Assessing pharmacologically induced dopamine receptor sensitivity changes with the ungerstedt turning model

Rats were lesioned unilaterally in the substantia nigra with 6-hydroxydopamine. Turning in response to apomorphine and amphetamine was assessed before and 5 days after 3-week treatment with haloperidol. After haloperidol withdrawal, contralateral turning, measured at 5 min following IP injection of 1 mg/kg apomorphine, was significantly less than before haloperidol treatment and ipsilateral turning, measured at 30 min following IP injection of 2 mg/kg amphetamine, was significantly greater than before the haloperidol treatment. These results suggest that dopamine receptor sensitivity increased on the unlesioned side compared to the lesioned side.     

Effects of dopamine supersensitivity on lateral hypothalamic self-stimulation in rats

Dopamine (DA) receptor supersensitivity was demonstrated by potentiated d-amphetamine stereotypy after a three-day treatment regimen in which the DA receptor blocker pimozide (4.0 mg/kg) was administered twice daily. Similarly-induced DA supersensitivity produced a significant increase in the rate of lever-pressing for lateral hypothalamic (LH) intracranial self-stimulation (ICSS) and a significant decrease in ICSS thresholds. No change from pretreatment baselines was observed in vehicle-treated control animals. Following three-day treatment with the noradrenaline-(NA) and DA-receptor blocker, haloperidol (4.0 mg/kg twice daily), a single injection of the alpha-adrenergic agonist clonidine (0.15 mg/kg) caused increased running behavior. In contrast clonidine decreased running in rats pretreated with chronic pimozide or vehicle. These results indicate an increase in the sensitivity of central NA receptors following chronic haloperidol but not chronic pimozide. Taken together, these findings were interpreted as a potentiation in the reinforcing properties of LH-ICSS after chronic pimozide treatments due to increases in the sensitivity of DA and not NA receptors.     

Time-dependent recovery from the effects of 6-hydroxydopamine lesions of the rat nucleus accumbens on cocaine self-administration and the levels of dopamine in microdialysates

Rationale Neurotoxin induced lesions of dopamine-releasing neurons that innervate the nucleus accumbens (NAcc) alter cocaine self-administration. In addition, elevated extracellular levels of NAcc dopamine (DA) are thought to be central to the biological mechanisms that underlie this behavior.Objectives This study assessed the long-term effects of 6-hydroxydopamine (6-OHDA) induced lesions of the NAcc on cocaine self-administration and the dialysate levels of dopamine ([DA]_d) in this structure to determine if recovery of drug intake was correlated with the DA response.Methods Rats implanted with jugular catheters and bilateral cannulas were trained to self-administer cocaine and subsequently received bilateral intracranial micro-injections of 6-OHDA or vehicle into the NAcc. The levels of DA and cocaine were determined in microdialysates of the NAcc collected during experimental sessions 6–7, 14–16, 29–30, and 44–46 days post-treatment.Results The 6-OHDA induced lesions significantly reduced cocaine self-administration for 3 weeks while vehicle treatment had a moderate effect for the first several days. Cocaine-induced increases in NAcc [DA]_d did not return to sham/vehicle treated control levels for 6 weeks in the lesioned group and DA content in the NAcc was 46% of control at 44 days post-lesion.Conclusions Although dopaminergic lesions of the NAcc produced profound effects on cocaine self-administration, responding recovered to control levels before cocaine-induced increases in NAcc [DA]_d while content of DA in the NAcc did not recover. These data suggest that the plasticity of neuronal systems in the NAcc related to cocaine self-administration and their response following 6-OHDA lesions is more complex than restoration of DAergic tone.     

