Effects of the administration of amphetamine, either alone or in combination with reserpine or cocaine, on regional brain beta-phenylethylamine and dopamine release.

The effect of amphetamine sulfate (AMPH) on beta-phenylethylamine (PEA) and 3-methoxytyramine (3MT) levels in the rat frontal and cingulate cortices, the nucleus accumbens, and the striatum were evaluated after the administration of either cocaine or reserpine alone and in combination with AMPH. The purpose of this study was to evaluate the neuromodulator properties of PEA on dopamine (DA) release as reflected by 3MT steady-state concentrations. The highest concentration of PEA was found in the nucleus accumbens, followed by the cingulate and frontal cortices, and then the striatum. Time-course effects of the intraperitoneal administration of 5 mg/kg AMPH on PEA and 3MT concentrations were similar but not identical. AMPH at a dosage of 1 mg/kg significantly increased PEA concentration only in the striatum. A dosage of 2.5 mg/kg reserpine, which markedly depressed 3MT levels in all brain regions studied except the striatum, significantly reduced PEA concentrations only in the nucleus accumbens. This dosage of reserpine reduced DA concentrations by more than 80% in all regions examined, but its effects on norepinephrine were less marked. Pretreatment with cocaine (10 mg/kg) or reserpine (2.5 mg/kg) potentiated the effects of 1 mg/kg AMPH on PEA and 3MT levels in the frontal cortex and of 3MT in the striatum. Pretreatment with either 1 mg/kg reserpine (specifically used to partially mobilize DA storage) or cocaine (10 mg/kg) produced quantitative changes in the effects of 5 mg/kg AMPH on PEA and 3MT levels that were region-specific. For example, in contrast to the cortical regions and the nucleus accumbens, the AMPH-induced increase in 3MT was potentiated in the striatum. On the other hand, the increase in brain PEA produced by AMPH (5 mg/kg) was not influenced by either increased cytoplasmic DA (as deduced from the effects of 1 mg/kg reserpine pretreatment) or DA uptake inhibition (as deduced from the effect of cocaine pretreatment) in the frontal cortex or the nucleus accumbens. Furthermore, the increase in PEA produced by AMPH (5 mg/kg) in the cingulate cortex and the striatum were abolished and potentiated, respectively, by these drug pretreatments. Our results suggest that although DA release and PEA formation are stimulated by AMPH, these effects appear to involve mechanisms that are not directly related and hence suggest a dissociation between 3MT and PEA formation in the brain. Our work also suggests that PEA is most likely not to be co-released with DA following the administration of AMPH. Therefore, it is concluded that whatever physiological role PEA may play in central synaptic transmission, its effects do not appear to be dependent on DA release.     

Acute administration of amphetamine: differential regulation of dopamine synthesis in dopamine projection fields.

In order to study the inhibitory mechanisms regulating dopamine (DA) synthesis in vivo, the effect of amphetamine in the presence and absence of selective D1 and D2-DA receptor antagonists was examined in various brain regions. In response to amphetamine (3 mg/kg s.c.) administration, DA synthesis in the striatum, but not the nucleus accumbens or the medial prefrontal cortex, exhibited a biphasic response (increased followed by decreased). The D1 selective antagonist, SCH 23390 (0.5 mg/kg s.c., 60 min), modestly increased DA synthesis (30%) in the striatum but not in the nucleus accumbens or the prefrontal cortex. However, pretreatment with the D1 DA receptor antagonist did not prevent the amphetamine-induced elevation of striatal DA synthesis 45 min after amphetamine administration. The D2 selective antagonist, eticlopride (2 mg/kg s.c., 60 min), increased DA synthesis in both the striatum and the nucleus accumbens but not in the prefrontal cortex. Although amphetamine alone increased DA synthesis only in the striatum, in the presence of D2-DA receptor blockade, amphetamine increased DA synthesis in the striatum, the nucleus accumbens and the medial prefrontal cortex. The results support the hypothesis that DA synthesis is differentially regulated by distinct inhibitory mechanisms depending on the projection field. The apparent differences in regulatory mechanisms may allow selective alteration of DA synthesis in one particular projection field, while other areas remain unaffected.     

