Phencyclidine-induced potentiation of brain stimulation reward: acute effects are not altered by repeated administration

Rats were given daily injections of bromocriptine (5.0 mg/kg IP) or vehicle either in the home cage or in a test box equipped with photocells to measure locomotion. The animals were then tested in the photocell boxes for their locomotor response to cocaine (10.0 mg/kg IP), heroin (0.5 mg/kg IP), or quinpirole (0.1 mg/kg IP). Repeated bromocriptine in the test box but not in the home cage caused progressive increases in sensitivity to the locomotor-stimulating effects of bromocriptine and increases in the subsequent sensitivity to quinpirole but caused only trivial signs of cross-sensitization to cocaine or heroin. Cross-sensitization to quinpirole was temporary; responsiveness to quinpirole decreased with further quinpirole injections. Lack of significant cross-sensitization between bromocriptine and either cocaine or heroin and lack of permanence of the cross-sensitization between bromocriptine and quinpirole raise questions as to the biological basis of psychomotor stimulant sensitization.     

In vivo imaging of disturbed pre- and post-synaptic dopaminergic signaling via arachidonic acid in a rat model of Parkinson's disease

BACKGROUND: Parkinson's disease involves loss of dopamine (DA)-producing neurons in the substantia nigra, associated with fewer pre-synaptic DA transporters (DATs) but more post-synaptic dopaminergic D2 receptors in terminal areas of these neurons. HYPOTHESIS: Arachidonic acid (AA) signaling via post-synaptic D2 receptors coupled to cytosolic phospholipase A2 (cPLA2) will be reduced in terminal areas ipsilateral to a chronic unilateral substantia nigra lesion in rats given D-amphetamine, which reverses the direction of the DAT, but will be increased in rats given quinpirole, a D2-receptor agonist. METHODS: D-amphetamine (5.0 mg/kg i.p.), quinpirole (1.0 mg/kg i.v.), or saline was administered to unanesthetized rats having a chronic unilateral lesion of the substantia nigra. AA incorporation coefficients, k* (radioactivity/integrated plasma radioactivity), markers of AA signaling, were measured using quantitative autoradiography in 62 bilateral brain regions following intravenous [1-(14)C]AA. RESULTS: In rats given saline (baseline), k* was elevated in 13 regions in the lesioned compared with intact hemisphere. Quinpirole increased k* in frontal cortical and basal ganglia regions bilaterally, more so in the lesioned than intact hemisphere. D-amphetamine increased k* bilaterally but less so in the lesioned hemisphere. CONCLUSIONS: Increased baseline elevations of k* and increased responsiveness to quinpirole in the lesioned hemisphere are consistent with their higher D2-receptor and cPLA2 activity levels, whereas reduced responsiveness to D-amphetamine is consistent with dropout of pre-synaptic elements containing the DAT. In vivo imaging of AA signaling using dopaminergic drugs can identify pre- and post-synaptic DA changes in animal models of Parkinson's disease.     

Nicotine blocks quinpirole-induced behavior in rats: psychiatric implications

Rationale and objectives: Because of known and imputed roles of dopaminergic and nicotinic cholinergic systems in a variety of neurological and neuropsychiatric disorders, combined neurochemical and behavioral methods assessments were made to study the intermodulatory roles of these neurochemical systems. Methods: Rats were treated daily during postnatal ontogeny with the dopamine D₂/D₃ agonist, quinpirole (QNP) HCl (1.0 mg/kg/day), for the first 3 weeks from birth. This priming process replicated previous findings of behavioral sensitization, manifested as hyperlocomotion, increased paw treading with jumping, and increased yawning. Results: All effects were partially or totally blocked by acute treatment with nicotine (0.3 mg/kg, i.p.). The effects of nicotine, in turn, were partially or totally blocked by the nicotinic antagonist, mecamylamine (1.0 mg/kg, i.p.). In concert with these behavioral actions, QNP-primed rats displayed greater binding of [³H]cytisine in midbrain and cerebellum and greater [¹²⁵I]α-bungarotoxin binding in hippocampus and striatum. Conclusions: Accordingly, these selective ligands for α₄β₂ and α₇ nicotinic receptors, respectively, demonstrate that nicotinic receptors are altered by dopamine D₂/D₃ agonist treatment of rats with primed dopamine receptors. We propose that nicotinic agonists may have a therapeutic benefit in behavioral disorders brought about by central dopaminergic imbalance. Received: 1 January 1999 / Final version: 25 March 1999     

Dopamine D2 receptor-mediated modulation of the GABAergic inhibition of substantia nigra pars reticulata neurons

