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Biomedical subjects

H E Criswell

Publications and source records attributed to H E Criswell.

At least 19 recordsLinked to original sources
PubMed1992

Comparison of the D1-dopamine agonists SKF-38393 and A-68930 in neonatal 6-hydroxydopamine-lesioned rats: behavioral effects and induction of c-fos-like immunoreactivity.

Administration of the selective D1-dopamine receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (SKF-38393) to neonatal 6-hydroxydopamine-lesioned rats results in profound behavioral manifestations and induction of striatal c-fos-like immunoreactivity. The full D1-dopamine agonist I,[R,S]1-aminomethyl-3,4-dihydro-5,6-dihydroxy-3-phenyl-1H-2-benzopyran hydrochloride (A-68930), like SKF-38393, produced a dose-dependent, D1-selective increase in locomotor activity and striatal c-fos-like immunoreactivity. These responses were antagonized by a D1-dopamine antagonist, but not by a D2-dopamine antagonist. A-68930 produced locomotor activation at a lower dose than SKF-38393, but no dose of A-68930 was able to produce the magnitude of locomotor activation seen with SKF-38393. Both A-68930 and SKF-38393 induced similar stereotyped behaviors and possessed similar propensities to induce self-injurious behavior in neonatally lesioned rats; however, A-68930 was significantly more potent than SKF-38393 in inducing these behaviors. When either SKF-38393 or A-68930 were administered repeatedly at 2-week intervals, behavioral sensitization (priming) occurred. However, unlike SKF-38393, a high dose of A-68930 produced seizure activity and markedly desensitized D1-dopamine receptor activation for up to 3 days after administration. These results with A-68930 provide additional evidence that the specific behavioral and biochemical responses observed in neonatally lesioned rats after SKF-38393 administration are due to actions on D1-dopamine receptors, and indicate that A-68930 provides a new tool for investigating D1-dopamine receptor function.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Augmented sensitivity of D1-dopamine receptors in lateral but not medial striatum after 6-hydroxydopamine-induced lesions in the neonatal rat.

Lesioning of neonatal rats with the neurotoxin 6-hydroxydopamine (6-OHDA) reduced striatal dopamine (DA) levels to 3% of control levels and produced marked increases in the behavioral effects of the selective D1-DA receptor agonist SKF-38393 in these animals when tested as adults. However, no differences were observed, either in basal or D1-DA-stimulated striatal cAMP formation or in forskolin-stimulated or GTP-stimulated cAMP production, between control and lesioned animals. C-fos-like immunoreactivity after SKF-38393 was significantly greater in dorsolateral vs. ventromedial aspects of the striatum in lesioned animals. Like the c-fos response, augmented electrophysiological responsiveness to SKF-38393 occurred in lesioned rats in lateral, but not medial, portions of the striatum. No differences were found in nucleus accumbens in sensitivity to SKF-38393 between control and lesioned rats. Although autoradiographic determination of D1-DA receptor binding throughout the striatum and nucleus accumbens revealed no differences between unlesioned and lesioned rats, tyrosine hydroxylase-like immunoreactivity was reduced with a regional distribution inversely related to c-fos-like immunohistochemical expression. These findings demonstrate that regionally enhanced electrophysiological sensitivity of striatal neurons to D1-DA receptor agonists after neonatal 6-OHDA-induced lesions is associated with regional changes in c-fos-like immunoreactivity and tyrosine hydroxylase-like immunohistochemistry, but not with changes in D1-DA receptor autoradiography or D1-DA-stimulated adenylyl cyclase activity. Such regional consequences of 6-OHDA-induced lesions in neonates may contribute to the unique behavioral patterns observed when these rats are challenged with L-dopa or D1-DA agonists as adults.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1992

Pharmacologic evaluation of SCH-39166, A-69024, NO-0756, and SCH-23390 in neonatal-6-OHDA-lesioned rats. Further evidence that self-mutilatory behavior induced by L-dopa is related to D1 dopamine receptors.

