamine-stimulated locomotor activity was attenuated. These results suggest that nicotine acutely alters the presynaptic dopaminergic activity without significantly affecting the postsynaptic dopaminergic function.     

The effect of dopamine receptor agonist treatment on haloperidol-induced supersensitivity in mice

Mice were pretreated with haloperidol (HP) (3-4 mg/kg/day in drinking water) or vehicle for 21 days. On the 25th day, HP-pretreated mice were supersensitive to the locomotor stimulant effects of apomorphine (after acute premedication with reserpine and alpha-methyl-p-tyrosine). This behavioural supersensitivity was accompanied by a 25-39% increase in the number of [3H]-spiperone binding sites in the striata of HP-pretreated mice. Short-term repeated administration of the dopamine (DA) agonist drugs d-amphetamine and L-DOPA during the HP withdrawal phase (days 22, 23 and 24) had no effect on either measure of DA receptor supersensitivity. In contrast, the administration of apomorphine on days 22, 23 and 24 enhanced the HP-induced behavioural supersensitivity but decreased the HP-induced elevation of the number of [3H]-spiperone binding sites. Apomorphine treatment alone did not alter either measure. The results do not support the hypothesis that supersensitive DA receptors can be down-regulated by short-term treatment with DA agonist drugs and, moreover, indicate that important discrepancies may exist between behavioural and biochemical measures of DA receptor supersensitivity.     

Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.     

The effect of chronic administration and withdrawal of amphetamine on cerebral dopamine receptor sensitivity

Mice with a 6-hydroxydopamine induced unilateral nigro-striatal lesion received (+)-amphetamine sulphate (2.5–20 mg/kg) over a 3-month period by daily incorporation into the drinking water. During this period the circling response to apomorphine hydrochloride (0.01–0.5 mg/kg, s.c.) was increasingly suppressed in comparison to control animals, while spontaneous locomotor activity increased. Following drug withdrawal the circling response to apomorphine remained suppressed two months later. However, spontaneous locomotor activity was also reduced up to 1 month following drug removal.The dopamine content of the lesioned side of the forebrain was 25% of the intact side in control animals and was not further reduced by amphetamine administration. The dopamine content of the intact forebrain was reduced by 43% during amphetamine administration and remained 18% depressed 1 month following drug withdrawal. No changes in 5-hydroxytryptamine or noradrenaline concentrations were observed in either the intact or lesioned side.This data, while showing that chronic amphetamine treatment can induce persistent changes in dopamine receptor sensitivity, can be interpreted in terms of increased striatal receptor sensitivity or as a decreased response of dopamine receptors in the nucleus accumbens.     

Behavioral and biochemical aspects of neuroleptic-induced dopaminergic supersensitivity: Studies with chronic clozapine and haloperidol

Rats were chronically injected with saline, clozapine, or haloperidol and tested for alterations in dopamine (DA)-mediated behavior, DA receptor binding, and both acetylcholine (ACH) concentration and cholien acetylase activity. Behaviorally, chronic haloperidol significantly enhanced apomorphine-induced chewing and sniffing stereotypies, associated with DA nigrostriatal activation, while clozapine selectively enhanced apomorphine locomotor activity and cage-floor crossing, behavior associated with DA mesolimbic activation. Biochemically, chronic haloperidol significantly enhanced ³H-spiroperidol binding in striatum and in mesolimbic loci (nucleus accumbens/olfactory tuberele) while chronic clozapine failed to produce such enhancement. Acute haloperidol induced an initial decrease in striatal ACH concentration followed by a return of ACH to normal levels within 1 week. There was no change in choline acetylase activity during the same time interval. These findings suggest that haloperidol may inhibit DA mechanisms in both the nigrostriatal and mesolimbic systems, but that the effect of clozapine on DA mechanisms may be specific to mesolimbic rather than striatal structures. At the same time, the lack of effect of clozapine on ³H-spiroperidol binding may indicate that behaviorally important changes in DA sensitivity can develop independent of changes in post-synaptic DA receptors. The pattern of cholinergic changes with chronic haloperidol suggests that the increase in striatal DA receptor number seen with chronic treatment re-establishes DA inhibition of cholinergic firing within the striatum.     

