Biomedical subjects

M T Bardo

Publications and source records attributed to M T Bardo.

At least 37 records · Page 2Linked to original sources

PubMed2000

Dopamine D(2)-like receptor binding in the brain of male Japanese quail (Coturnix japonica).

Japanese quail (Coturnix japonica) have been used extensively to study appetitive behaviors. However, little is known about the appetitive-relevant neurochemical systems in this species. The present investigation examined the distribution of D(2)-like dopamine receptors in the quail brain. [(3)H]Spiperone was incubated in brain tissue homogenates and non-specific binding was defined using (-)-sulpiride. Scatchard analysis of whole brain without cerebellum and forebrain alone indicated approximate K(d)'s of 0.08 and 0.04 nM, respectively. In addition, the preferential D(3) agonist (+/-)-2-dipropylamino-7-hydroxy-1,2,3, 4-tetrahydronaphthalene hydrobromide (7-OH-DPAT) did not displace [(3)H]spiperone binding in quail forebrain. Finally, regional analysis showed that the highest densities of D(2)-like receptors were located in the forebrain. Overall, these results indicate that there is some conservation of dopaminergic mechanisms between aves and mammals. Thus, Japanese quail may be useful for examining the neuropharmacological mechanisms of dopaminergic stimulant drugs that work via D(2)-like receptor activation.

Animals↗

PubMed2000

Nornicotine pretreatment decreases intravenous nicotine self-administration in rats.

RATIONALE: Nicotine has been shown to be effective as a treatment for reducing tobacco dependence. However, few studies have examined the effect of other nicotinic agonists to determine if they can also decrease nicotine self-administration. OBJECTIVE: The present study determined if nornicotine, a tobacco alkaloid and major nicotine metabolite in brain, could reduce nicotine self-administration in rats. METHODS: Each rat was prepared with an indwelling jugular catheter and trained to self-administer intravenous nicotine (0.03 mg/kg per infusion). After nicotine self-administration stabilized, rats were pretreated with either (-)-nicotine (0, 0.1, 0.3, and 1.0 mg/kg free base) or (+/-)-nornicotine (0, 1, 3, 5.6, and 10.0 mg/kg free base) and assessed for nicotine self-administration. A separate group of rats was maintained on sucrose reinforced responding and pretreated with nornicotine to determine the specificity of the pretreatment effect. In another group of rats, the time course of the pretreatment effect of either (-)-nicotine (0.56 and 1.0 mg/kg) or (+/-)-nornicotine (5.6 and 10.0 mg/kg) was examined. RESULTS: Nicotine and nornicotine each produced a dose-dependent decrease in nicotine self-administration. Furthermore, the decrease in nicotine self-administration in response to the 5.6 mg/kg nornicotine pretreatment was specific to nicotine self-administration, as this dose did not decrease sucrose reinforced responding in tolerant animals. In addition, within the dose range tested, the suppressant effect of nornicotine had a two-fold longer duration than that of nicotine (120 versus 60 min). CONCLUSION: These results suggest that nornicotine may be an effective treatment for tobacco dependence.

Animals↗

PubMed2000

Conditioned place preference: what does it add to our preclinical understanding of drug reward?

RATIONALE: Among the various experimental protocols that have been used to measure drug reward in laboratory animals, conditioned place preference (CPP) has been one of the most popular. However, a number of controversial issues have surrounded the use of this experimental protocol. OBJECTIVE: The present review provides a theoretical overview of some critical issues relevant to CPP. The advantages and limitations of CPP are also covered. RESULTS: Based on modern and traditional theoretical formulations of Pavlovian conditioning, CPP appears to reflect a preference for a context due to the contiguous association between the context and a drug stimulus. Within this theoretical framework, it seems clear that CPP measures a learning process that is fundamentally distinct from drug self-administration. The main advantages of CPP are that it: (1) tests animals in a drug-free state; (2) is sensitive to both reward and aversion; (3) allows for simultaneous determination of CPP and locomotor activity; (4) is adaptable to a variety of species; (5) typically yields dose-effect curves that are monophasic rather than biphasic; and (6) has utility in probing the neural circuits involved in drug reward. The main limitations of CPP are that it: (1) is subject to interpretation based on the notion of novelty seeking; (2) is cumbersome for providing the graded dose-effect curves needed for answering some pharmacological questions; (3) is difficult to interpret when animals prefer one context prior to drug conditioning; and (4) lacks face validity as an experimental protocol of drug reward in humans. CONCLUSION: Despite some limitations, CPP provides unique information about the rewarding effect of contextual cues associated with a drug stimulus.

