Biomedical subjects

M T Bardo

Publications and source records attributed to M T Bardo.

At least 73 records · Page 4Linked to original sources

PubMed1992

Depletion of dopamine binding sites and changes in dopamine and dihydroxyphenylacetic acid levels in 17- and 90-day-old rat striatum after irreversible receptor antagonism.

Irreversible antagonism of dopamine (DA) receptors by the alkylating compound N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) results in a depression of DA agonist mediated behaviors in adult, but not preweanling rats. DA D1 and D2 receptors, dihydroxyphenylacetic acid (DOPAC) and DA levels were assessed in 17- and 90-day-old rats in order to identify a neurochemical mechanism for this difference. EEDQ caused a depletion in D1 and D2 receptors in both young and adult rats, with the depletion in adults being relatively greater. In both age groups, EEDQ caused an unexpected decrease in DA levels which returned to normal levels by 30 days post-injection. In addition, DOPAC levels of adult rats, but not rat pups, were elevated after EEDQ treatment. The depletion of endogenous DA levels must be considered when interpreting the effects of EEDQ. Age-dependent differences in DA metabolism may be important for understanding the ontogenetic differences in EEDQ's behavioral effects.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

The biphasic effect of morphine on odor conditioning in neonatal rats.

Three experiments examined the dose-dependent biphasic effect of morphine on odor conditioning in neonatal rats. In Experiment 1, a single pairing of an odor and a low dose of morphine (0.5 mg/kg) in 5-day-old rats produced an odor preference, relative to an unpaired control group. In Experiment 2, pairing an odor with a high dose of morphine (2.0 mg/kg) produced an odor aversion, relative to an unpaired control group. A third experiment compared performance of a group given odor and morphine (2.0 mg/kg) paired to that of two unpaired groups: one given morphine 24 hr prior to and the other 24 hr after odor exposure. The paired group showed an odor aversion relative to both of the unpaired groups, which did not differ. The latter finding suggests that even if morphine metabolism is incomplete after 24 hr, behavior is unaffected. These results are discussed in reference to the functional development of the opioid system in rats.

Aging↗

PubMed1991

Serotonin, but not dopamine, metabolites are increased in selected brain regions of subordinate male rats in a colony environment.

Subordinate male laboratory rats maintained in mixed-sex groups in a Visible Burrow System habitat show a complex pattern of stress-related changes including enhanced defensive behavior, early mortality and increased voluntary ethanol consumption. Analysis of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels indicated that 5-HT levels do not differ between colony subordinates, colony dominants, and singly-housed control animals. However, 5-HIAA levels were higher in subordinates than either dominants or control animals in the preoptic area, amygdala, hippocampus, and spinal cord, and, were higher than dominants only, in entorhinal cortex. Subordinates' regional 5-HIAA/5-HT ratios were reliably higher than those of dominant or control animals in midbrain and spinal cord and reliably higher than dominants only, in hypothalamus. Dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) levels and DA/DOPAC ratios were affected neither in hypothalamus nor midbrain. These findings suggest that a consistent increase of 5-HIAA levels in selected brain regions of subordinate rats may represent a biological substrate for a well-characterized pattern of alterations in defensive behaviors for these animals.

Animals↗

PubMed1991

Ontogenetic changes in dopaminergic pre and postsynaptic elements in rat brain: effects of quinpirole and sulpiride.

The effects of quinpirole and sulpiride on dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and accumulation of dihydroxyphenylalanine (DOPA) after inhibition of DOPA decarboxylase were determined for the striatum and tegmentum of 11- and 17-day-old rat pups. In both 11- and 17-day-olds, sulpiride enhanced striatal DOPAC and DOPA accumulation; whereas, quinpirole decreased DOPAC levels and increased DA levels. In the tegmentum, sulpiride enhanced DOPA accumulation in the 11-day-olds only. 3H-spiroperidol binding sites were also measured in the striatum, nucleus accumbens, tegmentum, medial frontal cortex, and the hippocampo-entorhinal area of 11- and 17-day-old pups. Age-dependent increases in binding site density were found in the striatum and nucleus accumbens.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Neurochemical and behavioral effects of acute and chronic treatment with apomorphine in rats.

