Bilateral changes in striatal dopamine metabolism after unilateral intracarotid and intrastriatal administration of apomorphine.

Following cannulation of the common carotid artery of female Sprague-Dawley rats, 3 microCi (10 micrograms) of [3H]apomorphine were infused. At various time intervals, drug concentrations were determined in the right and left striata, anterior forebrains, posterior forebrains and cerebella. One minute following intracarotid infusion of apomorphine, approximately a 65-fold right/left difference in apomorphine concentrations was attained in all forebrain structures, and this difference steadily diminished with time as a result of declining drug levels in the infused hemisphere. The concentrations of dopamine and its metabolites (DOPAC, HVA and 3-MT) were quantified by gas chromatography-mass spectrometry in the right and left striata at 5 and 15 min after unilateral intracarotid infusion of 1 microgram apomorphine. At both time intervals and regardless of the side infused, the metabolites of dopamine increased ipsilateral to the side of infusion. Moreover, 3-MT levels were significantly decreased in the contralateral striatum. After direct intrastriatal injection of either 0.1 or 1.0 microgram apomorphine into the right striatum, the levels of dopamine metabolites were again increased in the ipsilateral striatum. 3-MT levels were also decreased significantly in the left striatum. In contrast to the effects observed after systemic administration of apomorphine, these results demonstrate that dopamine release in the striatum is increased by selectively delivering higher concentrations of apomorphine to the nerve terminals of the nigrostriatal neurons. The effects of unilateral apomorphine on dopamine metabolism in the contralateral striatum are most likely the effect of interhemispheric communication.

Effects of prenatal phencyclidine on 3H-PCP binding and PCP-induced motor activity and ataxia.

Either phencyclidine hydrochloride (PCP) (5, 10, or 20 mg/kg) or saline was administered by subcutaneous injection to gravid CF-1 mice during either Mid (E6-15) or Late (E12-18) gestation. A nontreated control group (UTC) was left undisturbed during pregnancy. All treated and control litters were fostered at birth to untreated dams. Although postnatal challenge of PCP increased motor activity and ataxia in a dose-related manner, prenatal PCP had no effect on postnatal motor activity, ataxia or 3H-PCP binding. However, treatment period did have a significant effect on ataxia and 3H-PCP binding. In response to challenge doses of 5.0 and 7.5 mg/kg PCP, ataxia scores of the Late gestation offspring were significantly greater than the UTC offspring which in turn were significantly greater than the ataxia scores of the Mid gestation group. The results are discussed in relation to other animal and clinical reports of prenatal PCP exposure.

Dopamine autoreceptor agonists attenuate spontaneous motor activity but not spontaneous fighting in individually-housed mice.

The present study was conducted to determine whether or not two behavioral characteristics of individually-housed mice, hyperactivity in a novel environment and intermale fighting, are attenuated by the dopamine (DA) agonists, apomorphine, (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP). Autoreceptor-activating doses of these drugs which reduced spontaneous activity in a novel environment did not inhibit spontaneous fighting with conspecific olfactory bulbectomized males. Individually-housed mice were more active in a novel environment and showed a significant reduction of activity at lower doses of apomorphine, (+)- and (-)-3-PPP than group-housed mice. However, the ED50's for the inhibition of spontaneous activity in a novel environment in group- and individually-housed mice were similar: apomorphine, 0.02 vs. 0.012 mg/kg, SC; (+)-3-PPP, 0.50 vs. 0.51 mg/kg, SC; and (-)-3-PPP, 1.0 vs. 0.56 mg/kg, SC, for group- and individually-housed mice respectively. A significant proportion of individually-housed mice, but not group-housed mice, displayed catalepsy in response to high doses of (-)-3-PPP. These data suggest that DA autoreceptor agonists can modulate the hyperactivity syndrome but not spontaneous fighting behavior in individually-housed mice.

Phencyclidine during pregnancy: fetal brain levels and neurobehavioral effects.

