Agonist Amphetamine Research Articles

Dopaminergic function in the neostriatum and nucleus accumbens of young and aged fischer 344 rats

Age-dependent alterations in behavioral and neuronal functioning were assessed in young (2–3 month), middle-aged (12 month), and aged (24 month) Fischer 344 rats treated with the indirect dopamine agonist amphetamine (2.25 or 5 mg/kg), the D 1 agonist SKF 38393 (7.5, 15, 30 mg/kg), or the D 2 agonist quinpirole (0.3, 1.0, 3.0 mg/kg). Drug-induced changes in activity and stereotypy were measured during a 90-min testing session, with Fos immunohistochemistry being used to assess the neuronal response to dopamine agonist treatment. As expected, aged rats given amphetamine (5 mg/kg) had fewer activity counts and higher stereotypy scores than young rats. Middle-aged rats also had fewer activity counts but were similar in stereotypy scores to young rats. Amphetamine also induced different patterns of Fos immunoreactivity in the neostriatum and nucleus accumbens of young and aged rats, as Fos expression in aged rats exhibited a distinctive dorsal to ventral pattern of decline. In general, SKF 38393 had few age-related actions, although aged rats did show a slight relative increase in stereotypy. In contrast, the D 2 agonist quinpirole substantially enhanced the motor activity and Fos expression of young rats, while only modestly affecting aged rats. Hence, these results suggest that the D 2 receptor is more vulnerable to the effects of aging than the D 1 receptor.

Free radicals and taste aversion learning in the rat; Nitric oxide, radiation and dopamine

1. 1. Injection of sodium nitroprusside (SNP) or N- tert-butyl-α-phenyl nitrone (PBN) produces a conditioned taste aversion (CTA) in rats. The CTA can be prevented by pretreatment with N ω-nitro-L-argimne (L-NArg), indicating that nitric oxide (NO) is a behaviorally toxic compound. 2. 2. Radiation-induced CTA learning is not affect by pretreatment with L-NArg or by preexposure to PBN, indicating that a radiation-stimulated formation of NO does not mediate the toxic effects of radiation on behavior. 3. 4. Pretreating rats with the dopamine antagonist haloperidol prevented the acquisition of the CTA produced by SNP and attenuated, but did not eliminate, the PBN-induced CTA. Preexposure to the dopamine agonist amphetamine, attenuated a PBN-induced CTA, although PBN preexposure did not affect an amphetamine-induced CTA. 4. 5. The results are interpreted as supporting a role for NO-stimulated dopamine release in the acquisition of taste aversions following injection of SNP or PBN.

Plasma homovanillic acid concentrations in catatonia

We investigated the dopamine metabolite plasma homovanillic acid (plasma HVA) levels in 37 catatonic patients on the day of admission before initial medication as well as in 17 healthy controls. In a prospective study catatonic syndrome was diagnosed according to criteria of Lohr and Wiesniwski (1987) and Rosebush et al (1990) whereas comorbid diagnosis was made by Diagnostic and Statistical Manual of Mental Disorders, 3rd ed, revised (DSM III/R) (APA 1987). On the day of admission blood samples were taken before initial medication. Compared to controls (80.1 +/- 40.1 pmol/mliter) catatonic patients showed significantly (P = 0.0286) increased plasma HVA (140.9 +/- 53.6 pmol/mliter). Catatonic patients free of neuroleptic medication (n = 21) differed significantly (p = 0.0416) from controls whereas neuroleptically treated catatonics (n = 16) did not. Our findings of increased plasma HVA in catatonia are explained by an alteration in either mesolimbic or mesocortical dopaminergic function, as is assumed in the case of schizophrenia. As an alternative, it may be due to increased nigrostriatal function, which can lead, as shown in animal experiments with the dopamine agonist amphetamine, to hypokinetic states resembling catatonia in humans.

A single injection of amphetamine or methamphetamine induces dynamic alterations in c-fos, zif/268 and preprodynorphin messenger RNA expression in rat forebrain.