The purpose of the present investigation was to explore further the hypothesis that the self-injurious behavior induced by L-dihydroxyphenylalanine (L-DOPA) in neonatal-6-hydroxydopamine (OHDA)-lesioned rats is associated with an action on D1 dopamine receptors. This was accomplished by examining the behavioral responses induced by SKF-38393, quinpirole, and L-DOPA after treatment with the D1 antagonist SCH-23390 and three new pharmacologic agents, SCH-39166, NO-0756, and A-69024, reported to be D1 antagonists. All putative D1 antagonists were found to antagonize the action of SKF-38393 without reducing the increased locomotion and behavioral responses induced by quinpirole, consistent with an in vivo action on D1 receptors. The potency hierarchy of the compounds against the action of SKF-38393 on activity, from strongest to weakest, was: SCH-39166 equaled SCH-23390 and these were greater than NO-0756, which was greater than A-69024. All compounds were found to antagonize L-DOPA-induced self-mutilatory behavior (SMB) in neonatal-6-OHDA-lesioned rats in a dose-related manner. The potency hierarchy against this behavior, from strongest to weakest, was: SCH-23390, SCH-39166, NO-0756, and A-69024. The correlation between the ED50 for the ability of these drugs to antagonize SKF-38393-induced activity and their ability to reduce SMB by L-DOPA was greater than 0.99. In conclusion, the present findings provide additional evidence in vivo that NO-0756, SCH-39166, and A-69024 are selective D1 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Ethanol potentiates gamma-aminobutyric acid-mediated inhibition in the inferior colliculus: evidence for local ethanol/gamma-aminobutyric acid interactions.

The effect of ethanol on gamma-aminobutyric acid (GABA)-mediated inhibition of neurons of the inferior collicular cortex (IC) was investigated. Systemic administration of 0.5 g/kg ethanol, but not 0.25 g/kg ethanol, potentiated the inhibitory effect of GABA on IC neuronal activity. As with systemic administration of ethanol, local application of two concentrations of ethanol potentiated, in a dose-dependent and concentration-dependent manner, GABA-mediated inhibition of IC activity. When utilizing the lower ethanol concentration (270 mM), increasing ethanol ejection currents produced a correspondingly greater amount of augmentation of GABA inhibition without concomitant changes in spontaneous neural activity. At the highest ejection current tested (90 nA), ethanol doubled the inhibitory effects of GABA on IC neuronal activity. Local application of a higher concentration of ethanol (2.7 M) also potentiated GABA-mediated inhibition, with greater ejection currents producing greater potentiation of GABA-inhibition. Compared to the lower ethanol concentration, the higher ethanol concentration required lower ejection currents to produce comparable amounts of potentiation of GABA inhibition. These findings demonstrate that ethanol potentiates GABA inhibition of IC activity via a local action. In contrast to the effects of ethanol on GABA inhibition, locally applied ethanol failed to potentiate the inhibition by glycine of IC activity, indicating that ethanol does not indiscriminately potentiate all types of inhibition of IC neural activity. Additionally, locally applied ethanol failed to potentiate inhibition by GABA in the lateral septum, indicating that ethanol/GABA interactions are site specific. These findings indicate that ethanol specifically potentiates GABA-mediated inhibition of neural activity, and that this action occurs via a local action at specific sites in brain.

Animals↗
PubMed1991

Ethanol inhibits NMDA-evoked electrophysiological activity in vivo.

Recent studies have demonstrated that ethanol blocks N-methyl-D-aspartate (NMDA) responses in vitro. In the present study, evidence is provided that ethanol, when administered by the systemic route to rats, also inhibits NMDA-evoked electrophysiological activity in vivo at behaviorally relevant doses. Ethanol, at doses in rats ranging from those producing minimal changes in spontaneous behavioral activity (0.75 g/kg) to those producing marked suppression of behavioral activity (2.5 g/kg), produced a dose-dependent inhibition of the ability of NMDA, when iontophoresed onto neurons of the medial septum (MS), to activate MS neurons. However, at all doses of ethanol tested, a proportion of MS neurons responded to ethanol with essentially complete inhibition of NMDA-evoked activity, whereas other MS neurons responded to ethanol with little or no inhibition of NMDA-evoked activity. By way of comparison, MK-801, a non-competitive NMDA antagonist, antagonized NMDA-evoked activity in all MS neurons tested. In contrast to the actions of ethanol, MK-801 increased, rather than decreased, behavioral activity even at doses that completely inhibited NMDA-evoked activity in all MS neurons tested. These latter findings provide evidence that inhibition of NMDA-evoked activity cannot account for all of the behavioral effects of ethanol. In conclusion, while the present results demonstrate for the first time that ethanol can inhibit NMDA-evoked neuronal activity in vivo, they also indicate that additional neural actions must contribute to ethanol's pharmacological profile.

Animals↗
PubMed1990

Long-term D1-dopamine receptor sensitization in neonatal 6-OHDA-lesioned rats is blocked by an NMDA antagonist.

