Analysis of the effects of intra-accumbens SKF-38393 and LY-171555 upon the behavioural satiety sequence

The outcome of intra-accumbens infusions of the dopamine D₁ receptor family agonist SKF-38393 and the D₂ receptor family agonist LY-171555 upon measures taken during the behavioural satiety sequence was assessed (0.01 µg, 0.1 µg, 1.0 µg in each case). Each drug was infused either separately, or together as a co-infusion in order to examine the functional relationship between these dopamine receptor subtypes within the nucleus accumbens. Measures of feeding did not change following infusions of SKF-38393 or LY-171555, whether infused separately or together. However, following separate infusion of the lowest dose tested of each drug (0.01 µg), the onset of resting was advanced. Moderate to high doses of SKF-38393 and LY-171555 (0.1 µg, 1.0 µg) infused separately resulted in a marked increase in activity at the expense of resting. Co-infusion of 0.01 µg of each drug also resulted in a dramatic increase in activity. Thus, measures of feeding behaviour were unchanged following excitation of D₁ and D₂ dopamine receptor families within the nucleus accumbens. In marked contrast, locomotor behaviour appeared to be under the potent synergistic control of these receptor families.     

中枢D_1和D_2亚型多巴胺受体与左旋四氢巴马汀镇痛的关系

在兔耳K~+透入测痛模型上,左旋四氢巴马汀(1-THP,8mg/kg,iv)的镇痛作用被双侧脑室注射多巴胺(DA)受体广谱激动剂DA或去水吗啡(Apo)以及选择性D_1受体激动剂SKF-38393减弱,被选择性D_2受体激动剂喹吡罗加强。另外,采用放射免疫分析和高效液相色谱——电化学检测法分别观察到1-THP镇痛时脑脊液中cAMP含量降低,及DA及其代谢产物DOPAC含量升高。提示1-THP镇痛与中枢D_1和D_2亚型DA受体有关,其中D_1受体的阻断导致其镇痛,而D_2受体的阻断不利于其镇痛。     

Place conditioning with dopamine D1 and D2 agonists injected peripherally or into nucleus accumbens

The conditioned place preference technique was used to assess the affective properties of the direct dopamine D1 agonist, SKF38393, and the direct D2 agonist, LY171555 (quinpirole). A three compartment apparatus was used: the animals' pre-experimental preference for the two choice compartments was equal and, within each experimental group, half the rats received drug pairings in each choice compartment. Intraperitoneal injections of SKF38393 produced conditioned place aversions at all doses tested (1.0–4.0 mg/kg); LY171555 produced weak conditioned place preferences at 1.0 and 2.0 mg/kg, but no reliable effect at 4.0 mg/kg. Bilateral intra-accumbens microinjections of SKF38393 produced strong preferences at all doses tested (0.5–2.0 µg/side); LY171555 produced strong preferences at two doses (0.5 and 1.0 µg/side) and no effect at a third dose (2.0 µg/side). These results suggest that activation of either D1 or D2 receptors in the nucleus accumbens can produce reward, and that D1 receptors (and possibly also D2 receptors) located elsewhere in the brain or in the periphery may mediate aversive effects.     

The anorectic effect of SK&F 38393, a selective dopamine D1 receptor agonist: a microstructural analysis of feeding and related behaviour

An observational study was undertaken to provide a microstructural analysis of the effects of the selective dopamine D₁ receptor agonist, SK&F 38393, on feeding and associated behaviours in the rat. Adult, male non-deprived rats were adapted to eating a meal of sweetened mash in a 30-min period. SK&F 38393 (3.0 and 10 mg/kg, SC) significantly reduced food consumption). It also reduced the frequency of feeding bouts and the local rate of eating, while there was an increase, at 10 mg/kg, in the mean duration of individual feeding episodes. The D₁ receptor agonist also reduced the total duration of locomotor activity, but did not affect the total duration of rearing, grooming, sniffing, oral behaviours (other than feeding), or resting. The frequency of bouts of locomotion, rearing, grooming, and sniffing were reduced by SK&F 38393. Consideration of the time-courses for the several responses suggested that SK&F 38393 did not materially affect the form and sequence of behavioural responses in the test, although some changes occurred.     

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.     

Mesolimbic dopaminergic mechanisms underlying individual differences in sugar consumption and amphetamine hyperlocomotion in Wistar rats

Individual differences within strains of rats have been demonstrated for dopamine-mediated behaviours and responses to dopaminergic drugs. Differences in mesolimbic dopamine function may underlie individual differences in some of these behaviours, including sugar consumption and amphetamine hyperlocomotion. The present study addressed two potential mechanisms for these differences in dopamine-mediated behaviours. The possibility of functional differences in dopamine receptor subtypes was tested in LOW and HIGH sugar feeders. LOW and HIGH feeders did not differ in their response to the partial D₁ agonist SKF-38393. The highest dose (2.5 mg/kg) of the D₂ agonist quinpirole stimulated locomotor activity to a greater degree in a subset of HIGH sugar feeders as compared with LOW feeders. All doses of amphetamine induced a greater locomotor response in HIGH feeders as compared with LOW feeders, and HIGH feeders exhibited higher levels of extracellular dopamine in the nucleus accumbens than LOW feeders following exposure to sugar and treatment with amphetamine. These results support the interpretation that LOW and HIGH feeders exhibit differences in presynaptic nucleus accumbens dopamine function that account for the expression of individual differences in sugar consumption and response to amphetamine treatments. A subset of HIGH feeders may also exhibit greater D₂ receptor function.     