In three experiments, rats were injected once daily with 5.0 mg/kg apomorphine or vehicle and tested for locomotor activity for 10-14 days. In each experiment, apomorphine produced behavioral sensitization, characterized by a progressively greater increase in locomotor activity with each succeeding injection. On day 11 of testing, in an experiment designed to assess the synthesis of dopamine (DA), rats were injected with 5.0 mg/kg apomorphine or vehicle, followed by 100 mg/kg NSD-1015, an inhibitor of the enzyme l-aromatic amino acid decarboxylase. After administration of NSD-1015, concentrations of dihydroxyphenylalanine (DOPA) were determined in striatal and mesolimbic tissues by high performance liquid chromatography (HPLC) with electrochemical detection. The results revealed a significant decrease in accumulation of DOPA in both striatal and mesolimbic tissue after acute treatment with apomorphine. More important, chronic treatment with apomorphine produced a significant increase in accumulation of DOPA in both areas. In subsequent experiments, rats on day 14 of testing were sacrificed for determination of levels of DA, 3,4-dihydroxyphenylacetic acid (DOPAC) or specific binding of [3H]spiperone in the striatum and mesolimbic region. Although levels of DOPAC were significantly reduced in the regions of the brain after an acute injection of apomorphine, chronic treatment with apomorphine did not significantly affect levels of DA, DOPAC or specific binding of [3H]spiperone. These findings suggest that the development of behavioral sensitization to apomorphine may be related to an alteration in the synthesis of DA.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1991

Catalepsy produced by striatal microinjections of the D1 dopamine receptor antagonist SCH 23390 in neonatal rats.

Systemic injection of the D1 dopamine receptor antagonist SCH 23390 produces catalepsy that is of lesser magnitude in neonatal than in adult rats. The present experiments were conducted in order to determine if SCH 23390 would produce catalepsy in neonatal rats following intrastriatal injection and if the ontogenetic pattern of catalepsy induced by intrastriatal SCH 23390 would be similar to the pattern observed with systemic injections. Rat pups (11 or 28 days of age) were microinjected unilaterally with SCH 23390 (0.2, 1, 5 or 10 micrograms) and tested for catalepsy using the forepaw-on-horizontal-bar test. The results demonstrated that robust catalepsy occurred at both ages following intrastriatal injection and that catalepsy induced by 5 micrograms SCH 23390 was of lesser magnitude in 11-day-olds than in 28-day-olds. A separate study assessed the distribution of [3H]SCH 23390 (5 micrograms) following intrastriatal injection in 28-day-olds. Results of the distribution study indicated that [3H]SCH 23390 was localized primarily within the striatum. Taken together, these results suggest that the striatal mechanisms for catalepsy produced by D1 receptor blockade are present, but not fully mature, in preweanling rat pups.

Age Factors↗

PubMed1991

Autoradiographic localization of dopamine D1 and D2 receptors in rat nucleus accumbens: resistance to differential rearing conditions.

The radioligands [3H]SCH 23390 and [3H]spiroperidol were used to label dopamine D1 and D2 receptors, respectively, in rat brain slices. Striatal sections were incubated in one of various concentrations of radioligand in the presence or absence of (+)-butaclamol and the resulting labeling was determined by liquid scintillation spectrometry. Scatchard analyses of the data revealed KD values of 1.18 nM for D1 receptors and 0.33 nM for D2 receptors. Tissue sections taken from the entire rostrocaudal extent of the nucleus accumbens, as well as other brain regions, were then processed for autoradiographic analysis of D1 and D2 receptors using a radioligand concentration equal to 1.5 X KD. After apposing the slices to 3H-sensitive film, topographical differences among brain areas were analysed using a quantitative densitometry system which determined the absolute amount of ligand binding relative to calibrated optical density standards. The nucleus accumbens exhibited a rostral-to-caudal density gradient for both D1 and D2 receptors. For D1 receptors, the density was similar across most of the nucleus accumbens, although the most caudal portion examined had a lower density than rostral portions. In contrast, the density of D2 receptors exhibited a more gradual gradient across the entire rostrocaudal extent of the nucleus accumbens. There was no significant rostrocaudal density gradient of either D1 or D2 receptors in either the olfactory tubercle or caudate-putamen in the same tissue sections. A lateral-to-medial gradient of D2 receptors was also present in the nucleus accumbens. That is, while there was no difference in the density of D1 receptors between the lateral core and medial shell subdivisions, the shell had a lower density of D2 receptors than did the core. The density of D1 and D2 receptors in the mesolimbic and nigrostriatal systems was compared in groups of animals raised from 30 to 60 days of age in an impoverished condition, a group-caged condition or an enriched condition. While the brain weight of enriched condition animals was higher than impoverished condition animals, there were no significant differences in the density of D1 or D2 receptors among the different groups. Apparently, the densities of D1 and D2 receptors in the brain are resistant to differential rearing conditions.

Animals↗

PubMed1991

Chronic ascorbate potentiates the effects of chronic haloperidol on behavioral supersensitivity but not D2 dopamine receptor binding.