Effects of dopamine D4 receptor-selective antagonists on motor hyperactivity in rats with neonatal 6-hydroxydopamine lesions

RATIONALE: Dopamine D4 receptor gene polymorphism has been repeatedly associated with attention deficit hyperactivity disorder (ADHD) and related personality traits. We recently reported that motor hyperactivity in an animal model of ADHD was dose-dependently reversed by CP-293,019, a D4 receptor-selective antagonist. However, behavioral effects of this agent may not be attributed exclusively to D4 receptor blockade, since it interacts with other sites including serotonin receptors. OBJECTIVES: To test further the hypothesis that D4 receptor blockade can reduce motor hyperactivity, behavioral effects of three chemically and pharmacologically dissimilar D4 antagonists were compared to that of ketanserin, a serotonin 5-HT(2A/2C) antagonist. METHODS: Selective dopamine lesions were made in male rats at postnatal day (PD) 5 with intracisternal 6-hydroxydopamine (100 microg) after desipramine pretreatment (25 mg/kg, SC) to protect noradrenergic neurons. Effects of D4 receptor-selective antagonists and ketanserin on lesion-induced motor hyperactivity were examined during the periadolescent period (postnatal days 23-26) with an infrared photobeam activity system. RESULTS: The D4 antagonists L-745,870 and U-101,958 dose-dependently inhibited motor hyperactivity in rats with neonatal lesions, whereas S-18126 lacked this effect at doses up to 30 mg/kg. None of these drugs affected motor behavior in sham control rats. In contrast, ketanserin produced apparent sedative effects in both lesioned and intact control rats without normalizing hyperactivity. CONCLUSIONS: Motor hyperactivity in this ADHD model was selectively antagonized by three of four dopamine D4 receptor antagonists evaluated, encouraging clinical assessment of D4 antagonists in patients with ADHD.     

Effects of chemical sympathectomy on hypertension and stroke in stroke-prone spontaneously hypertensive rats

Neonates of male stroke-prone spontaneously hypertensive rats (SHRSP) were treated with 6-hydroxydopamine (6-OHDA) on two different schedules. Peripheral sympathectomy, which was evaluated by the pressor response to exogenous noradrenaline (NA) or by the decrease in NA content of the spleen, was more evident in the NB-8 group (treated on 8th and 15th day after birth) than in the NB-1 group (treated at 6, 24 and 72 h after birth). The reduction of the NA content in the cerebral cortex was more prominent in the NB-1 group than in the NB-8 group. The blood pressure from 7 to 23 weeks of age was lower in the treated groups; NB-8 < NB-1 < control. Therefore, the reduction of blood pressure in the treated groups could be related to the severity of peripheral sympathectomy. The incidence of stroke wa also lower in the treated groups; 38, 11 and 0% in the control NB-1 and NB-8 groups, respectively. Loading with 1% NaCl solution from 11 weeks of age enhanced the rise in blood pressure and increased the incidence of stroke in each group of rats; 100, 20 and 40% in the control, NB-1 and NB-8 groups, respectively. However, the onset of stroke after exhibiting a severe hypertension (> 200 mmHg) was delayed in the treated groups. It seems that the activated tone in the peripheral sympathetic nerve is likely to participate in the development of spontaneous hypertension. In addition to the high blood pressure level, the activated tone of sympathetic nerve innervating the cerebral vasculature may be partly involved in the developement of stroke in the new strain of the SHR rats, SHRSP.     

Periventricular preoptic-hypothalamic lesions: Effects on isoproterenol-induced thirst

Lesions of the periventricular tissue surrounding the anteroventral third ventricle (AV3V) have been shown to block the dipsogenic properties of many experimental manipulations, including injections of angiotensin. The present study examines the ability of rats with ablations of the AV3V to initiate drinking responses following administrations of isoproterenol, a beta-adrenergic agonist which is thought to elicit drinking in part by activating the peripheral renin-angiotensin system. It was found that rats bearing lesions of the AV3V region drank significantly less across a range of doses than animals with sham lesions. When taken together with results from other studies, the present findings suggest that destroying the AV3V region inhibits the thirst-inducing properties of endogenous, as well as exogenous angiotensin.     