Effects of acute and chronic clozapine and haloperidol on in vitro release of acetylcholine and dopamine from striatum and nucleus accumbens

The purpose of this investigation was to determine if striatal or nucleus accumbens dopamine (DA) release, ACh release or DA receptor function were altered by acute and chronic haloperidol or clozapine treatment in a manner consistent with the reported pharmacological effects of each drug on A9 and A10 DA cell bodies and projection areas, when experiments were performed without a drug-free, or washout, period after drug treatment. The release of neurotransmitters reported here was evaluated using a slice-superfusion assay system. Transmitter release was induced either by an electrical field (for DA and ACh) or by application of either amphetamine or amfonelic acid (DA only). Dopaminergic receptor function was assessed by inhibiting electrically stimulated ACh release with in vitro TL-99 (a dopaminergic agonist) and by reversing that inhibition with in vitro neuroleptics or with ex vivo experimental paradigms (the in vitro analysis of transmitter release subsequent to in vivo drug administration). These data suggest that although there are differences between haloperidol and clozapine, there is no difference between the degree of postsynaptic DA receptor blockade produced that can be attributed to the duration of neuroleptic treatment. Chronic clozapine (20 mg/kg x 21 days) reversed TL-99-induced inhibition of ACh release in the nucleus accumbens only, whereas chronic haloperidol (0.5 mg/kg x 21 days) produced a similar reversal in both brain areas. One possible explanation for the lack of effect of chronic clozapine treatment in the striatum is that carrier-mediated (amphetamine-stimulated) DA release is enhanced in the striatum but not in the nucleus accumbens, suggesting that the potential DA receptor block in the striatum may be compromised by enhanced striatal DA levels. Acute haloperidol (0.5 mg/kg) was found to increase electrically stimulated ACh release in the striatum and DA release in the nucleus accumbens. Tolerance developed in the striatum, but not the nucleus accumbens, with repeated administration. However, acute clozapine had no effect on ACh release in either area, but it was found to enhance DA release in the striatum, an effect to which tolerance developed with chronic administration. Further, comparison of these data with data obtained using haloperidol and clozapine in vitro suggests that it is unlikely that these effects are due to residual drug still present in these tissues at the time of experimentation. These data are discussed with regard to electrophysiological and pharmacological differences observed between clozapine and haloperidol on the activity of A9 and A10 DA cells after chronic neuroleptic treatment.     

Behavioral and neurochemical effects of acute and daily cocaine administration in rats

Daily cocaine injection into rodents produces a progressive increase in the motor stimulant effect of acute cocaine administration. In this study it was found that daily cocaine injection (15 mg/kg i.p. x 3 days) produced an enhanced motor stimulant response to acute cocaine injection. The behavioral augmentation was linear with regards to dose in horizontal activity and behavioral intensity rating, but was biphasic in vertical activity. Augmented vertical, but not horizontal, activity in response to acute cocaine was found to persist for 2 weeks after the last daily injection of cocaine. Acute injection of cocaine was found to significantly decrease the level of dopamine (DA) metabolites in the nucleus accumbens, striatum and A10 DA region. In rats pretreated with daily injections of cocaine (15 mg/kg i.p. x 3 days), an acute challenge of cocaine 14 days after the last daily injection produced a more consistent decrease in DA metabolites in the nucleus accumbens, striatum and prefrontal cortex compared to daily saline-pretreated rats. In contrast, daily cocaine treatment abolished the decrease in DA metabolites produced in the A10 region by an acute cocaine challenge. Acute injection with cocaine was found to significantly depress dopa accumulation in the A10 region, nucleus accumbens and striatum. This effect was abolished in the A10 region in rats pretreated 14 days previously with daily injections of cocaine (7.5, 15.0 or 30 mg/kg i.p. x 3 days), but remained intact in the nucleus accumbens and striatum, except after daily pretreatment with the highest dose of cocaine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sensitization to repeated morphine injection in the rat: possible involvement of A10 dopamine neurons