Repeated administration of the D1-dopamine agonist SKF-38393 to adult rats having had dopaminergic neurons destroyed early in development results in an increasing enhancement of the behavioral response to SKF-38393 with each dose until a maximum is reached. This increased sensitivity lasts for at least 6 months. In the present study, this long-lasting change in behavioral responsiveness to repeated treatment with SKF-38393, referred to as D1-dopamine receptor priming, was shown to be dose dependent with smaller doses requiring an increased number of administrations to produce a maximal response when compared to higher doses. In addition, priming occurred equally well when treatment intervals ranged from 1 day to 14 days. These latter data reinforced the view that activation of D1-dopamine receptors results in a prolonged change in neural function. In subsequent experiments, D1-dopamine receptor priming was blocked by pretreatment with the NMDA-receptor antagonist MK-801. This antagonism of priming could not be attributed to a blockade of D1-dopamine receptors by MK-801 or to the induction of interfering behaviors. Because an NMDA antagonist interfered with D1-receptor priming as it does with other long-term neural messages, a common requirement for these diverse forms of neuronal plasticity appears to involve activation of the NMDA receptor. This functional link between NMDA receptors and dopaminergic function and its relationship to neuronal plasticity could have relevance to the biochemical mechanisms involved in learning and to symptoms in central disorders during development that worsen over time, particularly those proposed to involve malfunctioning dopaminergic mechanisms.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

Evidence that lack of brain dopamine during development can increase the susceptibility for aggression and self-injurious behavior by influencing D1-dopamine receptor function.

1. Lesch-Nyhan disease has a defined neurological lesion that is accompanied by abnormal motor function, aggression and self-injurious behavior. 2. The dopamine deficiency in Lesch-Nyhan disease has been modelled by destroying dopamine-containing neurons in neonatal rats with 6-hydroxydopamine. 3. Because D1-dopamine antagonists will block self-injurious behavior induced by L-DOPA in neonatal-6-OHDA-lesioned rats, D1-dopamine antagonists are proposed as a potential therapy for aggression and self-injurious behavior in patients with these symptoms. 4. The determination that the drug SCH-12679, which exhibited effectiveness against aggressiveness in mentally retarded patients, is a D1-dopamine antagonist supports the view that new D1-dopamine antagonists being developed will be an effective therapy for some types of aberrant behavior in this population.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1990

A dopamine deficiency model of Lesch-Nyhan disease--the neonatal-6-OHDA-lesioned rat.

Lesch-Nyhan syndrome is characterized by a deficiency of the enzyme hypoxanthine phosphoribosyl transferase (HPRT), compulsive self-mutilatory behavior (SMB), and a loss of central dopaminergic neurons. In order to model the loss of central dopamine-containing neurons in this developmental disorder, neonatal rat pups 3 days of age were given the neurotoxin 6-OHDA intracisternally to reduce brain dopamine. Accompanying the profound loss of dopamine produced by this treatment was an increase in striatal serotonin content. When these neonatally lesioned rats were challenged as adults with systemically administered L-DOPA or with muscimol administration into substantia nigra reticulata (SNR), SMB was observed, a response not observed in unlesioned rats. Thus, the neonatally lesioned rats exhibit increased susceptibility for SMB. Since a D1-dopamine antagonist blocked the SMB response to L-DOPA, it was proposed that D1-dopamine receptors were critical to this behavioral response. Basic investigations concerning D1-dopamine receptor mechanisms in the lesioned rats have been performed and these are reviewed. The data in the neonatally lesioned rats provide convincing evidence that the absence of central dopaminergic neurons is responsible for at least some of the neurological symptoms of the Lesch-Nyhan syndrome, a finding consistent with data collected in mice with an HPRT deficiency.

Animals↗
PubMed1990

Pharmacological evaluation of SCH-12679: evidence for an in vivo antagonism of D1-dopamine receptors.

The benzazepine compound SCH-12679 has been shown to have clinical efficacy against aggressive behavior in mentally deficient patients. The purpose of the present investigation was to evaluate the potential mechanism of action of SCH-12679. Because of the structural similarity of SCH-12679 to compounds influencing D1-dopamine receptors, even though in vitro studies indicated no direct action on this receptor, investigations focused on the possibility that in vivo SCH-12679 antagonizes the function of this dopamine receptor subtype. After i.p. administration to neonatal-6-hydroxydopamine (6-OHDA)-lesioned rats, SCH-12679 reduced, dose-dependently, the locomotor activity induced by SKF-38393, a D1-dopamine agonist. A dose of SCH-12679 that antagonized the activity induced by SKF-38393 in neonatally lesioned rats also blocked various behaviors observed after administration of this D1-dopamine agonist. SCH-12679 did not alter the activity or behavioral responses induced by quinpirole, a D2-dopamine agonist, when administered to 6-OHDA-lesioned rats. SCH-12679 antagonized the self-mutilation behavior and behavioral responses induced by L-dihydroxyphenylalanine in neonatal-6-OHDA lesioned rats in a manner similar to the prototypic D1-dopamine antagonist SCH-23390 and, like SCH-23390, produced a deficit in avoidance responding in unlesioned rats. SCH-12679 produced a small, transient activation of locomotor activity immediately after administration to neonatal-6-OHDA-lesioned rats that was not observed in unlesioned or adult-6-OHDA-lesioned rats.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Clozapine antagonism of D-1 and D-2 dopamine receptor-mediated behaviors.