Neurons of the substantia nigra pars reticulata can be readily and fully inhibited by endogenously released or iontophoretically applied GABA. We have previously shown that co-application of dopamine or the D₂-like agonist quinpirole causes a current-dependent attenuation of the inhibitory response of these neurons to GABA. To determine if the modulation of GABA responsiveness was mediated by activation of D₂ receptors, effects of iontophoretic quinpirole were examined after various treatments which block or inactivate D₂ receptors, or uncouple D₂ receptors from their G-proteins. Results showed that the GABA-attenuating effect of quinpirole could be attributed to stimulation of D₂ receptors, and not a non-specific effect of the drug, since (1) co-iontophoresis of the D₂ antagonist YM 09151-2 antagonized the GABA-modulatory effect of quinpirole, (2) prior intranigral injection of the receptor inactivatorN-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ; 50 nmol/0.5 ml one day before recording) prevented the response to quinpirole, and (3) prior intranigral injection of the G_i-G_o-protein inactivator pertussis toxin (1 mg/ml 0.9% NaCl 24 h before recording) completely abolished the ability of quinpirole to lessen the inhibitory response to GABA. The location of the involved D₂ receptors was examined using selective lesioning approaches. Kainic acid lesions of the striatonigral pathway did not prevent the ability of quinpirole to attenuate responses of pars reticulata neurons to GABA. Similarly, in previous studies [59], 6-hydroxydopamine lesions of the adjacent pars compacta dopamine neurons were found not to abolish the GABA-attenuating effect of dopamine. Thus, it appears that the receptors mediating the response are not localized to either striatonigral terminals nor to the adjacent dopamine neurons, leaving open the possibility that the response is mediated by D₂ receptors located on pars reticulata neurons. Collectively these results suggest that dendritically released dopamine may act via nigral D₂ receptors, perhaps located on pars reticulata neurons themselves, to regulate basal ganglia output from the substantia nigra.     

Subsensitivity to rewarding and locomotor stimulant effects of a dopamine agonist following chronic mild stress

Chronic exposure to very mild unpredictable stress has previously been found to reduce or abolish the acquisition of place preference conditioning. In the present study, chronic mild stress was found to abolish the acquisition of preferences for a distinctive environment paired with systemic administration of amphetamine (0.5 mg/kg) or quinpirole (100–400 µg/kg) or with quinpirole (0.75 µg) administered bilaterally within the nucleus accumbens. The locomotor stimulant effects of quinpirole (100–400 µg/kg) were also attenuated in stressed animals. The results suggest that decreased sensitivity to reward following chronic mild stress results from a decreased sensitivity of dopamine D₂ receptors within the nucleus accumbens.     

SKF 38393 alters the rate-dependent D2-mediated inhibition of nigrostriatal but not mesoaccumbens dopamine neurons

Previous electrophysiological studies have failed to identify significant effects of the D1 dopamine (DA) agonist SKF 38393, either alone or in combination with the D2 agonist quinpirole (LY 171555), on the spontaneous firing rate of midbrain DA neurons. We have utilized extracellular single-unit recording techniques to examine whether SKF 38393 can alter D2-mediated inhibition of DA cell activity. Quinpirole-induced inhibition of the spontaneous activity of midbrain DA neurons was observed to be positively correlated with the basal firing rate of the neuron being examined (i.e., faster cells required higher doses to achieve 50% and maximal inhibition). Pretreatment with SKF 38393 (1.0 mg/kg, i.v.; 4 minutes) eliminated the rate dependency of quinpirole-induced inhibition of nigrostriatal but not mesoaccumbens DA neurons. This effect of SKF 38393 was blocked both by the D1 antagonist SCH 23390 and by hemitransections of the forebrain. In summary, SKF 38393 appears to exert Dl-specific, feedback pathway-dependent effects on the profile of responsiveness of nigrostriatal DA neurons to D2-mediated inhibition of cell firing rate.     

Effects of acute dopamine depletion on responsiveness to D1 and D2 receptor agonists in infant and weanling rat pups

The behavioral responses to separate and combined administration of the D₁ agonist SKF-38393 and the D₂ agonist quinpirole following acute dopamine (DA) depletion via alpha-methyl-p-tyrosine (AMPT) or AMPT/reserpine were examined in infant (10-day-old) and weanling (21-day-old) rat pups. At both ages, AMPT pretreatment generally had little impact on D₁- or D₂-agonist-induced responding, whereas the greater DA depletion observed following AMPT/reserpine pretreatment was generally associated with suppression of both D₁ and D₂ agonist-typical responding. Thus, whereas in adult animals some degree of D₁ receptor activation by endogenous dopamine appears to be necessary for D₂ responding but not vice versa (e.g. White et al. 1988), in young animals there appears to be a reciprocal co-dependence of these two receptor subtypes, with extensive DA depletion suppressing responding to both agonists when administered separately. At 10 days of age, some D₁ and D₂ agonist-induced behaviors that were previously blocked by AMPT/reserpine were reinstated following combined administration of both agonists. In contrast, no clear evidence for reinstatement was seen following administration of the combined agonists to AMPT/reserpine-pretreated weanlings, perhaps due to the induction of potential competing behaviors. Whereas DA depletion blocked many D₁- and D₂-induced behaviors, such depletion conversely promoted the expression in agonist-treated animals of a number of behaviors that were not normally induced by the agonists in non-depleted animals. These behaviors typically involved an oral component and included grooming and mouthing following SKF-38393 in depleted 10-day-old pups, mouthing following administration of either agonist to depleted weanlings, and probing and intense self-mutilation (forepaw and tongue biting) following the combined agonists in depleted weanlings. This rapid induction of potentiated agonist responsiveness following acute DA depletion early in life may have significant implications with regard to animal models for the developmental disorder of Lesch-Nyhan syndrome.     

