Day/night differences in D1 but not D2 DA receptor protection from EEDQ denaturation in rats treated with continuous cocaine

The effect of chronic cocaine administration on the in vivo occupation of dopamine (DA) receptor subtypes was examined using the irreversible receptor blocker N-ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ). Rats were given continuous infusions of cocaine (vehicle, 2.5, 7.5, or 22.5 mg/day) via subcutaneous implants of Alzet osmotic minipumps for 14 days. Some groups were also given the D1 antagonist SCH 23390 and/or the D2 antagonist raclopride for this same time period. DA receptor binding techniques were used 24 hours post-EEDQ injection (Day 15, 5 mg/kg, intraperitoneally [ip]) in order to examine changes in D1 and D2 receptor densities in the striatum. Half of the rats were killed in the day with the other half killed at night in order to examine day/night differences in the effects of cocaine treatment. Results showed that chronic cocaine increased the protection of D1 receptors from EEDQ inactivation in a dosedependent fashion during the day, and decreased D1 protection from EEDQ at night. Since EEDQ has a low affinity for the DA receptor relative to endogenous DA or the exogenous ligands in this study, only receptors that are vacant are inactivated thereby allowing for an estimate of DA receptor occupation in vivo. Cocaine can therefore be said to increase D1 receptor occupation by DA in vivo during the day and decrease it at night. Coadministration of the DA antagonists eliminated this cocaine-induced day/night difference and, in the case of the D1 antagonist, produced opposite D1 receptor effects when administered alone. Chronic SCH 23390 treatment protected D1 receptors from EEDQ denaturation while D2 receptors were protected by chronic raclopride. In addition, raclopride was found to affect the affinity of both the D1 and the D2 receptors to the [³H]SCH 23390 and [³H] spiperone ligands, respectively. Since no day/night differences were found in D2 receptor density with respect to chronic cocaine treatment these findings have implications for a phasic D1/tonic D2 receptor hypothesis such that cocaine treatment selectively alters the level of DA at sites containing D1 receptors with differential effects depending on the day/night cycle. © 1993 Wiley-Liss, Inc.     

Effects of REMS deprivation on striatal dopamine and acetylcholine in rats.

Changes in the concentration of striatal dopamine (DA) and acetylcholine (ACh) in rats deprived of REM sleep for 10 days were compared with those obtained after a 4 day deprivation procedure. Animals placed on small (7 cm dia.) islands surrounded by water were completely deprived of REM sleep but able to obtain some slow-wave sleep. Concentration of striatal DA was significantly increased after 4 days and 10 days of REM sleep deprivation by 73 and 133%, respectively when compared to controls. Levels of ACh in the striatum were significantly enhanced (by 28%) after 10 day, but failed to show significant change after 4 day REM sleep deprivation procedure. The short term locomotor activity was significantly higher in REM sleep-deprived animals. Our data indicate that REM sleep deprivation results in marked alterations of both cholinergic and dopaminergic mechanisms in the rat striatum.     

Central dopaminergic neurons: effects of alterations in impulse flow on the accumulation of dihydroxyphenylacetic acid.

Stimulation of the nigro-neostriatal or mesolimbic dopamine pathway results in a stimulus dependent increase in the accumulation of dihydroxyphenylacetic acid (DOPAC) in the neostriatum and olfactory tubercles, respectively. A block of impulse flow induced pharamacologically by administration of gamma-butyrolactone or by placement of a lesion in the dopamine pathway results in a decrease in the steady state levels of DOPAC. Drugs which have previously been shown to alter impulse flow in central dopaminergic neurons also produce a predictable change in the brain levels of DOPAC. Drugs which increase impulse flow in nigro-neostriatal or mesolimbic dopamine neurons increase DOPAC levels in the striatum and olfactory tubercles and drugs which reduce impulse flow cause a reduction in DOPAC. Pargyline, a monoamine oxidase inhibitor, causes a rapid depletion of striatal DOPAC suggesting that this metabolite is rapidly cleared from the brain. Administration of benztropine, a potent inhibitor of dopamine reuptake, causes a significant decrease in striatal DOPAC and partially prevents the stimulus-induced increase in the accumulation of DOPAC. These observations together with the finding that about 85% of the DOPAC in the striatum disappears when the dopamine neurons in the nigro-neostriatal pathway are destroyed suggests that the majority of striatal DOPAC is formed within the dopaminergic neurons and may reflect the metabolism of dopamine which has been released and recaptured. We conclude that short-term changes in brain levels of DOPAC appear to provide a useful index of alterations in the functional activity of central dopaminergic neurons.     