When tested in rats supersensitive to dopamine agonists, the atypical neuroleptic clozapine displayed pharmacological properties expected of both a D-1 and D-2 receptor antagonist. The locomotor response induced by the D-1 receptor agonist SKF-38393 in neonatal-6-hydroxydopamine (6-OHDA)-lesioned rats was reversed in a dose-related fashion, although a complete blockade of this behavior was not observed indicative for only a partial antagonism of D-1 receptor function. Clozapine also blocked the self mutilation resulting from L-dihydroxyphenylalanine (L-DOPA) administration to neonatal-6-OHDA-lesioned rats, an effect previously linked to D-1 receptor activation. At higher doses, clozapine blocked the locomotor activity elicited by the D-2 agonist LY-171555 in adult-6-OHDA-lesioned rats. Therefore, the action of clozapine on D-1 as well as D-2 receptor-mediated behaviors contributes to its pharmacological effects. The ability of clozapine to stop self-mutilatory behavior in neonatal-6-OHDA-lesioned rats suggests that this drug might be an effective treatment for self-injurious behavior associated with the Lesch-Nyhan syndrome and mental retardation.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

Serotonergic innervation of the rat caudate following a neonatal 6-hydroxydopamine lesion: an anatomical, biochemical and pharmacological study.

6-Hydroxydopamine (6-OHDA) treatment of neonatal rats resulted in a dose-related loss of striatal dopamine (DA). These reductions corresponded closely with the loss of tyrosine hydroxylase-containing terminals at this brain site. Striatal serotonin (5-HT) concentration increased only after DA was maximally depleted by the highest dose of 6-OHDA. Quantitative immunohistochemistry revealed that the increased 5-HT content after neonatal 6-OHDA lesioning was due to a proliferation of 5-HT nerve terminals. The density of immunoreactive 5-HT-containing terminals appeared to increase more than did the 5-HT content. The present study examined whether 5-HT hyperinnervation was playing a role in behavioral responses induced by D1-DA agonists and antagonists in neonatally lesioned rats, because reports have suggested that these drugs may interact with 5-HT receptors. However, SCH-23390, the D1-DA antagonist (0.3 mg/kg), did not alter behavioral responses to 5-HTP and SKF-38393 (3 mg/kg), a D1-DA agonist did not produce any signs of activating 5-HT receptors in 5,7-DHT-lesioned rats. These data indicate that these compounds affecting D1-DA receptors do not have a significant effect on 5-HT function at doses which have maximal effects on D1-DA receptor function. Pretreatment with the 5-HT antagonist methysergide did not produce a change in apomorphine-induced locomotion and did not antagonize the self-mutilation or the other behaviors produced by L-DOPA or SKF-38393 in neonatally lesioned rats, suggesting that 5-HT hyperinnervation is not responsible for these drug-induced changes in neonatal 6-OHDA-lesioned rats.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1989

A conflict procedure not requiring deprivation: evidence that chronic ethanol treatment induces tolerance to the anticonflict action of ethanol and chlordiazepoxide.

A conflict task that does not require food or water deprivation is described. Drugs with known anticonflict action including chlordiazepoxide, methysergide, ethanol, and TRH were active in this test while amphetamine, buspirone, and morphine were not. Because this procedure did not require food or water deprivation, the effect of chronic ethanol administered in a liquid diet on the anticonflict actions of ethanol and chlordiazepoxide could be examined. Seven or 12 days of chronic ethanol treatment resulted in tolerance to the acute anticonflict action of ethanol whereas 3 days of treatment did not. Tolerance was not observed to a dose of ethanol administered 3 hr after a previous ethanol treatment. Following a chronic ethanol liquid diet, cross-tolerance to the anticonflict action of chloridazepoxide was observed. This latter observation is consistent with the view that ethanol influences a neural mechanism associated with benzodiazepine function. The importance of tolerance to the anticonflict action of ethanol is discussed.