Daily administration of morphine in rats produces an increase in the motor stimulant effect of subsequent morphine injections. This study was designed to characterize the behavioral sensitization produced by daily morphine and to evaluate the involvement of the mesolimbic and/or mesocortical dopamine (DA) neurons. Daily injection of morphine for 7 days produced an increase in both horizontal and vertical photocell counts. There was no difference in morphine levels in the blood or brain between daily morphine- and daily saline-treated rats at 30 or 90 min after acute injection of morphine. The increase was present for 60 days after initiating treatment and was associated with increases in locomotion, rearing, sniffing, grooming and bursting. Sensitization to morphine was prevented by pretreatment with naloxone i.p. or naltrexone methobromide injection into the ventral tegmental area (VTA; location of A10 DA perikarya projecting to limbic and cortical areas). In contrast, pretreatment with the same dose of naltrexone methobromide injected into the nucleus accumbens (limbic DA terminal field) or lateral ventricles did not significantly attenuate behavioral sensitization to morphine. Daily intra-VTA injections of the mu opioid agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol enhanced the behavioral stimulant effect of acute morphine. The effects of daily morphine treatment on DA systems were evaluated by measuring DA metabolism, dopa accumulation and DA depletion in the VTA and various DA terminal fields including the prefrontal cortex, nucleus accumbens and striatum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Interactions of neurotensin with brain dopamine systems: biochemical and behavioral studies

Intracisternal (i.c.) injection of neurotensin (NT) to rats or mice attenuated the locomotor hyperactivity induced by d-amphetamine, methylphenidate or cocaine, but not the increased activity induced by apomorphine or lergotrile. The reduction of methylphenidate-induced locomotor activity by i.c. NT was not due to an increased drug metabolism because i.c. NT did not change plasma methylphenidate concentrations. These actions of NT are distinct from those of the dopamine receptor antagonist haloperidol, which blocked the locomotor hyperactivity induced by all five stimulant drugs in rats. A further difference between NT and neuroleptics was demonstrated by the observation that i.c. NT did not block apomorphine-induced stereotypic behavior. In vitro, NT did not displace [3H]spiperone from its binding sites in homogenates of either the striatum or nucleus accumbens from rat brain. Moreover, i.c. injection of NT did not alter the subsequent in vitro binding of [3H]spiperone to membranes of the nucleus accumbens or striatum. In addition, NT did not alter basal or dopamine-stimulated adenylate cyclase activity in homogenates of the nucleus accumbens or striatum. However, i.c. injection of NT produced a significant increase in the concentrations of homovanillic acid, a major dopamine metabolite, in the nucleus accumbens, olfactory tubercles and striatum. In addition, the concentration of dihydroxyphenylacetic acid was increased in the nucleus accumbens and olfactory tubercles after i.c. NT. Peripheral injection of haloperidol produced qualitatively similar effects on dopamine metabolism, but the effects of haloperidol, unlike those of i.c. NT, were attenuated by apomorphine injection. Taken together, these data indicate that centrally administered NT affects certain brain dopamine systems without interacting directly with those dopamine receptors labeled by [3H]spiperone, coupled to adenylate cyclase or mediating the pharmacological effects of apomorphine.     

Sigma receptor "antagonist" BMY 14802 increases neurotensin concentrations in the rat nucleus accumbens and caudate

Acute and chronic treatment with antipsychotic drugs, such as haloperidol, selectively increases the concentrations of neurotensin (NT) in the nucleus accumbens and caudate of the rat. These increases in NT concentration in the nucleus accumbens and caudate have been hypothesized to underlie the therapeutic and extrapyramidal effects of antipsychotic drugs, respectively. The present study evaluates the effects of the putative antipsychotic and selective sigma receptor "antagonist" BMY 14802 on regional brain NT concentrations. NT concentrations in discrete brain regions of adult, male, Sprague-Dawley rats were measured by a sensitive and specific radioimmunoassay. Like haloperidol (1 mg/kg i.p.), acute and chronic treatment with BMY 14802 (35 mg/kg/day i.p.) produced significant increases in the concentrations of NT in the nucleus accumbens and anterior and posterior caudate. This effect was dose-dependent. Maximal increases in NT concentration were observed 18 hr after a single dose of BMY 14802. Neither acute nor chronic treatment with the sigma "agonist" (+)-SKF 10,047 (20 mg/kg i.p.), the N-methyl-D-aspartate-phencyclidine binding site antagonist MK-801 (0.25 mg/kg i.p.) or the selective D2 antagonist sulpiride (100 mg/kg i.p.), produced the pattern of NT alterations observed after the administration of BMY 14802. These findings suggest that the blockade of sigma receptors modulates NT concentrations in these brain regions.     