Ample behavioral evidence suggests that ascorbate parallels the action of haloperidol, a widely used neuroleptic. To determine the extent to which this parallel extends to chronic treatment, 21 days of exposure to ascorbate (100 or 500 mg/kg) alone or combined with haloperidol (0.5 mg/kg) were assessed on stereotyped behavior and neostriatal D2 dopamine receptor binding in rats. Our results indicate that when challenged with the dopamine agonist, apomorphine (0.5 mg/kg), animals chronically treated with haloperidol or high-dose ascorbate alone display a supersensitive sniffing response relative to controls, while animals chronically treated with the combination of haloperidol and high-dose ascorbate display a further potentiation of sniffing relative to the haloperidol groups. In addition, [3H]spiperone saturation studies showed, as expected, an up-regulation of striatal D2 dopamine receptors in rats treated with haloperidol as reflected by a change in receptor density (Bmax) but not affinity (KD). Ascorbate treatment, however, had no effect on D2 receptor density or the distribution of [3H]apomorphine in whole brain. Even though chronic treatment with the haloperidol-high-dose-ascorbate combination produced an up-regulation of striatal D2 dopamine receptors, this treatment did not cause a further up-regulation relative to haloperidol alone nor did it have any effect on [3H]apomorphine distribution. Taken together, these findings indicate that although chronic ascorbate produces behavioral supersensitivity to apomorphine through central mechanisms, they appear to differ from those induced by chronic haloperidol.

Amphetamines↗

PubMed1990

Conditioned taste aversion and place preference with buspirone and gepirone.

The effects of the nonbenzodiazepine anxiolytics buspirone and gepirone were compared to diazepam at 1, 3, and 10 mg/kg using the conditioned taste aversion (CTA) paradigm. Buspirone and gepirone produced stronger CTA than diazepam (3 and 10 mg/kg) across repeated conditioning trials, indicating that these nonbenzodiazepine anxiolytics may have stronger aversive properties than diazepam. The effects of buspirone and gepirone (1 and 3 mg/kg) were also assessed using the conditioned place preference (CPP) paradigm. Both buspirone (1 and 3 mg/kg) and gepirone (3 mg/kg only) produced CPP, indicating that these drugs may have rewarding properties, and that buspirone is more potent than gepirone in producing CPP. These findings demonstrate that buspirone and gepirone have affective properties similar to abused drugs, and may therefore have abuse potential. It was also demonstrated that buspirone (3 mg/kg), but not gepirone (3 mg/kg), increased dopamine (DA) synthesis in the nucleus accumbens, a mesolimbic brain area thought to be involved in drug reward.

Animals↗

PubMed1990

Changes in locomotion and dopamine neurotransmission following amphetamine, haloperidol, and exposure to novel environmental stimuli.

Locomotor behavior and dopamine (DA) neurotransmission were assessed in rats exposed to either a novel or familiar stimulus environment while under the influence of amphetamine, haloperidol or saline. The behavioral results indicated that, as expected, amphetamine increased horizontal locomotor activity in a dose-dependent manner. Exposure to novelty also increased horizontal activity, and this behavioral effect was disrupted by both amphetamine and haloperidol. Regardless of whether the animals were exposed to the novel or familiar stimulus environment, amphetamine increased DA synthesis in the nigrostriatal system, but not in the mesolimbic system, whereas haloperidol increased DA synthesis in both the nigrostriatal and mesolimbic systems. Amphetamine also decreased DA metabolism and haloperidol increased DA metabolism in both the nigrostriatal and mesolimbic systems. In contrast, exposure to novelty alone was without effect on DA synthesis or metabolism in any region examined, suggesting that novelty-induced hyperactivity and amphetamine-induced hyperactivity involve different neurochemical mechanisms. However, exposure to novelty while under the influence of haloperidol produced a significant increase in DA metabolism in both the nigrostriatal and mesolimbic systems. These latter results suggest that exposure to novelty may produce a measurable activation of DA systems when the autoreceptors involved in the negative feedback loop are blocked.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1990

Conditioning of morphine-induced taste aversion and analgesia.

The process of selective associations is evident in the aversive conditioning literature, where it has been shown that external cues are readily associated with peripheral pain, whereas taste cues are more easily associated with effects of drug administration. Within this framework, it is of interest that the failures to obtain a conditioned analgesic response to a morphine-associated CS have used external cues as conditioned stimuli. In Experiment 1, subjects re-exposed to a morphine-associated CS not only expressed the anticipated taste aversion, but also exhibited a decrease in pain sensitivity that was evident 15 or 30 min following CS re-exposure. Experiment 2 suggested that the conditioned analgesic response was opioid mediated, as pre-test administration of naloxone blocked expression of the analgesic CR. In Experiment 3, an increase in opiate receptor sensitivity produced by chronic naltrexone treatment did not affect the strength of the taste aversion, but resulted in an increase in the magnitude of the conditioned analgesic response. Collectively, these data suggest a neuropharmacological dissociation in systems mediating the two responses.