Either phencyclidine (PCP) (5, 10, or 20 mg/kg) or saline was administered SC to pregnant CF-1 mice during either MID (E6-E15) or LATE (E12-E18) gestation. Because of the reported prolonged persistence of PCP in adult tissues we first determined its half-life in fetal brain for both treatment periods. PCP appeared rapidly in fetal tissues after maternal administration but was not detected after 8 hours. Then, other treated and control litters were fostered to untreated controls, growth determined and the ontogeny of isolation-induced aggressive behavior examined. Subteratogenic doses of PCP produced mild maternal toxicity without lethality. There was an apparent selective embryolethal effect on males but PCP did not produce an effect on postnatal growth. Prenatal PCP did not alter the ontogeny or intensity of isolation-induced aggressive behavior in male offspring. The results are discussed in relation to other prenatal studies of PCP toxicity and teratogenicity.

The effects of phencyclidine on fighting in differentially housed mice.

The effects of phencyclidine (PCP) on the fighting of individually housed male mice were examined (1) after different lengths (5-35 days) of individual housing, and (2) in mice of different ages (35, 70 or 170 days old) at the onset of individual housing. Significant increases in the total time spent fighting in a 10-minute aggression test were observed at 19-21 and 32-35 days of individual housing with 1.25 mg/kg PCP and at 10 and 32-35 days with 2.50 mg/kg PCP. Relative to control groups, the percentage of mice fighting after 19-21 and 32-35 days of individual housing was significantly decreased with 2.5 mg/kg. At 1.25 mg/kg, PCP increased total fighting time and decreased the latency to the first fight in mice at 35 or 70, but not 170 days of age at the onset of individual housing. No increases in motor activity in individually housed mice were recorded at these doses. These results suggest that PCP may facilitate fighting in mice when individually housed for a minimum of 10 days.

Behavioral and biochemical studies of dopamine receptor sensitivity in differentially housed mice.

Group housed and individually housed mice were compared in (1) the motor activity responses to direct and indirect dopamine (DA) agonists, (2) in vivo presynaptic autoreceptor sensitivity and (3) in vitro binding of 3H-spiperone. Relative to group housed mice, individually housed mice showed an increased motor activity response to amphetamine, 1.25 and 0.625 mg/kg. Using two in vivo measures of presynaptic DA receptor sensitivity, the antagonism of spontaneous locomotor activity and the antagonism of dihydroxyphenylalanine (DOPA) accumulation by apomorphine (APO), individually housed mice showed greater activity counts and higher DOPA accumulations than group housed mice. Levels of tyrosine were significantly greater in individually housed mice. Significant effects of housing were also noted with the motor activity response to APO, 0.075-0.300 mg/kg, following pretreatment with reserpine, an in vivo measure of postsynaptic receptor sensitivity. However, there was no effect of housing on the number or affinity of 3H-spiperone binding sites in the striatum. These results are discussed in terms of the presynaptic activity of catecholaminergic neurons and the postsynaptic receptor sensitivity to APO in individually housed mice.

Morphine enhances high-affinity choline uptake in mouse striatum.

The effects of morphine (2 mg/kg-60 mg/kg) on cholinergic neuronal activity were examined by the method of high-affinity, Na+-dependent [3H]choline uptake into synaptosomes isolated from mouse corpus striatum. Acute administration of analgesic doses of morphine (10 mg/kg, 20 mg/kg) significantly stimulated choline uptake into synaptosomes in a naloxone-reversible manner. When synaptosomes were directly exposed to pharmacologically effective concentrations of morphine (0.1 microM-10.0 microM) in vitro however, choline transport was not significantly different from control transport, suggesting that morphine (10 mg/kg, 20 mg/kg) does not stimulate choline uptake by a direct effect on the cholinergic nerve terminal. The possibility that acute morphine administration indirectly enhances striatal cholinergic neuronal activity by inhibiting dopaminergic function was supported pharmacologically since the dopaminergic agonists, apomorphine (10 mg/kg) or amantadine (50 mg/kg), reversed the stimulatory effect of morphine on choline uptake. High-affinity choline transport into synaptosomes was not significantly different from control uptake in response to a sub-analgesic dose of morphine (2 mg/kg) or in response to 60 mg/kg, a dose that elicited hypermotility. These data suggest that analgesic doses of morphine may indirectly enhance cholinergic neuronal activity in the mouse corpus striatum.