Repeated 7-OH-DPAT treatments: behavioral sensitization,dopamine synthesis and subsequent sensitivity to apomorphine and cocaine

Male Wistar rats (250–350 g) were injected (SC) daily with the putative selective dopamine D₃ receptor agonist, 7-OH-DPAT (0.01, 0.10, or 1.0 g/kg) or vehicle for 10 days. Fifteen minutes after each injection, the rats were tested for locomotor activity in photocell arenas for 20 min or 2 h. In two experiments, following this subchronic treatment, all rats received a challenge injection of apomorphine (1.0 mg/kg, SC), or cocaine (10 mg/kg, IP) on day 11, and were tested for locomotor activity. In a third experiment, dopamine synthesis in striatal and mesolimbic (nucleus accumbens-olfactory turbercle) tissue was assessed following acute or chronic 7-OH-DPAT treatments by measuring the accumulation of dihydroxyphenylalanine (DOPA) after treatment with a DOPA decarboxylase inhibitor. Major findings were as follows: a) acute 7-OH-DPAT treatment produced a dose-dependent decrease in locomotor activity; b) when tested for 2 h, the 1.0 mg/kg dose of 7-OH-DPAT produced a progressively greater increase in activity across the 10 test days (i.e., behavioral sensitization); c) subchronic treatment with 7-OH-DPAT did not result in cross-sensitization to either apomorphine or cocaine; d) acute treatment with the 1.0 mg/kg dose of 7-OH-DPAT significantly decreased dopamine synthesis in both striatal and mesolimbic regions; and e) chronic 7-OH-DPAT treatments did not affect basal dopamine synthesis in either brain region. Although the behavioral effects of 7-OH-DPAT were similar to the reported effects of the D₂/D₃ dopamine agonist quinpirole, the effects of repeated 7-OH-DPAT treatments differed from those of quinpirole in terms of cross-sensitization and basal dopamine synthesis. These results suggest that locomotor inhibition produced by low doses of 7-OH-DPAT is not related to dopamine autoreceptor stimulation, and the development of behavioral sensitization to high doses of 7-OH-DPAT is not due to the development of dopamine autoreceptor subsensitivity.     

Effects of B-HT 920 on nigrostriatal and mesolimbic dopamine systems in normosensitive and supersensitive rats.

1. B-HT 920, a D2 dopamine receptor agonist, was tested for its ability to exert presynaptic actions in normosensitive rats, and for possible postsynaptic actions in rats made 'supersensitive' to apomorphine. 2. In normosensitive rats, B-HT 920 (0.01-0.3 mg kg-1, i.p.) increased dopamine concentrations and lowered metabolite levels to a similar extent in all four terminal regions examined (medial prefrontal cortex, olfactory tubercle, nucleus accumbens, caudate-putamen). Analogous effects were seen for 5-hydroxytryptamine and its metabolite 5-hydroxyindoleacetic acid. 3. Rats which received bilateral 6-hydroxydopamine (6-OHDA) infusions into the caudate-putamen showed signs of postsynaptic dopamine receptor activation (stereotyped behaviour) in response to B-HT 920 (0.1 and 1.0 mg kg-1, i.p.) and to apomorphine (0.2 mg kg-1, s.c.). Similarly, B-HT 920 (0.1 mg kg-1) induced contralateral circling in rats that had received unilateral 6-OHDA infusions into the medial forebrain bundle; the rate of circling increased gradually over several weeks. 4. In contrast, bilateral 6-OHDA infusions into the nucleus accumbens resulted in a supersensitive (locomotor stimulant) response to a low dose of apomorphine (0.1 mg kg-1, s.c.), but not to B-HT 920 (0.01 and 0.1 mg kg-1). 5. In intact rats, withdrawal of chronic haloperidol treatment induced behavioural supersensitivity to apomorphine but not to B-HT 920.     