Analgesia↗

PubMed1990

Naloxone enhances the expression of morphine-induced conditioned place preference.

The present study examined the effects of naloxone on acquisition and expression of morphine-induced conditioned place preference (CPP). Three groups of rats were given morphine (5 mg/kg, SC), both morphine and naloxone (1 mg/kg, SC), or saline paired with a distinctive environment. On alternating days they were given saline paired with another distinctive environment. After four exposures to each environment, the animals were given a preference test in which they had access to both environments simultaneously while under the influence of either naloxone (1 mg/kg, SC) or saline. Morphine-conditioned animals showed CPP evident as an increased amount of time spent in the drug-associated environment relative to saline controls. Rats given both naloxone and morphine during conditioning, and saline on the test day, did not show CPP. In contrast, morphine-conditioned animals given naloxone on the test day showed stronger CPP than morphine-conditioned animals given saline. These findings indicate that naloxone blocks the acquisition, but enhances the expression of morphine-induced CPP. In a separate experiment, the effects of naloxone on locomotor activity were determined during the CPP test. The results indicated that naloxone decreased locomotor activity. In morphine-conditioned animals only, naloxone also produced an increase in the amount of time per entry in the drug-associated environment. The results suggest that naloxone may enhance morphine-induced CPP by decreasing locomotor activity that may otherwise compete with expression of CPP.

Animals↗

PubMed1990

Effects of apomorphine on novelty-induced place preference behavior in rats.

Adult male rats were exposed to one of two different stimulus compartments by being placed into the compartment for 30 min on each of eight consecutive days. Following this exposure, each rat was administered 0, 0.05, 0.1, 0.5 or 5.0 mg/kg apomorphine. Thirty min after injection, each animal was given free-choice access to the familiar (exposed) compartment and to the novel (nonexposed) compartment. As expected, saline-injected control animals displayed a preference for the novel compartment. This novelty preference was disrupted in animals given either 0.05 or 0.1 mg/kg apomorphine, but not in animals given either 0.5 or 5.0 mg/kg apomorphine. The disruption in novelty preference by the low doses of apomorphine did not reflect a disruption of locomotor activity, as there was no direct relationship between the preference for novelty and the rate of horizontal or vertical activity among the different treatment groups. Instead, the low doses of apomorphine may have inhibited dopamine function by blocking presynaptic autoreceptors selectively, and thus the reinforcing effect of the novel stimulation may have been attenuated.

Animals↗

PubMed1990

Effect of forebrain dopamine depletion on novelty-induced place preference behavior in rats.

Novelty-induced place preference behavior of rats was studied in two experiments. In the first experiment, separate groups of animals were habituated to a distinct environment 30 min daily for either zero, one, two, four or eight days. On the day following the last habituation day, animals were allowed 15 min free access to both the habituated (familiar) and a distinct novel environment. The results revealed a significant novelty preference in the two-, four- and eight-day habituation groups. In these same animals, the rate of horizontal and vertical activity was lower in the novel environment relative to the familiar environment. The influence of forebrain dopamine (DA) projections on novelty preference behavior was studied in the second experiment. Animals were given an injection of 6-hydroxydopamine (6-OHDA) into the nucleus accumbens or were given sham surgery, and then they were given four habituation days to one environment. Novelty-induced place preference was blocked in the lesioned animals, as the amount of time spent in the novel and familiar environments was not significantly different. Lesioned animals also failed to show a difference in locomotor activity between the novel and familiar environments. Subsequent assay data revealed that the 6-OHDA lesion reduced DA levels in the nucleus accumbens, anterior striatum and olfactory tubercles by over 65% as compared to sham surgery. These results suggest that novelty preference behavior may be mediated by a central DA pathway similar to that involved in other types of reinforcing stimuli, such as food, water and drugs of abuse.

Animals↗

PubMed1989

Opioid mediation of cocaine-induced hyperactivity and reinforcement.

The mechanisms by which cocaine produces hyperactivity and reinforcement remain poorly understood. Since reinforcement is also a property of other drugs of abuse including opiates, we examined the possible mediation of these cocaine-induced behaviors by endogenous opioid peptides. In this study, we have confirmed reports that cocaine increases locomotor activity and conditioned place preference in rats. We have also demonstrated that opioid receptor blockade with naloxone antagonizes completely the locomotor-activating effect of cocaine and attenuates the strength of the place preference conditioning produced by cocaine. These data support the thesis that endogenous opioids are involved in mediation of cocaine-induced behavior.