Cocaine potentiates ketamine-induced loss of the righting reflex and sleeping time in mice. Role of catecholamines.

Cocaine in graded doses potentiated ketamine-induced loss of the righting reflex and sleeping time. Potentiation of drug-induced sleep with cocaine was not a generalized phenomenon inasmuch as it had no effect on sleep induced by pentobarbital or hexobarbital and decreased sleep induced by phenobarbital. Pentylenetetrazole reduced ketamine sleep but d-amphetamine had a potentiative action. dl-alpha-Methyl-p-tyrosine methyl ester itself increased both the number losing the righting reflex and the sleeping time induced by ketamine. However, the effect cocaine on sleeping time was blocked 3 h after the dl-alpha-methyl-p-tyrosine methyl ester was given. The alpha and beta adrenergic blocking drugs, phenoxybenzamine and propranolol, increased the number of animals losing the righting reflex with ketamine, and phenoxybenzamine lengthened the sleeping time. Alpha and beta adrenergic agonists, l-phenylephrine and isoproterenol, increased the number of animals going to sleep with ketamine but did not significantly alter how long they would sleep. The agonists had no effect on the cocaine interaction with ketamine, whereas the antagonists blocked the effect of cocaine. Both stimulation and blockade of dopamine receptors led to increased loss of the righting reflex and sleeping time with ketamine but only receptor blockade antagonized the effect of cocaine on ketamine-induced sleep. Thus, both the noradrenergic and dopaminergic systems appear to be involved in the ability of cocaine to potentiate ketamine-induced sleep.

Effect of narcotics on monoamine oxidase activity of mouse brain.

The effect of morphine, levorphanol and methadone on the monoamine oxidase (MAO) activity of mouse brain was studied. Both methadone and levorphanol produced a concentration-dependent inhibition of whole brain mitochondrial MAO in vitro with an IC50 of approximately 7.4 x 10(-4) for levorphanol and 2.5 x 10(-6)M for methadone. Methadone also produced a 60% inhibition of the MAO activity of the hippocampus, a 32% inhibition of the striatal and hypothalamic enzyme, a 30% inhibition of liver, and a 20 and 23% inhibition of the cerebral cortex and cerebellum, respectively. Naloxone did not antagonize this effect of methadone. In contrast, morphine had little effect in vitro except at very high concentrations where it was inhibitory. This was not linear with concentration and no IC50 could be estimated. This would imply that the inhibition by morphine is non-specific. When acutely administered to mice, morphine and methadone, again differed. Methadone produced a slight but significant inhibition of whole brain MAO and a 34% inhibition of the striatal enzyme. Morphine, on the other hand, produced a marked enhancement in the activity of the striatal enzyme. Since this action could not be demonstrated in vitro, it would suggest that the in vivo effect of morphine is indirect resulting from an alteration of some other modulating system.

Studies on the role of dopaminergic systems in morphine-induced motor activity. Comparison with noradrenergic and cholinergic systems.

The role of dopaminergic, noradrenergic and cholinergic systems in morphine-induced motor activity was investigated in mice using both blockers and stimulators of the receptors of the respective systems. The dopaminergic blocking drugs, spiroperidol and clothiapine, significantly reduced while stimulating dopaminergic receptors with amantadine significantly increased morphine-induced motor activity. Blockade of noradrenergic receptors with phenoxybenzamine and cholinergic receptors with atropine significantly reduced morphine activity whereas stimulation of either of these systems with DOPS and physostigmine respectively, had no effect. These data suggest that a dopaminergic system mediates morphine-induced motor activity and that this can be modified by interrupting either noradrenergic or cholinergic systems.