Neuromedin N mimics the actions of neurotensin in the ventral tegmental area but not in the nucleus accumbens

Neuromedin N (NN) is a hexapeptide recently isolated from porcine spinal cord that shares a four-amino acid homology with the C-terminus of the biologically active tridecapeptide neurotensin (NT). Microinjection with NT into the ventral tegmental area or nucleus accumbens of rats has been shown to increase locomotor activity and dopamine (DA) metabolism in some limbic areas or to inhibit the motor stimulant effect of intra-accumbens administration of DA, respectively. In this study the effects of microinjected NN were compared with those of NT. After injection into the ventral tegmental area, NN was shown to be more potent than NT at increasing spontaneous motor activity and to produce an increase in DA metabolism in the nucleus accumbens, prefrontal cortex, diagonal band of Broca and septum. However, when injected into the nucleus accumbens, NN was markedly less potent than NT at inhibiting DA-induced behavioral hyperactivity. In addition to DA-related effects, i.c.v. injection with NT causes hypothermia, and i.c.v. administration with NN was without effect on colonic temperature. These data demonstrate that NN has a behavioral profile distinct from that of NT.     

Neurotensin-induced dopamine release in vivo and in vitro from substantia nigra and nucleus caudate

We compared the dopamine (DA) releasing effects of neurotensin (NT) from cell bodies (substantia nigra) and nerve terminals (nucleus caudate). In rats implanted with push-pull cannula, NT induced DA release from substantia nigra and nucleus caudate. NT was more potent in releasing DA from the substantia nigra than from the nucleus caudate (EC50%, 1.1 microM in substantia nigra and 9.8 microM in nucleus caudate). In vitro, in superfused rabbit brain slices, NT enhanced the depolarization-evoked release of DA and exerted a direct releasing effect. The latter was greater in the substantia nigra, and the former in the nucleus caudate. The direct releasing effect of NT was not inhibited, but enhanced by nomifensine (3 microM). Sulpiride, a D2 DA receptor antagonist, failed to modify NT-induced DA release; in addition, NT did not affect the inhibition of DA and acetylcholine release produced by LY-171555, a D2 DA agonist. In both the substantia nigra and the nucleus caudate, desensitization to the releasing effect of NT was observed, either after 2.5, 5, or 10 min of exposure to the peptide. A synergistic interaction on DA release was observed between NT and potassium (K+), and between NT and electrical stimulation. Greater synergism was observed with high extracellular K+. Pretreatment of striatal slices with 15 mM K+ produced a 9-fold enhancement of NT-induced DA release. When K+ (25 mM, 2 min) was given together with NT there was a 2- to 3-fold increase in DA release compared to the release evoked by K+ in the absence of NT.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of repeated treatment with haloperidol and clozapine on dopamine release and metabolism in the striatum and the nucleus accumbens.

The differential effects of haloperidol (HAL) and clozapine (CLOZ) on dopamine (DA) release and metabolism (dihydroxyphenylacetic acid levels) in striatum and nucleus accumbens (accumbens) of freely moving rats were investigated using microdialysis. Chronic HAL (2 mg/kg/day x 21 days in drinking water) decreased basal DA release and metabolism in both regions, and produced tolerance to HAL-induced increase in DA metabolism in striatum. No modification of HAL-induced increases in DA release and metabolism were observed in accumbens. Together with D2 receptor blockade, this may produce decreased dopaminergic neurotransmission in both regions during chronic treatment. Chronic HAL (0.5 mg/kg/day x 21 days in drinking water) also decreased basal DA release and metabolism in both regions which were not reversed by 25 micrograms/kg of (-)-apomorphine, s.c. In marked contrast, chronic CLOZ (20 mg/kg/day x 21 days in drinking water) had no effect on basal DA release and metabolism in either region, whereas it produced tolerance to CLOZ-induced increase in DA release and metabolism in accumbens. Together with weak D2 receptor blockade, this may lead to slightly decreased dopaminergic neurotransmission in accumbens and slightly increased dopaminergic neurotransmission in striatum during chronic CLOZ treatment. These differences may contribute to the clinical differences between the two agents.     