Animals↗
PubMed1989

Dopamine deficiency in self-injurious behavior.

Based on the report that patients with Lesch-Nyhan Syndrome (LNS) have a central deficiency of dopamine similar in magnitude to that seen in Parkinsonism, the age at which dopaminergic neurons are disrupted was proposed to explain the differing symptoms observed in these two disorders. To investigate this hypothesis, brain dopaminergic neurons were lesioned in neonatal and adult rats with 6-hydroxy-dopamine (6-OHDA). Results demonstrated that neonatally lesioned rats had learning deficits and elevated levels of serotonin in the striatum--characteristics observed in LNS. Administration of L-dopa produced self-injurious behavior (SIB) in neonatally lesioned but not adult lesioned rats. Subsequent studies revealed that the SIB induced by L-dopa was dependent upon activation of D1 receptors. The elevated susceptibility of neonatally lesioned rats for SIB was demonstrated further by the enhanced occurrence of SIB when muscimol was administered into the substantia nigra reticulata (SNR). Other studies demonstrated that adenosine agonists could antagonize SIB, suggesting that the reduced adenosine observed in LNS may contribute to this symptom. The basic work being performed should be relevant to LNS and to other developmental disorders exhibiting SIB.

Animals↗
PubMed1987

Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine.

Behavioral and neurochemical effects of haloperidol (D2-dopamine antagonist) and SCH-23390 (D1-dopamine antagonist) were examined in unlesioned rats and in rats lesioned with 6-hydroxy-dopamine (6-OHDA) as adults or as neonates. In unlesioned rats, chronic haloperidol treatment (15 days) resulted in an increase in D2-dopamine receptor density, as measured with [3H]spiperone, in the nucleus accumbens and in the caudate-putamen. Rats treated as adults with 6-OHDA responded to chronic haloperidol similarly to controls. However, adult rats treated with 6-OHDA as neonates did not exhibit an increase in [3H]spiperone binding in response to chronic haloperidol treatment. Control and adult 6-OHDA-treated rats given haloperidol exhibited a profound akinesia. In contrast, rats that received 6-OHDA as neonates and were tested as adults did not display a significant behavioral response to haloperidol at doses as high as 2 mg/kg. Results similar to those for haloperidol were also found for SCH-23390. Chronic treatment (15 days) with this D1-dopamine antagonist increased [3H]SCH-23390 binding in the nucleus accumbens and caudate-putamen in unlesioned rats as well as in adult 6-OHDA-treated rats. However, after neonatal 6-OHDA treatment, an elevation in [3H]SCH-23390 binding did not occur after chronic SCH-23390 treatment. SCH-23390 produced akinesia similar to that produced by haloperidol in unlesioned and in adult 6-OHDA-treated rats. In contrast, rats lesioned with 6-OHDA as neonates and tested as adults did not exhibit a significant behavioral response to SCH-23390 under our test conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1978

A flexible low cost signal averager.

A 2 channel signal averager based on the KIM-1 microcomputer module is described which can be easily assembled for under $500. Number of samples per pass can be set to 128 or 256 and sample time is variable from 1 msec to 256 msec. Averaged data can be displayed on an oscilloscope, output slowly for use of a chart recorder, or stored on a low cost audio cassette recorder for later analysis. Simply adding additional memory (for less than $100) allows it to be expanded to 8 channels.

Computers↗
PubMed1977

A simple chronic microinjection system for use with chemitrodes.

An inexpensive, electrically operated microinjection system is described which is small enough to be mounted on the animal side of a standard Mercury commutator. This eliminates the troublesome swivel joint needed for chronic microinjection in freely moving animals. This system allows simultaneous electrical stimulation or recording and chemical stimulation via a chemitrode using a standard 4-channel Mercury commutator.

Animals↗
PubMed1976

Analgesia and hyperractivity following morphine microinjection into mouse brain.

Analgesia and a paradoxical hyperreactivity to stimuli of sudden onset have recently been reported following the microinjection of morphine into the periacqueductal gray matter of rats. These effects have not been systematically investigated in other species. In the present study, both analgesia and hyperreactivity were observed as dose dependent effects of morphine microinjection into the periacqueductal gray matter of several strains of mice. Analgesia alone was produced by low doses of morphine while at higher doses analgesia was accompanied by hyperreactivity. Strain differences were noted with B6D2F1 mice being more susceptible to the hyperreactivity following morphine than BALB/c mice.

Analgesia↗