Risperidone: a novel antipsychotic with many “atypical” properties?

The acute and chronic administration effects of risperidone (Ris), a mixed 5HT₂/D₂ receptor antagonist, versus haloperidol (Hal) on dopaminergic and serotoninergic activity were investigated in the rat prefrontal cortex (Pfc), and the whole striatum (Str) as well as separately, in dorsal striatum (StrD) and nucleus accumbens (Acb). During acute administration, Hal was found to be more potent than Ris in increasing DA turnover rate in StrD. In contrast, during chronic administration, Ris but not Hal, continued to increase DA turnover activity in StrD. Moreover, in contrast to Hal, chronic Ris treatment continued to increase DA and 5-HT turnover rate in Pfc. These differential effects reveal that Hal does not share common characteristics with Ris with respect to its neurochemical profile in the Str and Pfc.     

Regional distribution of metals and biogenic amines in the brain of monkeys exposed to manganese

Manganese chloride (20 mg/kg/day) was administered orally to male Rhesus monkeys. The levels of copper, calcium, manganese and biogenic amines m different regions of brain were determined after 18 months of manganese exposure. The levels of manganese were increased above control values in the cerebral cortex, cerebellum, diencephalon, corpus striatum, mid-brain and pons, but not in the medulla oblongata. Copper was increased only in the pons and medulla oblongata while calcium declined in pons, medulla oblongata and corpus striatum. Alterations in copper and calcium did not appear to be related to the altered metabolism of catecholamines in the brain.     

Effects of morphine on striatal dopamine metabolism: Possible mechanism of its opposite effect on locomotor activity in rats and mice

In rats, the catalepsy induced by analgesic doses of morphine was paralleled by a dose-dependent increase in the concentration of dopamine's (DA) metabolite, homovanillic acid (HVA) in the striatum. The effect of morphine on striatal HVA was supra-additive with the corresponding action of chlorpromazine (CPZ). It is concluded that in rats morphine induces catalepsy and a decrease in dopaminergic activity in the striatum by a mechanism different from that of other cataleptogenic agents, such as the neurologic CPZ. In mice, morphine induced an increased in locomotor activity (running); this effect was attenuated by bilateral lesions placed in the caudate nucleus. Pretreatment of mice with diethyldithiocarbamate (DDC), or d,l-α-methyl-p-tyrosine (αMT), inhibited the morphine-induced running activity. In αMT-treated mice 1-3,4-dihydroxyphenylalanine (l-dopa) restored the effectiveness of morphine whereas d,l-threo-3,4-dihydroxyphenylserine (dops) was ineffective. In contrast, in DDC-treated mice, dops and clonidine, but not 1-dopa, were effective in restoring morphine's effectiveness. Doses of morphine inducing running activity in mice produced a slight increase in striatal HVA level. It is concluded that in mice morphine produces locomotor hyperactivity by releasing DA from the presynaptic terminals in the striatum, thus increasing the dopaminergic activity in this structure. Norepinephrine has an important auxiliary function.     

