Sensitization Of Locomotor Activity Research Articles

Chronic treatment with Δ‐9‐tetrahydrocannabinol alters the structure of neurons in the nucleus accumbens shell and medial prefrontal cortex of rats

The potential of repeated exposure to Delta(9)-tetrahydrocannabinol (Delta(9)-THC) to produce long-lasting changes in synaptic connections in a manner similar to other drugs of abuse was evaluated in Sprague-Dawley rats. For 12 days, rats received two i.p. injections per day (8 h apart) of vehicle, a low dose of Delta(9)-THC (0.5 mg/kg), or escalating doses of Delta(9)-THC (0.5-4.0 mg/kg). Thirty days later, they were evaluated for sensitized locomotor activity (during the night cycle) for 60 min on each of three trials. Using a within-groups design, rats were tested following an injection of vehicle, 0.5 mg/kg Delta(9)-THC or 2.0 mg/kg Delta(9)-THC. The rats showed no evidence of sensitized locomotor activity in any group. Twenty-four hours after the final sensitization test, their brains were removed and then processed for Golgi-Cox staining. Prior exposure to Delta(9)-THC (both the low dose and the escalating doses) increased the length of the dendrites as well as the number of dendritic branches in the shell of the nucleus accumbens and in the medial prefrontal cortex, but not in the hippocampus, striatum, orbital frontal cortex, parietal cortex, or occipital cortex. These results are similar to those evident in brains of rats sensitized to amphetamine, and support previous findings that cannabinoids promote DA activity in the mesolimbic DA system.

Effect of a novel nicotinic receptor antagonist, N,N′-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats

Recent work has shown that the novel compound N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) may selectively block nicotinic acetylcholine receptors involved in regulating dopamine release. The current experiments examined the acute effect of bPiDDB on nicotine self-administration, sucrose-maintained responding, and nicotine-induced changes in acute and sensitized locomotor activity. Rats were first trained to respond for either nicotine (i.v.) or sucrose pellets using a standard two-lever operant conditioning procedure using a fixed ratio 5 schedule of reinforcement and were then pretreated with bPiDDB (0, 0.3, 1, or 3 mg kg(-1)) 15 min prior to the session. In separate experiments, rats were assessed for nicotine-induced changes in locomotor activity following pretreatment with bPiDDB (1 or 3 mg kg(-1)) or mecamylamine (1 mg kg(-1)); pretreatments were assessed with both acute and repeated nicotine (0.4 mg kg(-1)) treatment. Results showed that bPiDDB dose-dependently decreased nicotine self-administration, but not sucrose-maintained responding. In the locomotor experiments, bPiDDB attenuated the hyperactivity produced by acute and repeated nicotine; however, this effect was not robust compared to mecamylamine. In contrast to mecamylamine, bPiDDB did not block the initial hypoactivity produced by acute nicotine. Since bPiDDB decreased nicotine self-administration specifically, this novel nicotinic receptor antagonist may constitute a lead for the development of a clinically useful treatment for tobacco dependence.

Exposure to amphetamine in rats during periadolescence establishes behavioural and extrastriatal neural sensitization in adulthood

Drug abuse during adolescence may predispose towards later adult substance abuse and major depressive disorders (Brook et al., 2002). The purpose of the present study was to characterize whether behavioural sensitization to amphetamine occurred in adult rats following adolescent exposure to amphetamine [low (2 mg/kg.d) or high (10 mg/kg.d) i.p. for 10 d] and the pattern of neural activation associated with sensitized behaviour, in male Sprague-Dawley rats. Following initial treatment (post-natal days 33-41) and a subsequent 4-wk period of abstinence, rats initially treated with either amphetamine regime showed a similar sensitized locomotor activity upon re-challenge with amphetamine (1.5 mg/kg i.p.) compared to rats acutely challenged with this dose of amphetamine. Fos-IR expression in the "high" sensitized group was significantly greater than acutely challenged rats in all quadrants of the CPu. Both "low" and "high" sensitized groups demonstrated heightened Fos expression relative to acutely challenged rats in the medial and central amygdala, as well as rostroventrolateral medulla, whereas Fos-IR in the locus coeruleus and substantia nigra pars reticulata was significantly increased only in the "high" sensitized group compared to acute. Double-labelling for tyrosine hydroxylase confirmed an absence of Fos-IR in A9 and A10 regions. The present study has shown a robust and persistent sensitization in adulthood to amphetamine re-challenge following initial adolescent exposure in rats. This manifestation of sensitization apparently results in widespread neural activation in limbic and autonomic structures.

