Dopamine D3 receptors are involved in amphetamine-induced contralateral rotation in 6-OHDA lesioned rats.

The aim of the present experiment was to investigate the possibility that alterations in dopamine D3 receptors have a role in the normalization of function that occurs following a unilateral lesion of the medial forebrain bundle induced by 6-hydroxydopamine (6-OHDA). Unilateral lesions result in an enhanced rotational response to dopamine agonists that appears to be due to an increase in stimulatory D2 receptors on the lesioned side that occurs by about 1 week postlesion. The present experiment assessed the involvement of D3 receptors in rotational behavior by testing the animals at 48 h postlesion. At this time interval, D2 receptors have not become up-regulated. In contrast, D3 receptors have been shown to be down-regulated. Rats with > or = 98% dopamine depletion induced by 6-OHDA exhibited mostly ipsilateral rotation in response to an injection of amphetamine. This rotation was not affected by pretreatment with the D3 antagonist U-99194A. Rats with 80-97% dopamine depletion exhibited mostly contralateral rotation in response to amphetamine and this rotation was blocked by pretreatment with U-99194A. In addition, a decrease in D3 receptor binding was observed by 48 h postlesion. These results support the hypothesis that the decrease in D3 receptors seen following denervation is involved in the compensatory response of the system. This may have important clinical relevance in the treatment of disorders such as Parkinson's disease and drug abuse.

Effect of 6-hydroxydopamine or repeated amphetamine treatment on mesencephalic mRNA levels for AMPA glutamate receptor subunits in the rat.

Expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) subunit mRNAs were assayed in the ventral mesencephalon of rats that received either a unilateral microinjection of the dopamine neurotoxin 6-hydroxydopamine (6-OHDA; Experiment 1) or repeated treatment with amphetamine (Experiment 2). GluR2 levels were decreased 1 and 3 days after the lesion, and GluR1 and GluR3 levels also showed a transient decrease at 1 day after the lesion. Repeated amphetamine treatment did not significantly alter GluR1-4 levels measured 30 min after the third or tenth amphetamine injection, even though locomotor sensitization was obtained. Thus, while the present results indicate that AMPA receptor subunits are associated with dopamine-containing cell bodies in the ventral mesencephalon, these transcripts may not be responsible for the development of amphetamine sensitization.

Individual differences in novelty-induced activity and the rewarding effects of novelty and amphetamine in rats.

Previous work has shown that individual differences in locomotor behavior in an inescapable novel environment predict the locomotor-stimulant effect of amphetamine. Experiment 1 of the present study assessed if novelty-seeking behavior in a free choice situation also predicts the locomotor-stimulant effect of amphetamine. Rats were first assessed for their locomotor response to an inescapable novel environment and then were allowed to choose between this environment (familiar) and a novel environment. Activity in the inescapable novel environment was found to predict subsequent locomotor response to amphetamine, but approach to novelty in the free choice situation did not. In experiment 2, rats were assessed for their approach to novelty in the free choice situation and then assessed for amphetamine-induced conditioned place preference. It was found that rats who spent more time in a novel environment also showed a higher magnitude of amphetamine-induced conditioned place preference. These findings are consistent with the hypothesis that the rewarding properties of novelty and amphetamine may be mediated by a similar brain mechanism.

Effect of differential rearing environments on morphine-induced behaviors, opioid receptors and dopamine synthesis.

Rats were raised from weaning (21 days old) to young adulthood (50-60 days old) in either an enriched or impoverished stimulus environment. In the enriched condition (EC), rats were group-housed with various novel objects that were re-arranged daily. In the impoverished condition (IC), rats were housed individually without any objects. As adults, a four-trial conditioned place preference (CPP) test was used to assess locomotor activity and reward produced by morphine (0, 0.1, 1 or 10 mg/kg). On morphine conditioning day 1, both EC and IC rats displayed an inverted U-shaped dose-effect curve for locomotor activity and the locomotor stimulant effect of acute morphine was greater in IC than EC rats. Across morphine conditioning days 1-4, both EC and IC rats displayed locomotor sensitization; the locomotor sensitization following repeated morphine injections was greater in IC than EC rats. In contrast to the enhanced locomotor stimulant effect of morphine observed in IC rats, morphine-induced CPP was attenuated in IC rats relative to EC rats, indicating that the locomotor and rewarding effects of opioids depend upon different neural substrates. Measurement of mu opioid receptor density and rates of morphine-stimulated dopamine synthesis in the mesolimbic and nigrostriatal systems of EC and IC rats revealed no reliable differences between groups. Therefore, the ability of mu opioid receptors to modulate mesolimbic dopamine neurotransmission does not account for the differential behavioral effects of morphine in EC and IC rats.

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.