Effects of postnatal PCP treatment on locomotor behavior and striatal D2 receptor

Exposing the developing brain to the N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) has been shown to cause deficits in neurobehavioral functions, particularly on learning and memory and seizure sensitivity. Besides acting as a noncompetitive NMDA antagonist, PCP at high doses is known to affect the dopaminergic system. The present study assessed the effect of postnatal PCP treatment on locomotor activity and striatal dopamine (DA) D(2) receptor. Male and female rat pups were injected intraperitoneally (i.p.) with one of three doses of PCP (1, 3 and 5 mg/kg) or saline from postnatal day (PD) 5 to PD 15. Control and PCP-treated rats were given a challenge dose of PCP (10 mg/kg) as adults, and their locomotor behaviors--locomotion, stereotypy and ataxia--were scored. Postnatal PCP treatment did not have any significant effect in either sex on any of the PCP-induced locomotor behavioral paradigms studied. Separate groups of male and female rats were treated daily with saline or PCP (5 mg/kg i.p.) from PD 5 to PD 15 and sacrificed either as juveniles (PD 21) or adults, and D(2) receptor binding was measured in their striata. Striatal D(2) receptor density in juvenile and adult male postnatal PCP-treated rats did not differ from saline-treated controls. Adult female PCP-treated rats showed a slight but significant reduction in the maximal binding of striatal D(2) receptors. There was no effect of postnatal PCP on striatal D(2) receptor binding in female juvenile rats. These results support the hypothesis that blocking the developing NMDA receptor minimally affects PCP-induced locomotor behavior and the striatal D(2) receptor.     

Adaptive changes in the effects of angiotensin II on the convulsive-seizure threshold in cases of altered sensitivity of dopamine receptors

The adaptive changes in the effects of the neuropeptide angiotensin II (AT II) on the convulsive-seizure threshold were studied. AT II was injected intracerebroventricularly (i.c.v.) at a dose of 1 micrograms/mouse and convulsive seizures were induced by timed intravenous infusion of pentylenetetrazol (PTZ) in male albino mice. The sensitivity of DA receptors was altered by: repeated (14 days) intraperitoneal (i.p.) injection of the DA receptor antagonist pimozide (1 mg.kg-1) and subsequent withdrawal of the antagonist for 7 or 21 days; and repeated (14 days) subcutaneous (s.c.) injection of the DA receptor agonist apomorphine (0.5 mg.kg-1). The convulsive-seizure-increasing effect of AT II was enhanced after multiple administration of pimozide and particularly after its withdrawal for 21 days. This effect was also enhanced though to a lesser degree by repeated treatment with apomorphine. Apomorphine applied 21 days after withdrawal of pimozide decreased the pimozide-enhanced effect of AT II. All these adaptive changes in the effects of AT II on the PTZ convulsive-seizure threshold might be associated with the altered receptor-receptor (AT II-DA-GABA) interactions in the brain structures participating in the regulation of the convulsive-seizure threshold.     

Effects of daily SKF 38393, quinpirole,and SCH 23390 treatments on locomotor activity and subsequent sensitivity to apomorphine