Release of cholecystokinin from rat midbrain slices and modulatory effect of D2 DA receptor stimulation

Cholecystokinin octapeptide (CCK-8) is colocalized within a majority of dopamine (DA)-containing neurons of the rat midbrain. Exogenous CCK-8 can modulate the electrophysiological activity of DA neurons, at least in part, by direct actions on the somatodendritic region of these cells. If CCK-8 is somatodendritically released from DA neurons, it may influence DA cell function as has been shown for DA itself. In the present study, radioimmunoassay was used to determine if CCK-8 is released in vitro from slices of rat midbrain under basal and depolarizing (30 mM potassium) conditions. Low levels of CCK-8 were detected in the basal incubation medium. Thirty mM potassium caused about a 3-fold increase in the release of CCK-8. This stimulated release was abolished in calcium-free medium. The D₂ receptor agonist quinpirole, but not the D₁ agonist SKF 38393, attenuated the potassium-stimulated release of CCK-8 but did not affect basal release. These results show that CCK-8, like DA, can be released from midbrain slices, presumably from DA/CCK-8-containing neurons. This finding is in accordance with the possibility that CCK-8 plays a role in the regulation of DA neuronal function at the level of the cell body, where it might influence the excitability of the DA cell membrane.     

Differential regulation of female sexual behaviour by dopamine agonists in the medial preoptic area

The medial preoptic area (mPOA) is a brain region critical in the control of male sexual behaviour, and the neurotransmitter dopamine (DA) plays an important role within it. However, both the roles of DA and the mPOA in female sexual behaviour are not fully understood, with few studies producing consistent data. The present study examined the function of DA within the mPOA on the full cascade of female sexual behaviour. Ovariectomized female rats were bilaterally cannulated into the mPOA and partially hormonally primed with estradiol benzoate (EB). Different doses of a nonselective DA receptor agonist, and selective DA D1 and D2 receptor agonists (apomorphine, SKF 38393 and quinpirole, respectively) were infused bilaterally to the mPOA. Copulatory behaviour was then immediately tested over a period of 30 min in a bilevel chamber with a sexually experienced male. Precopulatory behaviours were increased in females following infusions of a low dose (0.25 μg) of apomorphine and both a low (0.05 μg) and a high dose (0.2 μg) of quinpirole. However, hops and/or darts were decreased following infusion of a low dose (0.05 μg) of SKF 38393. These results suggest that the ratio of DA D1/D2 activity within the mPOA of female rats is critical for the expression of precopulatory behaviours, and may work with other brain areas responsible for stimulating lordosis to control the timing of female sexual behaviour.     

Locomotor activity and cocaine-seeking behavior during acquisition and reinstatement of operant self-administration behavior in rats

Recent studies indicate that administration of dopamine D2-like receptor agonists reinstates drug-seeking behavior in rodents, whereas dopamine D1-like receptor agonists do not. These effects have been related to the ability of these agonists to facilitate the expression of sensitized locomotor activity. Presently, we describe experiments in which locomotor activity was assessed concomitantly with operant performance during acquisition, extinction and reinstatement. We report that locomotor activity was inversely related to drug-seeking behavior during acquisition of cocaine self-administration under a Fixed Ratio (FR) 1 schedule of reinforcement. During a single trial extinction session, animals that had acquired cocaine self-administration exhibited a conditioned increase in drug-seeking behavior, but there was no evidence of a conditioned locomotor response. During reinstatement, cocaine (20 mg/kg) significantly increased both locomotor activity and drug-seeking behavior. The dopamine D2-like receptor agonist quinpirole (0.5 mg/kg) increased drug-seeking behavior, but did not significantly increase locomotor activity. In contrast, the dopamine D1-like receptor agonist SKF 81297 (0.5 mg/kg) failed to reinstate drug-seeking behavior, but produced significant locomotor activation. To determine whether the inability of SKF 81297 to promote reinstatement is related to the strength of operant conditioning, additional rats were trained to self-administer cocaine using an FR-3 schedule of reinforcement. Despite achieving response rates during training almost four times higher compared to the FR-1 condition, administration of SKF 81297 again failed to significantly increase drug-seeking behavior during reinstatement testing. These results extend previous findings, confirming the important role of D2-like, but not D1-like receptor activation in the reinstatement of drug-seeking behavior. An understanding of the mechanisms by which D1- and D2-like agonists differentially influence locomotor activation and drug-seeking behavior in cocaine-experienced rodents may prove critical to the development of increasingly effective pharmacotherapies for substance abuse.