Sex- and estrous cycle-related differences in the effects of acute antipsychotic drug administration on neurotensin-containing neurons in the rat brain

The effects of a single injection of haloperidol (2.0 mg/kg), a typical antipsychotic drug, on neurotensin (NT) concentrations and NT/neuromedin N (NT/NN) mRNA expression in adult female and male rats were examined. There were significant estrous cycle stage-related differences in both NT concentrations and NT/NN mRNA expression in female control rats. Although acute administration of haloperidol increased NT concentrations and NT/NN mRNA expression in the caudate/putamen and nucleus accumbens of both male and female rats, haloperidol did not increase NT/NN mRNA expression during diestrus 2 or NT concentrations during proestrus in the nucleus accumbens of female rats. These results indicate the presence of both sex- and estrous cycle-related differences in the regulation of NT-containing neurons and in the effects of antipsychotic drug administration on the NT system of the rat brain.     

Preclinical studies on quinelorane, a potent and highly selective D2-dopaminergic agonist

Quinelorane (LY163502) has the endocrine, neurochemical and behavioral profile of a potent and highly selective D2-dopaminergic agonist. The administration of quinelorane produced dose-related decreases in serum prolactin concentration of reserpinized, male rats and increases in serum corticosterone concentration of male rats. The minimum effective doses (MED) for these effects were 10 and 30 micrograms/kg i.p., respectively. Quinelorane induced increases in 3-methoxy-4-hydroxyphenylglycol-sulfate levels in the brain stem (MED, 30 micrograms/kg i.p.) and decreases in hypothalamic epinephrine levels (MED, 100 micrograms/kg i.p.) in male rats as determined by high-pressure liquid chromatography with electrochemical detection methods. Quinelorane induced increases in extracellular ascorbic acid as determined by in vivo voltammetry in the nucleus accumbens and striatum of male rats. Quinelorane produced concentration-dependent suppression of K+-evoked release of acetylcholine from superfused caudate slices, with an IC50 of approximately 10(-8)M. Quinelorane administration produced dose-related increases in compulsive, contralateral turning in male rats with unilateral nigrostriatal lesions and increases in locomotor activity and stereotypic behavior in male rats. In dogs, quinelorane administration produced dose-related increases in emetic response with an ED50 of 7 micrograms/kg i.v. Quinelorane administration also produced dose-related decreases in the striatal concentrations of the dopamine metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic (MED, 1 microgram/kg i.p. for both metabolites) as determined by high-pressure liquid chromatography with electrochemical detection methods and decreases in extracellular concentrations of homovanillic acid in the nucleus accumbens and striatum as determined by in vivo voltammetry., Quinelorane produced concentration-dependent decreases in K+-evoked dopamine release from superfused striatal slices (IC50 = 3 X 10(-9) M).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increase of neurotensin content elicited by neuroleptics in nucleus accumbens

The content of neurotensin immunoreactive material (neurotensin-IR) of nucleus accumbens increases 16 hr after a single injection of 2 mg/kg i.p. of haloperidol; this increase persists for 8 hr or longer. Repeated injections of 2 mg/kg/day of haloperidol i.p. cause a gradual and progressive increase of neurotensin-IR. From 0.32 pmol/mg of protein, it increases to 0.57 pmol/mg (1 week) to 0.62 pmol/mg (2 weeks) and reaches 0.68 pmol/mg (3 weeks). A significant increase of neurotensin-IR content of nucleus accumbens is obtained with 0.5 mg/kg i.p. daily for 2 weeks. Maximal responses are obtained with 1 mg/kg/day in 3 weeks. The striatal neurotensin-IR content of rats injected for 2 weeks with 1 mg/kg/day of haloperidol is also increased. In these rats, the neurotensin-IR content of preoptic area hypothalamus, septum and amygdala failed to increase. The increase of neurotensin-IR material of nucleus accumbens was elicited also by chloropromazine (6 mg/kg), trifluoroperazine (2 mg/kg) and pimozide (1.5 mg/kg) while promazine (10 mg/kg) and promethazine (25 mg/kg) were ineffective. The increase of neurotensin-IR content caused by haloperidol chloropromazine, trifluoroperazine and pimozide in accumbens and striatum suggests a modulation of neurotensin metabolism, synthesis or utilization directly or indirectly through dopaminergic synapses.     