Animals↗

PubMed2000

D-amphetamine facilitation of morris water task performance is blocked by eticlopride and correlated with increased dopamine synthesis in the prefrontal cortex.

The effect of posttraining D-amphetamine on Morris water task (MWT) performance was analyzed in this study by training rats using a single training trial per day procedure. In addition to acquisition latency, learning was assessed by a probe trial given 24 h after the last training trial. Rats given immediate post-trial D-amphetamine demonstrated improved performance over saline rats on both acquisition and the probe trial. An analysis of the mechanisms underlying facilitation revealed that eticlopride (a D2 antagonist) blocked D-amphetamine's facilitatory effects on the probe trial and dopamine synthesis was increased in the medial prefrontal cortex in the D-amphetamine group relative to controls. These results show that chronic administration of posttraining D-amphetamine facilitated MWT performance, and this facilitation may be mediated by the dopaminergic system and dopamine synthesis in the prefrontal cortex.

Animals↗

PubMed1999

Conditioned increase in place preference by access to novel objects: antagonism by MK-801.

In three separate place conditioning experiments with rats, repeated access to novel objects in one of two distinct environments conditioned an increase in preference for the novelty-paired environment. A conditioned increase in preference was found whether novel objects were paired with a randomly chosen environment or with the less preferred of two environments (conditioned against a preference). This enhanced preference did not depend on the control group employed. Control groups exposed only to the place conditioning apparatus or to both the apparatus and the novel objects showed no systematic shift in place preference. Intravenous infusions of cocaine also produced an increase in preference using the procedures employed with novel objects. Pretreatment with the N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 (0.03 mg kg(-1)) blocked acquisition of the enhanced place preference conditioned by access to novel objects without decreasing time spent with objects or inducing a place aversion in controls. Combined, these results show that access to novel objects can serve as an appetitive stimulus like drugs of abuse and that this novelty-induced appetitive process involves NMDA receptors. These place-conditioning procedures may provide a good model for determining the behavioral and neural process underlying the appetitive effects of novelty.

Animals↗

PubMed1999

Locomotion and conditioned place preference produced by acute intravenous amphetamine: role of dopamine receptors and individual differences in amphetamine self-administration.

Although previous studies have shown that dopamine (DA) antagonists block amphetamine reward, these studies have utilized animal models that involve repeated exposures to amphetamine. The present investigation examined the effect of DA antagonists on single-trial conditioned place preference (CPP) produced by acute intravenous (i.v.) amphetamine in rats. In the first experiment, rats were prepared with a jugular catheter and then received an acute i.v. injection of amphetamine (0.1-3 mg/kg) paired with one compartment of a CPP apparatus. Relative to sham controls (no i.v. catheter), amphetamine produced a dose-dependent increase in locomotor activity and CPP. Two further experiments demonstrated that both effects of amphetamine were completely blocked by pretreating rats with the D1 DA antagonist SCH-23390 (0.025 and 0.25 mg/kg) or the D2 DA antagonist eticlopride (0.2 and 2 mg/kg) on the conditioning trial. In a final experiment, single-trial amphetamine CPP did not predict subsequent self-administration of i.v. amphetamine (10-50 micrograms/infusion) using either a fixed ratio (FR) 1 or progressive ratio (PR) schedule of reinforcement. Thus, while sharing a similar DA receptor mechanism, the present results indicate that single-trial CPP and self-administration are dissociable effects of i.v. amphetamine.