AngⅡ受体阻断剂与ACEI对肾性高血压大鼠血以及血浆和组织AngⅡ含量变化的影响

目的明确血管紧张素转换酶抑制剂(ACEI)卡托普利与血管紧张素Ⅱ(AngⅡ)受体阻断剂洛沙坦二类药物的药效和作用特点。方法本实验采用①离体血管环微量生物反应测定法检测AngⅡ引起的血管收缩反应;②建立两肾一夹型高血压大鼠模型;利用颈动脉插管法和鼠尾测压计检测血压,观测急性与慢性血压的变化;③用放射免疫法检测高血压大鼠血浆与肾组织中的AngⅡ含量。结果①离体血管环实验:AngⅡ能引起剂量依赖性的血管收缩反应,卡托普利(0.1 mg/kg)对低剂量AngⅡ收缩反应有轻度的抑制效应;随着外源性AngⅡ量增多,其抑制血管收缩作用明显减弱。同样条件下洛沙坦却能完全抑制AngⅡ所引起的血管收缩反应。②在体急性降压实验:最大有效剂量的卡托普利使模型鼠的平均动脉压由(18.4±3.9)kPa降为(8.7±1.2)kPa,降压幅度达到9.6 kPa,之后给洛沙坦最大降压有效剂量(2 mg/kg),血压未再下降;改变给药顺序,平均动脉压由(16.8±1.1)kPa降为(11.4±2.4)kPa,降压幅度为5.30 kPa,然后给最大有效降压剂量的卡托普利,血压持续降为(9.3±1.8)kPa,幅度达2.12 kPa,差异具有明显的统计学意义(P<0.05)。③慢性降压实验:高血压大鼠模型给予实验因素干预后,卡托普利组平均动脉压由(18.9±2.5)kPa降为(11.8±1.6)kPa,洛沙坦平均动脉压由(19.7±2.4)kPa降为(11.7±2.0)kPa,降压幅度分别为7.19 kPa和7.93 kPa,与对照组比较差异无统计学意义。④放射免疫实验:血浆中AngⅡ含量卡托普利组为(376±72)ng/L,明显低于对照组的(526±77)ng/L,而洛沙坦组为(1 036±159)ng/L,明显高于对照组(P<0.01),二者差异具有统计学意义。肾组织中AngⅡ含量,卡托普利组(392±81)pg/g,较对照组的(431±80)pg/g降低8.9%,洛沙坦组为(294±86)pg/g,较对照组降低32.4%(P<0.05)。结论①洛沙坦是通过阻断AngⅡ受体而发挥作用,而卡托普利只能够减少内源性AngⅡ的生成,离体状态下药效弱于洛沙坦。②急性在体实验卡托普利的最大降压效应强于洛沙坦;慢性在体实验二者药效差异无统计学意义。③长期作用下,肾组织的AngⅡ水平对调节血管张力起主要的作用,血浆中AngⅡ辅助起作用。     

Effect of chronic apomorphine on the development of denervation supersensitivity

We hypothesised that it would be possible to prevent the development of post-synaptic dopamine receptor supersensitivity to 6-hydroxydopamine lesions of the nigro-striatal tract in rats if they were constantly infused with the dopamine agonist apomorphine. Using osmotic minipumps to infuse apomorphine for 15 days in unilaterally lesioned rats, it was possible to delay the development of supersensitivity of the lesioned side for 9 days but not to prevent its eventual appearance. At the same time, evidence for the development of subsensitivity of presynaptic dopamine receptors of the intact side following chronic infusion of apomorphine was inferred from the production of rotations directed towards the lesioned side.     

Effects of 6-hydroxydopamine lesions of locus coeruleus on startle in rats

To examine the possible involvement of the norepinephrine (NE) containing neurons of the locus coeruleus in the modulation of behavioral reactivity to sensory stimulation, bilateral chemical lesions of the locus coeruleus were made by local injection of the catecholamine neurotoxin 6-hydroxydopamine. Both histochemical and biochemical analyses confirmed the effectiveness of the lesions in specifically eliminating the NE containing cell bodies of the locus coeruleus and reducing the NE content of the hippocampus and substantia nigra by 45% and 69% respectively. Rats were tested both 5 and 36 days after lesioning for their startle response to a repetitive series of tactile stimuli. On both days, locus coeruleus lesioned rats exhibited consistently reduced startle responses throughout the stimulus series. Additionally, lesioned rats showed a far more rapid rate of response habituation, particularly in the first test. The results are discussed in terms of a possible influence of the locus coeruleus on the process of sensitization to sensory stimuli.     