Enkephalin action on the mesolimbic system: a dopamine-dependent and a dopamine-independent increase in locomotor activity

Enkephalin has been identified by immunohistochemistry to be present in the vicinity of mesolimbic dopaminergic perikarya in the ventral tegmental area and axonal terminals in the nucleus accumbens. To evaluate the possibility that endogenous enkephalin may physiologically modulate the mesolimbic dopamine (DA) system, the effect of microinjection of the peptidase-resistant enkephalin analog, D-Ala2-Met5-enkephalinamide (DALA), in the ventral tegmental area and nucleus accumbens was examined. Locomotion and rearing behavior and alteration in concentration of DA and its metabolites in mesolimbic terminal areas were used to evaluate mesolimbic dopaminergic function. Microinjection of DALA into the ventral tegmental area produced a dose-dependent increase in locomotion and rearing which was antagonized by neuroleptic administration in the nucleus accumbens. Inasmuch as DALA administration into the ventral tegmentum was additive with a subthreshold dose of DA injected into the nucleus accumbens and produced a dose-related increase in 3,4-dihydroxyphenylacetic acid and the 3,4-dihydroxyphenylacetic acid/DA ratio, these data are consistent with the postulate that this treatment with DALA activates the mesolimbic DA system. DALA microinjection into the nucleus accumbens also produced a dose-dependent increase in locomotion and rearing. However, this behavioral effect was shown to be independent of the mesolimbic DA system because neither neuroleptic injection into the nucleus accumbens nor destruction of the mesolimbic DA system with 6-hydroxydopamine blocked the behavioral response produced by this treatment. Furthermore, DALA injection into the nucleus accumbens did not alter nucleus accumbens levels of DA or its metabolites at 15, 30 or 60 min after injection.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tachykinin gene expression in rat limbic nuclei: modulation by dopamine antagonists

The content and nature of the preprotachykinin (PPT; i.e., substance P/neurokinin A-encoding) messenger RNAs (mRNAs) present in rat brain striatum and limbic tissues were determined by RNA protection experiments. The rank order of PPT mRNA concentration was striatum greater than nucleus accumbens much greater than bed nucleus of the stria terminalis greater than hypothalamus, amygdala and septum. The proportion of beta-(full length) to gamma-(minus exon 4) PPT mRNA was invariant (40/60) among the tissues tested. Because these brain regions receive prominent dopaminergic innervations, the effects of repeated treatment with dopamine antagonists (antipsychotic drugs) on PPT gene expression were assessed. The prototypical dopamine antagonists haloperidol and chlorpromazine decreased striatal PPT mRNA, had no effect on PPT mRNA in the nucleus accumbens or bed nucleus of the stria terminalis, and increased septal PPT mRNA levels. In contrast, the atypical antipsychotic drugs clozapine and l-sulpiride did not alter striatal or septal PPT mRNA, but increased PPT mRNA content in the nucleus accumbens and bed nucleus. The correlation between the effects of typical and atypical antipsychotic drugs on rat striatal and limbic PPT gene expression and their clinical side effects and therapeutic efficacy is discussed.     