Amphetamine↗

PubMed1999

Acute and chronic effects of nornicotine on locomotor activity in rats: altered response to nicotine.

RATIONALE: Nicotine, a tobacco alkaloid, is known to be important in the acquisition and maintenance of tobacco smoking. Nornicotine, an active nicotine metabolite, stimulates nicotinic receptors and may produce psychomotor effects similar to nicotine. OBJECTIVE: The present study determined the effects of acute and repeated administration of nornicotine on locomotor activity and compared its effects with those of nicotine. METHODS: R(+)-Nornicotine (0.3-10 mg/kg), S(-)-nornicotine (0.3-10 mg/kg), S(-)-nicotine (0.1-1 mg/kg) or saline was administered s.c. to rats acutely or repeatedly (eight injections at 48-h intervals). Activity was recorded for 50 min immediately after each injection. RESULTS: S(-)-Nicotine produced transient hypoactivity, followed by dose-related hyperactivity. Repeated S(-)-nicotine administration resulted in tolerance to the hypoactivity and sensitization to the hyperactivity. Subsequent testing following a saline injection revealed evidence of conditioned hyperactivity. Acute administration of 0.3 mg/kg or 1 mg/kg R(+)- or S(-)-nornicotine produced no effect. Transient hypoactivity was observed at 3 mg/kg and 10 mg/kg R(+)-nornicotine and at 10 mg/kg S(-)-nornicotine. However, rebound hyperactivity was not observed following acute administration of either nornicotine enantiomer, suggesting that nornicotine-induced psychomotor effects differ qualitatively from those of S(-)-nicotine. Repeated R(+)-nornicotine resulted in tolerance to the transient hypoactivity, however hyperactivity was not observed. Repeated S(-)-nornicotine resulted in tolerance to the hypoactivity and the appearance of hyperactivity. Repeated administration of either nornicotine enantiomer resulted in a dose-dependent alteration in response to a 1 mg/kg S(-)-nicotine challenge, suggesting some commonalities in the mechanism of action. CONCLUSION: Nornicotine likely contributes to the neuropharmacological effects of nicotine and tobacco use.

Animals↗

PubMed1999

Nornicotine is self-administered intravenously by rats.

RATIONALE: Nicotine is a tobacco alkaloid known to be important in the acquisition and maintenance of tobacco smoking. However, other constituents in tobacco may contribute to the dependence liability. OBJECTIVE: The present report sought to determine whether nornicotine, a tobacco alkaloid and metabolite of nicotine, has a reinforcing effect. METHODS: Rats were prepared with a jugular catheter, then were allowed to self-administer intravenously either S(-)-nicotine (0.03 mg/kg/infusion), RS(+/-)-nornicotine (0.3 mg/kg/infusion) or saline using a two-lever operant procedure. The response requirement for each infusion was incremented gradually from a fixed ratio 1 (FR1) to FR5. When responding stabilized on the FR5, other doses of nicotine (0.01 mg/kg/infusion and 0.06 mg/kg/infusion) and nornicotine (0.075, 0.15, and 0.6 mg/kg/infusion) were tested for their ability to control responding. RESULTS: Similar to nicotine, rats self-administered nornicotine significantly above saline control levels. Within the dose ranges tested, both nicotine and nornicotine yielded relatively flat dose-response functions. Extinction of responding was evident when saline was substituted for nornicotine, and responding was reinstated when nornicotine again was available. The rate of nornicotine self-administration was similar between rats tested with either 24-h or 48-h inter-session intervals. CONCLUSION: These results indicate that nornicotine contributes to the dependence liability associated with tobacco use.

Animals↗

PubMed1999

Individual differences in novelty seeking on the playground maze predict amphetamine conditioned place preference.