Mesolimbic dopamine neurons: Effects of 6-hydroxydopamine-induced destruction and receptor blockade on drug-induced rotation of rats

Bilateral injections of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens greatly reduced the dopamine content of this nucleus and the olfactory tubercle and blocked the ipsilateral rotation induced by amphetamine and methamphetamine in rats with unilateral 6-OHDA lesions of the caudate nucleus. In contrast, apomorphine-induced contralateral rotation was enhanced. Similar results were obtained when the destruction of forebrain noradrenergic neurons, normally produced by the nucleus accumbens 6-OHDA lesion, was prevented by desipramine (DMI) pretreatment. Microinjections of the dopamine receptor antagonist haloperidol into the nucleus accumbens did not spread to the olfactory tubercle, as assessed by the distribution of ³H-haloperidol, and blocked circling induced by amphetamine and apomorphine. Amphetamine-induced circling was less effectively blocked by haloperidol injected into the olfactory tubercle. These results suggest that activity at nucleus accumbens dopamine receptors can greatly affect circling behavior, perhaps by amplifying asymmetries of nigrostriatal activity.     

DuP 753, a nonpeptide angiotensin II-1 receptor antagonist,alters dopaminergic function in rat striatum

Summary The purpose of this study was to determine if the nonpeptide angiotensin II-1 receptor antagonist DuP 753 after, acute or chronic administration in vivo or after in vitro exposure, altered indices of dopaminergic function in rat striatum. In vivo studies examined the effect of acute and chronic 21-day administration of DuP 753 (10 mg/kg, s.c.) on levels of dopamine (DA) and its metabolite, dihydroxyphenylacetic acid (DOPAC). To determine if chronic treatment with DuP 753 was able to inhibit the pressor response to angiotensin II, a single i.v. dose of angiotensin II (0.1 g/kg) was administered 18 hours after the last dose of DuP 753. Acute DuP 753 resulted in significantly decreased (14%) levels of DA. Chronic DuP 753 resulted in increased (1.64 fold) levels of DOPAC, although DA levels were not altered. The single i.v. administration of angiotensin II resulted in increased (88%) DOPAC levels regardless of chronic DuP 753.The in vitro effect of DuP 753 (0.1 nM–1.0 M) on basal and field stimulation-evoked release of DA and DOPAC was determined in superfused striatal slices from drug naive rats. DA was not detected in these experiments. DuP 753 did not alter basal outflow of DOPAC. At low concentrations (1.0–10 nM), DuP 753 decreased (53%) stimulation-evoked DOPAC overflow; however, at concentrations greater than 10 nM, the inhibitory effect was diminished. Nomifensine (10 M; a DA uptake inhibitor) was included in the superfusion buffer in order to measure the effect of DuP 753 on the concentration of DA in superfusate. DuP 753 had no effect on basal DA and DOPAC outflow. Nomifensine markedly potentiated the DuP 753-induced decrease in stimulation-evoked DOPAC and DA overflow. Pargyline (10 M; a monoamine oxidase (MAO) inhibitor) was included with nomifensine in the superfusion buffer to examine the contribution of MAO to the DuP 753-induced decrease in dopaminergic neurotransmission. The effect of DuP 753 on DA overflow was not altered by the presence of pargyline. Additionally, angiotensin II (1 and 10 M) increased the overflow of DOPAC from striatal slices under control conditions. Therefore, the results in vitro suggest that acutely the agonist increases DA neurotransmission and the antagonist decreases DA neurotransmission. In contrast, chronic in vivo adminitration of DuP 753 resulted in increased striatal DOPAC levels indicative of an increased dopaminergic neurotransmission. Therefore, chronic in vivo administration of DuP 753 appears to result in a compensatory response of the dopaminergic system in striatum. Send offprint requests to L.P. Dwoskin at the above addressThis study was supported by a grant from the American Heart Association (Local Kentucky Affiliate). Portions of the results were presented in preliminary form at the Federation of American Society for Experimental Biology in Atlanta, GA, April, 1991     

Dissociation of responses to extracellular thirst stimuli following zona incerta lesions.