Neurotensin levels in specific brain regions and hypnotic sensitivity to ethanol and pentobarbital as a function of time after haloperidol administration in selectively bred rat lines

Evidence indicates that sensitivity to ethanol is a good predictor of the development of alcoholism. Thus, identification of neuronal processes that regulate ethanol sensitivity has been the subject of much recent research. The present studies were designed to further test the hypothesis that neurotensinergic processes mediate, in part, hypnotic sensitivity to ethanol. Single doses of haloperidol were administered to lines of rats [selectively bred for high and low sensitivity (HAS and LAS, respectively) to hypnotic effects of ethanol] to produce increases in neurotensin (NT) levels in brain regions. At 20 h after administration, haloperidol produced dose-dependent increases in NT immunoreactivity levels in nucleus accumbens (NA) and caudate putamen (CP) in both HAS and LAS lines. Levels of NT in NA and CP returned to control values at 48 h after 4 mg/kg haloperidol. These studies used two measures of hypnotic sensitivity to ethanol: duration of loss of righting reflex (sleep time) and blood ethanol concentration at regain of righting reflex (BECRR). At 20 h, but not 48 h, after haloperidol treatment, both HAS and LAS rats displayed increases in ethanol-induced sleep time with concomitant decreases in BECRR. Pentobarbital-induced sleep time was not increased 20 h after administration of 4 mg/kg haloperidol; however, hypnotic sensitivity to both pentobarbital and ethanol was increased by acute (30-min) pretreatment with 1 mg/kg. These results suggest that NT levels in NA, acting via NT receptors, enhance hypnotic sensitivity to ethanol, but not pentobarbital.     

Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine

The abuse of psychostimulants, such as methamphetamine (METH), can cause long-lasting deficits in the dopamine (DA) innervation of the striatum. Although the consequences of large DA depletions on basal ganglia function have been well characterized, less is known about the alterations associated with smaller depletions, such as those produced by high doses of METH. The purpose of this study was to assess the long-term consequences of METH-induced DA depletion on basal ganglia function. Three weeks after rats were given multiple administrations of METH (5-10 mg/kg, four times at 2-h intervals), dose-related decreases in DA tissue content in striatum and tyrosine hydroxylase mRNA in the substantia nigra pars compacta were observed. In situ hybridization histochemistry revealed a selective decrease in preprotachykinin mRNA in striatum, predominantly at the highest dose of METH, and no change in striatal preprodynorphin, preproenkephalin, or neurotensin/neuromedin N mRNAs. Cytochrome oxidase activity was significantly elevated in the entopeduncular nucleus and substantia nigra pars reticulata of METH-treated rats, but not in the striatum, globus pallidus, or subthalamic nucleus, consistent with a selective decrease in striatonigral, but not striatopallidal, neuron function. Additionally, rats treated with a neurotoxic regimen of METH were impaired on a radial maze sequential learning task when tested 3 weeks following METH administration. These data indicate that exposure to a neurotoxic regimen of METH results in long-term changes in striatonigral, but not striatopallidal neuron function and, consequently, altered basal ganglia function.     

Effects of acute and subchronic administration of typical and atypical antipsychotic drugs on the neurotensin system of the rat brain

The acute and subchronic effects of a variety of doses of a prototype typical (haloperidol) or one of several atypical antipsychotic drugs (clozapine, olanzapine, risperidone, quetiapine, or sertindole) on regional brain neurotensin (NT) tissue concentrations, and NT receptor binding were examined. Acute administration of haloperidol, clozapine, olanzapine, and risperidone dose-dependently increased NT tissue concentrations in the nucleus accumbens. Haloperidol, olanzapine, risperidone, and sertindole also increased NT tissue concentrations in the caudate nucleus. NT tissue concentrations in the nucleus accumbens and caudate remained elevated after 14-day administration of haloperidol, olanzapine, sertindole, and risperidone. In contrast, at the doses studied, quetiapine decreased NT tissue concentrations in the nucleus accumbens; clozapine had no effect. Haloperidol significantly increased NT receptor binding in the substantia nigra after 14-day administration. All of the atypical antipsychotic drugs decreased NT receptor binding in the nucleus accumbens and in the substantia nigra. Although these studies do not conclusively support the hypothesis that increased NT neurotransmission is involved in the clinically relevant effects of all antipsychotic drugs, the extant evidence clearly suggests that further study is warranted. Inconsistencies in the data suggest that differential effects of antipsychotic drug administration on subpopulations of NT neurons must be scrutinized further.     

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.