The role of excitatory amino acids in behavioral sensitization to psychomotor stimulants

Behavioral sensitization refers to the progressive augmentation of behavioral responses to psychomotor stimulants that develops during their repeated administration and persists even after long periods of withdrawal. It provides an animal model for the intensification of drug craving believed to underlie addiction in humans.Mechanistic similarities between sensitization and other forms of neuronal plasticity were first suggested on the basis of the ability of N-methyl-D-aspartate (NMDA) receptor antagonists to prevent the development of sensitization [Karler, R., Calder, L. D., Chaudhry, I. A. and Turkanis, S. A. (1989) Blockade of “reverse tolerance” to cocaine and amphetamine by MK-801. Life Sci., 45, 599–606.]. This article will review the large number of subsequent studies addressing: (1) the roles of NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and metabotropic glutamate receptors in the development and expression of behavioral sensitization, (2) excitatory amino acids (EAAs) and the role of conditioning in sensitization, (3) controversies regarding EAA involvement in behavioral sensitization based on studies with MK-801, (4) the effects of acute and repeated stimulant administration on EAA neurochemistry and EAA receptor expression, and (5) the neuroanatomy of EAA involvement in sensitization.To summarize, NMDA, AMPA metabotropic glutamate receptors all participate in the development of sensitization, while maintenance of the sensitized state involves alterations in neurochemical measures of EAA transmission as well as in the expression and sensitivity of AMPA and NMDA receptors.While behavioral sensitization likely involves complex neuronal circuits, with EAAs participating at several points within this circuitry, EAA projections originating in prefrontal cortex may play a particularly important role in the development of sensitization, perhaps via their regulatory effects on midbrain dopamine neurons.The review concludes by critically evaluating various hypotheses to account for EAA involvement in the development of behavioral sensitization, and considering the question of whether EAA receptors are involved in mediating the rewarding effects of psychomotor stimulants and sensitization of such rewarding effects.     

(—)-Sulpiride activates the firing rate and tyrosine hydroxylase activity of dopaminergic neurons in unanesthetized rats

The effect of i.v. sulpiride on the firing rate of dopaminergic neurons in the substantia nigra, pars compacta (SN-DA cells) and tyrosine hydroxylase (TH) activity in the caudate nucleus was studied. In rats, paralyzed with succinylcholine and artificially respirated, (-)-sulpiride (10-50 mg/kg) produced a dose-related increase in the firing rate of SN-DA cells and in TH activity. On the contrary, in rats anesthetized with halothane, (-)-sulpiride (up to 50 mg/kg) activated neither dopaminergic firing nor TH activity. However, (-)-sulpiride (10-25 mg/kg) readily reversed the inhibitory effect of i.v. apomorphine (25 micrograms/kg) on dopaminergic firing in both anesthetized and unanesthetized rats. Since sulpiride fails to inhibit DA-sensitive adenylate cyclase, it may be concluded that DA receptors, whose blockade results in increased dopaminergic firing and TH activation, are not coupled with this enzyme. Moreover, the results indicate that the mechanism responsible for firing and TH stimulation is inhibited by halothane anesthesia. The latter significantly decreased also the stimulant effect of i.v. haloperidol on striatal TH activity.     

Cortical undercuts in the rat produce asymmetrical behavioral response without altering catecholamine concentrations

Baseline spontaneous activity of male Sprague-Dawley rats was established in home running wheel cages 3 weeks prior to cortical undercutting. Rats received unilateral 2-mm-diameter circular lesions undercutting layer VI of either the left or right frontal cortex. The right hemisphere lesion group showed a 63% increase in spontaneous activity and rats with left hemisphere lesions were no more active than sham-operated controls. No significant intergroup differences in norepinephrine concentrations were noted in the frontal or posterior cortex or locus ceruleus either ipsilateral or contralateral to the lesion site. In addition, there were no significant group differences in dopamine content of the caudate nucleus. Results suggest that the lateralized neural substrates controlling locomotor asymmetry are probably postsynaptic to cortical norepinephrine fibers and may involve glutamatergic corticostriatal projections.