In three experiments, male Wistar rats (250–350 g) were injected (SC) daily with the D₁-type dopamine receptor agonist, SKF 38393 (0.0, 4.0, 8.0, or 16.0 mg/kg), the D₂-type dopamine receptor agonist, quinpirole (0.0, 0.3, or 3.0 mg/kg), and/or the D₁-type dopamine receptor antagonist, SCH 23390 (0.0 or 0.5 mg/kg) for 8–10 days. After each daily injection, the rats were tested for locomotor activity in photocell arenas for 20 min. Following this subchronic pretreatment, all rats were challenged with the mixed dopamine receptor agonist apomorphine (1.0 mg/kg, SC) and tested for locomotor activity. SKF 38393 treatments produced a dose-dependent decrease in locomotor activity which did not significantly change across days. Quinpirole also depressed locomotor activity when first injected, but this quinpirole-induced inhibition of activity progressively decreased across days. When subsequently challenged with apomorphine, rats in both the SKF 38393 and the quinpirole pretreatment groups displayed greater locomotor activity than rats pretreated with only vehicle. Although SCH 23390 pretreatments did not affect subsequent sensitivity to apomorphine, SCH 23390 completely blocked the effect of quinpirole. These results suggest that although repeated D₁ receptor stimulation may be sufficient to induce behavioral sensitization to apomorphine, D₂ receptor stimulation also contributes to the effect.Portions of this paper were presented at the 1991 Society for Neuroscience meetings, New Orleans, La, USA.     

Antidepressant-like properties of the anti-Parkinson agent, piribedil, in rodents: mediation by dopamine D2 receptors

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.     

Effect of chronic treatment with NNC 756, a new D-1 receptor antagonist, or raclopride, a D-2 receptor antagonist, in drug-naive Cebus monkeys: dystonia, dyskinesia and D-1/D-2 supersensitivity

When given subcutaneously in gradually increasing doses, up to 1 mg/kg, NNC 756, a dopamine (DA) D-1 antagonist, failed to produce dystonia in eight drug-naive Cebus monkeys. In contrast, raclopride, a DA D-2 antagonist, produced dystonia at low doses (0.010-0.015 mg/kg). Following pre-treatment with raclopride, NNC 756 also induced dystonia at low doses (0.015-0.025 mg/kg), but continued treatment caused tolerance, and increasing doses of NNC 756 could be administered without induction of dystonia. NNC 756 induced a dose-dependent parkinsonism (slow, stiff movements and tremor), and more sedation than raclopride. After treatment for 14 weeks, withdrawal of raclopride (0.01 mg/kg) led to mild oral dyskinesia (tardive dyskinesia), while withdrawal of NNC 756 (1.0 mg/kg) led to a special grooming syndrome, but no dyskinesia. Withdrawal of raclopride as well as NNC 756 led to behavioural D-1 and D-2 dopamine supersensitivity in the form of increased dyskinesia (including grooming after NNC 756) induced by D-1 agonist (SKF 81297) and increased arousal induced by D-2 agonist (quinpirole). These results indicate that D-1 antagonists such as NNC 756 elicit fewer extrapyramidal symptoms (both acute and tardive) than D-2 antagonists such as raclopride, although extremely high doses may cause a special grooming withdrawal syndrome.     

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

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

Does tolerance develop to low doses of d- and l-amphetamine on locomotor activity in rats?

An observational study of the behavioural effects of chronic regimens of d- and l-amphetamine was designed to investigate possible mechanisms underlying any parallel behavioural changes: (1) Accumulation of p-hydroxynorephedrine in noradrenergic nerve terminals; (2) Altered sensitivity of dopaminergic receptors. The study revealed that locomotor activity seen with low doses of both isomers (2.0 mg/kg d- and 6.0 mg/kg l-) decreased with chronic once daily treatment. However, this was accompanied by an increase in directed sniffing activity and the behaviour came to resemble that seen with higher doses of amphetamine (8.0 mg/kg d- and 16.0 mg/kg l-). Nonsignificant decreases in locomotor activity and increases in directed sniffing to apomorphine administration were observed during chronic amphetamine treatment. These findings suggest that (1) p-hydroxynorephedrine, a metabolite of d- but not 1- amphetamine, does not play an important role in these alterations in behaviour with chronic treatment and (2) the tolerance to amphetamine observed under these conditions is due to an increased, rather than decreased, sensitivity of the rats to amphetamine.