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.

Addiction, dopamine, and the molecular mechanisms of memory.

We thank Pier Piazza, Eric Nestler, Charles O'Brien, Howard Eichenbaum, and Eric Kandel for their helpful comments and criticisms of earlier versions of the manuscript.

Effects of administering cocaine at the same versus varying times of day on circadian activity patterns and sensitization in rats.

The effects of different schedules of cocaine administration on circadian activity patterns and locomotor sensitization were studied. Rats received intraperitoneal injections of either saline or 20 mg/kg cocaine at either 24- or 33-hr intervals for 8 cycles (development). After a 2-day withdrawal, they were given a cocaine challenge in a novel environment. Rats given cocaine at 24-hr intervals were hypoactive 4 to 9 hr postinjection during development and, during cocaine challenge, showed sensitization of locomotor activity. Rats given cocaine at 33-hr intervals did not show these effects. On the 33-hr-period schedule, activity was enhanced beginning 24 hr after drug receipt. Different intermittent schedules of cocaine receipt may alter the vulnerability to cocaine, and altered vulnerability may be more likely when a subsequent cocaine injection interacts with a distal state of sensitivity produced by a prior injection.

Chronic phencyclidine increases NMDA receptor NR1 subunit mRNA in rat forebrain.

The present study was designed to determine whether the sensitization of locomotor activity that results from chronic phencyclidine (PCP) administration is associated with altered NMDA receptor function or mRNA in rat brain. Female Sprague-Dawley rats were administered PCP (20 mg/kg, i.p.) once daily for 5 days. After withdrawal for 72 hr, challenge with 3.2 mg/kg PCP (i.p.) revealed a significant sensitization to the locomotor activating effect of PCP. In situ hybridization analysis with an oligonucleotide probe complementary to the mRNA encoding the NR1 subunit of the NMDA receptor demonstrated that chronic PCP treatment resulted in a marked increase in NR1 subunit mRNA in the forebrain. Quantitative image analysis revealed a significant increase in the labeling of NR1 mRNA in the olfactory tubercle, piriform cortex, frontal cortex, and anterior striatum. However, no significant difference between PCP and saline-treated rats was found in the hippocampus or cerebellum. In a parallel study, possible functional alterations in the NMDA receptor were assessed by measuring NMDA-stimulated release of [3H]DA from slices of the olfactory tubercle and piriform cortex. NMDA-stimulated release was not affected by chronic PCP treatment, but the inhibition of this release by PCP, 7-chlorokynurenic acid (7-CK), and DL-2-amino-5-phosphovaleric acid (AP-5) was significantly diminished by chronic PCP. This suggests that the behavioral plasticity associated with chronic PCP may be related to an altered subunit stoichiometry of NMDA receptors in selective forebrain regions.

Acamprosate suppresses the expression of morphine-induced sensitization in rats but does not affect heroin self-administration or relapse induced by heroin or stress.