In male albino rats, bilateral lesions in the anterior zona incerta which decrease ad lib and food-deprivation water intake and osmotic thirst but leave hypovolemic thirst intact, severely impaired or abolished drinking in response to systemic injections of isoproterenol or central administration of angiotensin II. Water intake following water deprivation was reduced by one-fourth. Reasons for the dissociation of responses to hypovolemia, water deprivation, isoproterenol and angiotensin were suggested.     

Effects of single and long-term haloperidol administration on open field behavior of rats

The effects of single and long-term haloperidol administration on rat open field behavior was studied. Withdrawal from long-term haloperidol treatment induced a significant increase in all parameters of activity recorded, expcept rearing. There was a direct relationship between the impairment of motor function induced by the single haloperidol administration and the increment of general activity observed after withdrawal from repeated drug administration. The results were considered to be a consequence of the supersensitivity of central dopaminergic receptors probably, of the mesostriatal pathway, that occurred in order to maintain the animal's homeostasis.     

Effects of abrupt and gradual withdrawal from long-term haloperidol treatment on open field behavior of rats

The effects of abrupt and gradual withdrawal from long-term haloperidol treatment on rat open field behavior was studied. Abrupt withdrawal induced a significant increase in all parameters of activity observed except defecation, this increase being higher 72 h after the last haloperidol injection. Results were considered to be a consequence of supersensitivity of central dopaminergic receptors. These differences were almost unobservable in animals gradually withdrawn, thus suggesting that the phenomenon is reversible.     

On the cardiovascular action of dopamine in rats

Summary In rats anaesthetized with urethane the pressor effect of dopamine was not significantly altered by treatment with desipramine, which enhanced the action of noradrenaline on blood pressure and heart rate and abolished that of tyramine. Chemical sympathectomy with 6-hydroxydopamine in rats potentiated responses to noradrenaline and prevented the action of tyramine on blood pressure but did not significantly modify the pressor effects of dopamine. Furthermore, pretreatment with reserpine shifted the dose-response curves for dopamine and for tyramine on heart rate to the right. The dose-response curve for dopamine like that for noradrenaline on blood pressure was unaltered or shifted slightly to the left by reserpine. It is concluded that also in the rat an indirect, tyramine-like component contributes substantially to the cardiovascular action of dopamine.     

Long-lasting dopamine receptor up-regulation in amphetamine-treated rats following amphetamine neurotoxicity

Amphetamine (A) (9.2 mg/kg, IP), in combination with iprindole (I) (10.0 mg/kg, IP), caused long-lasting dopamine (DA) depletions in striatum (−49%, 4 weeks) but not in nucleus accumbens following one A/I injection. Striatal DA had recovered by 4 months. DA receptors (DAr) were up-regulated: 1) behavioral responses to a DA receptor agonist (apomorphine) were significantly elevated. These included apomorphine-induced locomotor activity (+ 103% and + 160%, on weeks 3 and 10) and apomorphine-induced stereotypy (day 10). 2) B_max for [³H]spiroperidol binding to striatal D₂ DAr (12 weeks) increased (+53%, week 12.). Injection of the DAr neuromodulator cyclo(leucyl-glycyl) (8 mg/kg/day × 4 days, SC) reversed the B_max increase. Thus toxicity (DA depletion) following high-dose amphetamine appears to induce compensatory changes in DAr. This DAr upregulation may explain the lack of abnormal movements despite enduring DA depletion. Additionally, the A/I paradigm as an animal model of long-lasting DAr up-regulation, could be used to screen neuromodulatory agents, like CLG, that might treat disorders (e.g., tardive dyskinesia and schizophrenia) thought to involve up-regulated DAr.     