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.     

Involvement of septal and striatal dopamine D-2 receptors in yawning behavior in rats

A behavioral study was performed in an attempt to understand the neuronal mechanisms involved in yawning behavior in rats. Subcutaneous injections of low doses of apomorphine (0.05–0.25 mg/kg) or piribedil (0.2–1.0 mg/kg), which preferentially activate presynaptic dopamine autoreceptors at those doses, evoked yawning. Marked yawning responses were also elicited by both 3-PPP (5–20 mg/kg, SC) and TL-99 (1–2 mg/kg, SC). SK & F 38393, a dopamine D-1 receptor agonist, at doses ranging from 0.1 to 8.0 mg/kg (SC) induced neither yawning nor stereotypy. However, bromocriptine (0.5–32.0 mg/kg, SC), a dopamine D-2 receptor agonist, induced yawning for which the dose-response curves showed a bell-shaped form. After a higher dose of 32 mg/kg (SC) bromocriptine, some rats occasionally showed sniffing and sawdust chewing. Yawning responses induced by systemic injection of apomorphine, piribedil, 3-PPP or bromocriptine were wholly suppressed after treatment with sulpiride (10 mg/kg SC), a dopamine D-2 receptor antagonist. Bilateral injections of apomorphine (20 g/side×2), piribedil (100 g/side×2) or 3-PPP (50, 100 g/side×2) into the striatum or septum also elicited marked yawning. The results indicate that low doses of apomorphine, piribedil, 3-PPP, TL-99 or bromocriptine elicit yawning by stimulating dopamine D-2 receptors and striatal and septal dopaminergic systems may be related to the occurrence of yawning behavior.     

The mode of action of bromocriptine following pretreatment with reserpine and α-methyl-p-tyrosine in rats

The ability of bromocriptine (BRC), a selective dopamine D-2 receptor agonist, to induce yawning responses was studied in rats pretreated with reserpine and -methyl-p-tyrosine (-MPT). BRC (1–20 mg/kg IP) evoked yawning responses, which were pronounced at 2.5 mg/kg and characterized by the head moving downward. Higher doses of BRC (5–20 mg/kg) dose-dependently delayed the onset and peak time of yawning. A low dose of the selective D-1 dopamine receptor agonist SK&F38393 did not induce yawning but enhanced the BRC-induced response. Pretreatment with reserpine (1 and 5 mg/kg SC), -MPT (100 and 300 mg/kg IP) and reserpine (1 mg/kg) plus -MPT (100 mg/kg) was able to significantly reduce BRC-induced yawning. The inhibitory effects were prevented by a low dose of SK&F38393 (0.5 mg/kg IP). In particular, combined treatment with reserpine (5 mg/kg) and BRC (10 and 20 mg/kg) elicited upright fighting and jumping behaviors which were inhibited by haloperidol (1 mg/kg IP), a non-selective D-1 and D-2 receptor antagonist, SCH23390 (0.05 mg/kg SC), a selective D-1 receptor antagonist, or sulpiride (20 mg/kg IP), a potent D-2 receptor antagonist, and were potentiated by SK&F38393 (0.5 mg/kg). SCH23390 (0.05 mg/kg) decreased BRC-induced yawning and the apomorphine (low doses)-induced potentiation of BRC yawning, and prevented the apomorphine (high doses)-induced reduction of BRC yawning. SCH23390 also inhibited apomorphine-induced stereotypy and BRC-induced potentiation of apomorphine stereotypy. Furthermore, haloperidol (0.02 and 1.0 mg/kg IP), sulpiride (20 mg/kg IP) or scopolamine (0.5 mg/kg IP) inhibited BRC-induced yawning, but prazosin (1.0 and 3.0 mg/kg IP), an -1 receptor antagonist, did not affect this behavior. These results suggest that BRC-induced yawning may be mediated via presynaptic dopaminergic neuron activity and that BRC, in addition to the stimulation of dopamine D-2 receptors, appears to require endogenous dopamine or receptor activation by another dopamine agonist (D-1 agonist) for the induction of yawning, stereotypy and upright fighting responses. The ability of dopamine agonists to induce these behaviors seems to depend apon the potency and ratio of D-2 versus D-1 receptor activity.     

Role of dopamine D-1 and D-2 receptor subtypes in mediating dopamine agonist effects on food consumption in rats

The effects of selective D-2 and D-1 dopamine (DA) receptor agonists on food consumption were investigated in free-feeding rats. A selective D-2 receptor agonist, (+)-4-propyl-9-hydroxynaphthoxazine (PHNO), increased the consumption of standard food pellets in the dose range of 7.5–120 g/kg, while SKF 38393 (5.0 mg/kg), a selective D-1 receptor agonist, decreased food pellet intake. The increase in food pellet intake produced by PHNO was blocked by haloperidol (an antagonist relatively selective for the D-2 receptor at the dose used, 0.05 mg/kg) and SCH 23390 (20 g/kg, a D-1 receptor selective antagonist). Increasing arousal by disturbance associated with repeated food weighting also increased food pellet consumption, but did not diminish PHNO-elecited feeding. However, the same range of doses of PHNO (7.5–120 g/kg) which increased food pellet intake decreased consumption of a liquid diet, and had no overall effect on a highly palatable liquid diet. The increase in consumption of solid food induced by PHNO appears to be secondary to enhancement of chewing behaviors. In contrast, the decrease in food intake induced by SKF 39393 may be due to a direct action of the drug on neural feeding mechanisms.