Acamprosate (calcium-acetyl homotaurinate) is a new compound used in the treatment of alcohol abuse. Because of the putative link between alcoholism and the endogenous opioid systems in both humans and laboratory animals, we tested in rats the effects of acamprosate on behavioral and neurochemical effects of opioid drugs related to their abuse potential. These included sensitization to the behavioral effects of morphine, morphine-induced dopamine (DA) release in the nucleus accumbens (NAS), intravenous (i.v.) heroin self-administration and relapse to heroin seeking in drug-free rats. In experiment 1, rats were injected daily with either morphine (10 mg/kg, s.c.) or saline for 14 days. Three days later in a test for the expression of sensitization, an injection of morphine (10 mg/kg) resulted in increased locomotor activity and enhanced DA release in the NAS in rats previously exposed to morphine. Acamprosate (two injections of 200 mg/kg, 12 h apart; i.p.) suppressed the expression of the sensitized responses, but did not alter the effects of morphine in drug-naive control rats. In experiment 2, it was found that acamprosate (two injections of 50-200 mg/ kg; i.p.) had no consistent effects on i.v. heroin self-administration (50 100 microg/kg per infusion) and, in experiment 3, that acamprosate (100-200 mg/ kg, i.p.) did not alter reinstatement of drug seeking induced by priming injections of heroin (0.25 mg/kg, s.c.) or a footshock stressor (15 min; 0.5 mA) after a 5- to 8-day period of extinction. Thus, although acamprosate attenuated the expression of sensitized locomotor activity and DA release in the NAS, it did not have any consistent effect on either the intake of heroin during the maintenance phase or the relapse to heroin seeking in a drug-free state. Thus, to the extent that the self-administration and the reinstatement procedures provide valid preclinical models for drug use and relapse in humans, our data suggest that acamprosate may not be effective in altering drug-taking behavior in heroin users.

Interactions of MK-801 and GYKI 52466 with morphine and amphetamine in place preference conditioning and behavioural sensitization

In an earlier study we showed that co-administration of the NMDA-receptor antagonist MK-801 during conditioning sessions blocks morphine-induced conditioned place preference (CPP). From this result, the question arose of whether this blockade is due to state-dependency effects induced by MK-801. Therefore, in a first experiment, animals were tested in the drugged state under which they had been conditioned. These animals did not show a CPP, thus it can be concluded that MK-801 does not make statedependent the morphine conditioning. In the same experiment those animals receiving only morphine during conditioning sessions showed a significant CPP when tested in an undrugged state but failed to show CPP when tested after injection of MK-801 (i.e., in the drugged state). These results indicate that MK-801 not only blocks the development of morphine-induced CPP but is also able to block the expression of a conditioned response that has been acquired before. In the same experiment repeated injection of neither morphine nor MK-801 produced sensitized locomotor activity. However, a strong sensitization was observed following repeated injection of morphine plus MK-801. There was also cross-sensitization between morphine plus MK-801 and MK-801 alone but not with morphine alone, and also between morphine and MK-801, but not vice versa. In a second experiment the effects of the AMPA-receptor antagonist GYKI 52466 were examined. It was found that GYKI 52466 did not produce CPP or behavioural sensitization. Finally, in a third experiment, CPP was induced by morphine and amphetamine (animals tested in the drug-free state), and behavioural sensitization was induced by amphetamine. When animals were tested after an injection of GYKI 52466, neither the morphine- nor the amphetamine-conditioned animals showed a CPP. Likewise, challenge of sensitized animals with amphetamine plus GYKI 52466 failed to produce a sensitized response. It can be concluded, that GYKI 52466, like MK-801, can block the expression of a conditioned response, and can also block the expression of sensitized behaviour.