Animals↗

PubMed1989

Ontogenetic changes in [3H]-spiroperidol binding sites in posthatch chick brain.

The ontogenetic development of [3H]-spiroperidol binding sites was measured in the optic tectum, cerebellum, forebrain base, and forebrain roof of 1-, 4-, and 16-day-old chicks. In the chick optic tectum and cerebellum both the density and the total number of [3H]-spiroperidol binding sites increased from 4- to 16-days-posthatch, but no significant differences were found in either brain area across the initial four posthatch days. In the forebrain base, [3H]-spiroperidol receptor density and total binding increased significantly between 1- and 4-days-posthatch, but at 16-days-posthatch there was a slight decrease in receptor density. Binding sites in the forebrain roof were minimal at all ages. As expected, saturation experiments yielded curvilinear plots indicating the presence of high- and low-affinity binding sites. The high-affinity sites probably reflect dopamine D-2 receptors; whereas, the low-affinity sites may reflect other receptor types, possibly serotonin S-2. These results suggest that large doses of haloperidol, which are normally used in chick behavioral research, may produce behavioral effects by antagonizing multiple receptors.

Aging↗

PubMed1989

Novelty-induced place preference behavior in rats: effects of opiate and dopaminergic drugs.

In Experiment 1, adult male rats were given eight 30-min exposures to one of two distinct environments. Control animals received either four exposures to each environment or were not exposed to either environment. When given free-choice access to both environments simultaneously, animals spent significantly more time in the novel environment relative to the familiar environment. In these same animals, horizontal and vertical activity rates were lower in the novel environment than in the familiar environment. In Experiments 2-5, animals were assessed for novelty preference behavior under the influence of either morphine (0, 0.1, 0.3, 1.0 or 3.0 mg/kg), naltrexone (0, 0.1, 0.3 or 1.0 mg/kg), amphetamine (0, 0.1, 0.3 or 1.0 mg/kg) or haloperidol (0, 0.03, 0.1, 0.3 or 1.0 mg/kg). Haloperidol produced a dose-dependent disruption in novelty preference behavior, while all other drugs tested were without effect. Haloperidol also disrupted the novelty-induced decrease in horizontal and vertical activity rates. These results suggest that haloperidol blocks the reinforcing and locomotor-depressant effects of a novel environment in a free-choice preference test.

Amphetamines↗

PubMed1989

Prefrontal cortex lesions differentially disrupt cocaine-reinforced conditioned place preference but not conditioned taste aversion.

The reinforcing efficacy of cocaine is thought to involve, at least in part, mesocortical dopaminergic (DA) neurons. Rats will self-administer cocaine applied directly into the medial prefrontal cortex but not into nucleus accumbens or the ventral tegmental area (Goeders & Smith, 1983). The present experiments were conducted to assess whether lesions of prefrontal cortex (mesocortical DA target regions) attenuate the reinforcing properties of systemically administered cocaine. Male Sprague-Dawley rats were anesthetized, and one of three subfields (medial, orbital, or precentral) of the prefrontal cortex was removed by aspiration or no brain injury was done (sham operates). In four experiments the rats were tested on conditioned place preference (CPP), conditioned taste aversion (saccharin conditioned stimulus, cocaine unconditioned stimulus), general activity in the running wheel and open field, and food-reinforced spatial alternation in the T-maze. Sham operates demonstrated a cocaine-induced place preference, rats with medial frontal lesions showed a cocaine-induced place aversion, and other operates showed neither a conditioned place preference nor an aversion. The results of this experiment suggest that lesions of the DA projection fields of the prefrontal cortex in the rat reduce the positive reinforcing properties of systemically injected cocaine. In the second experiment, all subjects showed a conditioned taste aversion of equal magnitude. This suggests that whereas the positive reinforcing properties were affected differentially by prefrontal cortex lesions, the aversive properties were not affected. In Experiment 3 there were no lesion-induced differences in activity in either the running wheel or the open field. Therefore, changes in motor activity cannot account for the CPP data. In the final experiment, the medial frontal operates were impaired relative to the precentral and sham operates on learning to alternate choices in the T-maze, but the orbital frontal operates' performance was not different from that of any other group. This suggests that a general disruption of all reinforcement mechanisms did not occur following these lesions. Instead, these results indicate that mesocortical DA projection regions are involved with mediating the reinforcing properties of cocaine and that there is a separate system mediating the aversive properties of cocaine.

Animals↗