Previous research has shown that a rat's level of activity in a novel environment can predict the strength of amphetamine-induced locomotor behavior and self-administration, but not amphetamine-conditioned place preference. The increase in activity observed when a rat is exposed to an inescapable novel environment may reflect escape behavior due to stress. To assess approach to novelty in a free-choice test, we examined the ability of a new test, the playground maze, to predict individual differences in response to amphetamine (1 or 3 mg/kg). Using the playground maze to categorize rats as either high or low novelty seekers, it was found that individual differences in novelty seeking did not predict amphetamine-induced changes in locomotor activity following either a single or repeated injections. However, high novelty seekers showed greater amphetamine-conditioned place preference than low novelty seekers. These results provide support for the hypothesis that novelty seeking and drug reward are neuropharmacologically related.

Amphetamine↗

PubMed1999

The effects of anxiolytic drugs on novelty-induced place preference.

Previous evidence has shown that rats exposed to a place preference apparatus prefer the novel compartment over the familiar. While this suggests that novelty is rewarding, an alternative interpretation is that rats avoid the familiar compartment because it is associated with some stress-related aversive event induced during the inescapable exposure sessions. To test this latter possibility, the benzodiazepine anxiolytic diazepam (0.1, 0.3, 1.0, 3.0 mg/kg) and the nonbenzodiazepine anxiolytic gepirone (0.1, 0.3, 1.0 mg/kg) were examined for their ability to alter novelty-induced place preference in rats. As expected, control animals showed a novelty-induced place preference. On the test day, this preference was disrupted by diazepam, but only at a dose (3 mg/kg) that also decreased locomotor activity. Gepirone failed to alter the preference behavior, even at a dose (1 mg/kg) that decreased locomotor behavior. In another experiment, rats spent more time in a familiar compartment that contained a novel object than in a familiar compartment with no object. These experiments indicate that preference for the novel compartment may reflect the rewarding effect of novelty rather than aversion to the familiar.

Animals↗

PubMed1999

Acquisition of a fixed ratio schedule in adult male rats neonatally exposed to ethanol and/or cocaine.

Acquisition of an operant learning task for sucrose reinforcement was examined in rats after neonatal exposure to ethanol and/or cocaine. Subjects were raised using an artificial rearing procedure from postnatal days 4 to 11 and were intragastrically fed a milk diet containing either ethanol (6 g/kg/day), cocaine (60 mg/kg/day), the combination (6 g/kg/day + 60 mg/kg/day), or an isocaloric control diet. There was also a suckled sham control. Adult male offspring (postnatal day 65 to postnatal day 68) were shaped to lever press for sucrose reinforcement and then began daily 15-min sessions of fixed ratio (FR) training. The number of days to acquire an FR 20 was measured. Neonatal exposure to the ethanol/cocaine combination significantly increased the number of days to reach the FR 20. There was also a trend for fewer of these subjects to reach the FR 20, although this difference was not statistically significant. These results suggest that subjects neonatally exposed to the ethanol/cocaine combination have difficulty learning an operant task. This impairment was unique to the ethanol/cocaine combination group and suggests that polydrug exposure during development may have a more adverse outcome than exposure to ethanol or cocaine alone.

Age Factors↗

PubMed1998

Olfactory cues and morphine-induced conditioned analgesia in rats.

In a Pavlovian conditioning procedure, rats were exposed to an odor conditioned stimulus (CS) and then were given morphine with its effect serving as the unconditioned stimulus (US). After four CS-US pairings, the CS was tested alone to assess the presence of an analgesic conditioned response (CR) using a hot-plate test. In Experiment 1a, two groups were conditioned by pairing either 10 mg/kg morphine or saline with an odor CS. In Experiment 1b, two groups were given an odor CS paired or unpaired with 10 mg/kg morphine. These results established that an odor cue can support a morphine-induced analgesic CR. Experiment 2 characterized the dose-effect curve (0, 3, 10, and 30 mg/kg morphine) using an odor conditioning procedure. The dose-effect curve showed an inverted U-shaped function, with the 10 mg/kg morphine group having significantly longer paw-lick latencies compared to all other groups. This finding contrasts with the monotonically ascending dose-effect curve for the analgesic unconditioned response (UR) to morphine.

Analgesia↗

PubMed1998

Morphine-induced conditioned place preference in preweanling and adult rats.