Decreased intoxicating effect of ethanol in rats after 6-hydroxydopamine-induced degeneration of ascending dopamine pathways

Selective lesion of ascending dopamine pathways was made by injecting the neurotoxin 6-OHDA (8 μg/4 μl) bilaterally close to the nigro-striatal dopamine pathway of 18 male Long Evans rats. Similar injections of the vehicle were given to 10 control rats. Two months after the operation intoxication was measured in a tilting-plane test after an injection of ethanol (2 g/kg, IP). Ethanol impaired the performance of the 6-OHDA-treated rats significantly less than that of the controls. This finding suggests a role for the central dopamine neurons in the intoxicating effect of ethanol.     

Effects of discontinuous drug administration on the development of dopamine receptor supersensitivity during chronic trifluoperazine or cis-flupenthixol administration to rats

Rats received continuous or discontinuous administration of trifluoperazine or cis-flupenthixol in drinking water for up to 12 months. Continuous and discontinuous trifluoperazine administration had no consistent effect on apomorphine-induced stereotyped behaviour and there was no difference between drug treatments. Continuous and discontinuous cis-flupenthixol administration enhanced apomorphine-induced stereotypy, but there was no difference in the effect of the two drug treatments. Both continuous and discontinuous administration of trifluoperazine increased the number of specific striatal ³H-spiperone binding sites (B _max). Over the period of treatment there was no difference in the effects of the different treatments. Continuous or discontinuous cis-flupenthixol intake did not increase B _max after 6 or 12 months intake. Continuous or discontinuous neuroleptic treatment produced no difference in functional striatal dopamine receptor activity as judged by apomorphine-induced stereotyped behaviour. Ligand binding studies also suggest that the overall change in striatal receptor function is not affected by the use of a discontinuous drug regime.     

Cocaine and local anesthetics: Stimulant activity in rats with nigral lesions

Cocaine and several other local anesthetics were tested for their ability to induce rotational behavior in rats with unilateral 6-hydroxydopamine lesions of substantia nigra. Acute administration of bupivacaine, chloroprocaine, etidocaine, lidocaine, mepivacaine, procaine or tetracaine failed to induce active rotation in this sensitive assay of dopamine agonist activity. On the other hand, cocaine or dimethocaine treatment induced active rotation directed ipsilaterally to the lesioned side, indicating indirect dopamine agonist activity. Repeated administration of cocaine or dimethocaine at 1-week intervals resulted in increased rotational response (i.e., sensitization) while there was no suggestion of sensitization or induction of rotational behavior after weekly repeated administration of procaine or tetracaine. Daily administration of mepivacaine, procaine or tetracaine for 5 days also failed to induce rotation. Dimethocaine thus was found similar to cocaine and different from the other local anesthetics tested both in terms of frank stimulant activity and development of sensitization upon repeated administration.     

Effects of 6-OHDA lesions of the central medial nucleus accumbens on rat intravenous morphine self-administration

The function of dopaminergic innervations of the central medial nucleus accumbens in the processes maintaining intravenous morphine self-administration was assessed by lesioning with 6-OHDA and comparing drug intake with sham-vehicle treated littermates. Localized bilateral lesions of this structure resulted in significant increases in morphine intake shifting the dose-effect relationship to the right with twice the dose necessary to maintain prelesion rates of self-administration. Content of dopamine and dihydroxyphenylacetic acid was decreased in the nucleus accumbens after the lesion, but unchanged in the adjacent pyriform cortex and anterior caudate nucleus-putamen, while serotonin was significantly decreased in the pyriform cortex. High affinity uptake measurements also suggested nucleus accumbens dopaminergic and pyriform cortex serotonergic innervations to be affected by the lesion. The shift to the right in the dose effect relationship after the lesion suggests these neuronal systems to be excitatory to the processes mediating self-administration.