Locomotor activation and dopamine release produced by nicotine and isoarecolone in rats

1. Isoarecolone was approximately 250 times less potent than nicotine as an inhibitor of [3H]-nicotine binding to rat brain membranes. Isoarecolone failed to inhibit the binding of the nicotinic ligand [125I]-alpha-bungarotoxin or of the muscarinic ligand [3H]-QNB. 2. Nicotine (0.01-30 microM) evoked the release of [3H]-dopamine from striatal and frontal cortex synaptosomes, with EC50 values of approximately 0.5 microM in each case. This release was largely mecamylamine-sensitive. 3. Isoarecolone (1-200 microM) evoked predominantly mecamylamine-sensitive dopamine release from both striatal and cortical synaptosomes, with a potency at least 20 times less than that of nicotine. The maximum effect of isoarecolone was less than that of nicotine, particularly in the frontal cortex preparation. 4. In control rats treated chronically with saline, neither nicotine nor isoarecolone had clear effects on locomotor activity at the doses tested. Chronic treatment with nicotine clearly sensitized rats to the locomotor activating effect of isoarecolone was seen at a dose about 40 times larger than that of nicotine. 5. The low potency and efficacy of isoarecolone in facilitating sensitized locomotor activity resembled its lower potency and efficacy, compared with nicotine, in evoking dopamine release in vitro. The agonist profile of the nicotinic receptor population mediating dopamine release may determine the pharmacological characteristics of consequent locomotor behaviour.

Evidence for N-methyl- d-aspartate receptor mediation of cocaine induced corticosterone release and cocaine conditioned stimulant effects

The role of the N-methyl- d-aspartate (NMDA) receptors in cocaine conditioning and sensitization of locomotor activity was studied in four groups of Sprague-Dawley rats. A sub-motoric dose of the NMDA antagonist MK-801 (0.1 mg/kg, i.p.) was employed using a novel dual-compartment Pavlovian drug conditioning paradigm. The animals were placed sequentially in two different test environments in which locomotor activity was monitored. In the first compartment, the animals always received a non-drug test for 20 min. Upon completion of this test, the animals received either saline, cocaine (10 mg/kg i.p.), MK-801 or MK-801 plus cocaine depending on group assignment and were then placed immediately into the second compartment and again tested for 20 min. A total of six non-drug and six drug tests were conducted every other day over a 12-day period. Across all drug/saline treatment and post-treatment tests for conditioning, there were no statistical differences in locomotor activity among the saline and drug treatment groups in the non-drug test environment. In the drug/saline associated environment, however, cocaine had a reliable stimulant effect on locomotion when administered alone or in combination with MK-801. Following a 1-day and again after 21-days of withdrawal, all animals were administered a non-drug test for conditioning in which no injections were administered. On both tests, all groups had equivalent activity levels in the non-drug environment. In the drug/saline environment, only the cocaine group of the three drug treatment groups exhibited conditioned hyperlocomotion. Importantly, MK-801 blocked conditioned hyperlocomotion in the combined cocaine + MK-801 group. MK-801 did not alter serum or brain cocaine concentration or the cocaine effects on dopamine metabolism in limbic brain tissue. The co-administration of MK-801 with cocaine, however, blocked the corticosterone release effect of cocaine. Thus, the NMDA receptor site appears critical for cocaine induced conditioning and for corticosterone release.

Dopamine receptor antagonists prevent expression, but not development, of morphine sensitization

The present experiments determined the effects of selective dopamine receptor antagonists on the initiation and expression of sensitization to the locomotor-stimulating effects of morphine in rats. Although both the dopamine D 1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride (SCH 23390, 0.25 mg/kg) and the dopamine D 2 receptor antagonist eticlopride (0.1 mg/kg) suppressed the ability of morphine (10 mg/kg) to elicit sensitized locomotor activity during the course of a 12 day treatment schedule, subsequent tests with morphine alone revealed significant sensitization. Sensitization in the SCH 23390 + morphine group could not be attributed to dopamine D 1 receptor supersensitivity caused by repeated SCH 23390 administration because electrophysiological recordings indicated that nucleus accumbens neurons in SCH 23390-treated rats were not more sensitive to the inhibitory effects of either dopamine or a dopamine D 1 receptor-selective agonist. Thus, dopamine receptor stimulation may be involved in expression, but not development, of morphine sensitization.