The ability of morphine to support a conditioned place preference (CPP) in preweanling (18-22-day-old) and adult (70-90-day-old) rats was assessed. Prior to a 15-min compartment preference test, subjects received a saline-paired, 30-min exposure to a distinct compartment 2 h prior to receiving an injection of 1 or 5 mg/kg of morphine or saline, paired with a 30-min exposure to an alternate compartment for 4 consecutive days. Although overall activity levels differed substantially across age, preweanling and adult rats displayed similar patterns of activity during conditioning. Moreover, only adults exhibited a significant sex difference; females were more active than were males following an injection of 5 mg/kg of morphine. Both doses of morphine supported a comparable CPP in preweanlings and adults, and both ages exhibited relatively low activity levels while in the morphine-paired compartment. These similarities across age suggest that the CPP procedure may prove to be useful in elucidating the ontogeny of learning, memory, and stimulus selection in rats.

Animals↗

PubMed1998

Morphine-conditioned changes in locomotor activity: role of the conditioned stimulus.

When a multisensory environment was reliably paired with morphine (2 mg/kg) in rats, that environment, in a drug-free test, evoked a hyperactive conditioned response (CR). When an olfactory cue (banana odor) was the only stimulus element reliably paired with morphine, it also elicited a hyperactive CR. However, a gustatory cue (saccharin solution) evoked a hypoactive CR. This taste-elicited decrease in activity was dose dependent; morphine at 2 and 4 mg/kg conditioned hypoactivity, whereas a higher dose (8 mg/kg) did not. A robust conditioned saccharin aversion occurred only at the highest dose of morphine, suggesting disassociation between the hypoactive CR and taste aversion. A taste cue present during context conditioning also prevented either acquisition or expression of the hyperactive CR to the context. The modality of the conditioned stimulus is a critical determinant of the form of the CR in a morphine locomotor conditioning paradigm.

Animals↗

PubMed1998

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

Animals↗

PubMed1997

Regional and temporal differences in real-time dopamine efflux in the nucleus accumbens during free-choice novelty.

To assess dopamine efflux during novelty-seeking behavior in rats, fast-scan cyclic voltammetry in the nucleus accumbens was combined with free-choice entry into a novel environment. Cyclic voltammograms, confirmed by in vitro testing, revealed that entry into novel, but not familiar, surroundings increased dopamine efflux in a regionally and temporally distinct pattern. Whereas dopamine failed to change in the core region of the accumbens and overlying neostriatum, an abrupt increase occurred in accumbal shell, a limbic-related area implicated in goal-directed behavior. Although the dopamine response was confined to the brief period of entry into novelty (approximately 8 s duration), a less rapid and more persistent dopamine change (> 20 s duration) occurred in the shell-core transition zone, the so-called shore. These results suggest that novelty mimics other positively reinforcing stimuli in enhancing dopamine transmission in the nucleus accumbens, but the regional and temporal heterogeneity of this effect may represent different aspects of accumbal dopamine function.

Animals↗

PubMed1997

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.

Animals↗

PubMed1997

7-OH-DPAT has d-amphetamine-like discriminative stimulus properties.

Rats were trained on a d-amphetamine (1 mg/kg) vs. saline discrimination task using food-maintained responding (fixed ratio = 25). In extinction tests, drug-appropriate responding decreased as the dose of amphetamine was substituted for the training dose decreased. The dopamine D2/D3 receptor agonist (+/-)7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) substituted fully for the amphetamine discriminative stimulus at the higher doses examined (0.1, 0.3, 1.0 mg/kg). This substitution was accompanied by a substantial decrease in overall response rates. Eticlopride, a dopamine D2/D3 receptor antagonist, partially blocked 7-OH-DPAT substitution. Thus, at the higher doses, 7-OH-DPAT shared sufficient discriminative stimulus properties with the amphetamine to prompt full substitution. Eticlopride antagonism suggests a role for the D2/D3 dopamine receptor in this substitution.

Animals↗