In this study, the effects of a single dose of the indirect dopamine agonists amphetamine and methamphetamine on behavior and messenger RNA expression were evaluated. Expression of c-fos, a member of the leucine zipper family, zif/268 (NGFI-A, egr1 and Krox-24), a member of the zinc finger family, and the opioid peptide, preprodynorphin, was investigated in various regions of rat forebrain with quantitative in situ hybridization histochemistry 1, 2, 3, 6 or 30 h after injection. Behavioral observations indicated that a qualitatively different behavioral syndrome was induced following methamphetamine (15 mg/kg, i.p.) as compared with that observed after amphetamine (5 mg/kg, i.p.). Similarly, methamphetamine induced a different pattern of c-fos and zif/268 messenger RNA induction in sensory/motor cortex, dorsal striatum (caudatoputamen) and ventral striatum (nucleus accumbens) than did amphetamine. The increase in c-fos messenger RNA expression peaked at 1 h and returned to basal levels in all regions by 3 h. In contrast, the increase in zif/268 messenger RNA expression in the cortical regions was equally strong at 1 and 2 h, gradually returning to basal levels by 6 h after either drug. However, in the striatal regions, zif/268 messenger RNA levels peaked at 1 h and declined gradually to basal levels by 6 h. Interestingly, methamphetamine caused an actual suppression of zif/268 gene expression (> 50%) in both caudatoputamen and nucleus accumbens at 3 h. Preprodynorphin messenger RNA expression was increased in a patchy motif in the caudatoputamen and nucleus accumbens beginning at 2 h and returning to basal levels by 30 h after injection of either drug. This study, together with our recently published observation that preprodynorphin messenger RNA is induced in the caudate 3, 6 and 18 h after amphetamine or methamphetamine injection, provides a detailed dynamic description of the differential modulation of c-fos, zif/268 and preprodynorphin messenger RNA expression in the cerebral cortex and striatum by amphetamines over time. These data implicate immediate early gene and preprodynorphin gene expression in the differential response of medium spiny striatal neurons to methamphetamine and amphetamine.

Priming of a D1 dopamine receptor behavioural response is dissociated from striatal immediate-early gene activity.

Repeated administration of direct-acting (apomorphine, SKF-38393, quinpirole) or indirect-acting (amphetamine, cocaine) dopaminergic agonists can produce enhancement of locomotor and sterotypic behaviours in response to subsequent dopamine agonist challenge. This sensitization of dopamine receptors, known as priming or reverse tolerance, is long-lasting and appears to be dependent upon the participation of the N-methyl-D-asparate excitatory amino acid receptor. The mechanism underlying dopamine receptor sensitization is not understood. Mounting evidence suggests that immediate-early genes may provide a link whereby extracellular stimuli are converted into long-term changes in neuronal activity. In the present study, behavioural measurements and immunohistochemical techniques were used to determine whether induction of the immediate-early gene c-fos is critical to the mechanism underlying priming of a D1-mediated behavioural response. It was demonstrated that in drug-naive rats bearing unilateral 6-hydroxydopamine lesions of the dopaminergic nigrostriatal pathway, the mixed D1/D2 agonist apomorphine produced a dramatic increase in the expression of Fos-like immunoreactivity in the ipsilateral caudoputamen, nucleus accumbens and globus pallidus, and was a potent primer of SKF-38393-mediated rotational behaviour. In contrast, saline administration did not increase Fos expression and did not prime SKF-38393-elicited rotation. Preadministration of MK-801 at 0.5 mg/kg significantly reduced apomorphine's effect on Fos expression and prevented apomorphine priming of SKF-38393-induced rotation. However, at a lower dose of 0.1 mg/kg, MK-801 had little effect on apomorphine-mediated Fos expression but did block the priming response. In another experiment, the D2 family-selective agonist quinpirole was found to be an affective primer of SKF-38393-mediated rotation, and to produce increase Fos expression in the ipsilateral globus pallidus only. Preadministration of MK-801 at 0.1 mg/kg blocked quinpirole priming of SKF-38393-mediated rotation and significantly reduced the number of Fos-positive neurons in the ipsilateral globus pallidus. Administration of the indirect dopamine agonist amphetamine increased Fos expression in the intact striatum, but not in the ipsilateral (lesioned) striatum or globus pallidus, and did not sensitize (prime) animals to behavioural effects of SKF-38393. In a separate group of animals. Northern blot analysis demonstrated that a priming dose of apomorphine significantly increased the messenger RNA signals for c-fos, c-jun, ngfi-A and jun-B in denervated striatum. Administration of 0.1 mg/kg MK-801 prior to apomorphine had no significant effect on signal intensities.(ABSTRACT TRUNCATED AT 400 WORDS)

Non-specific inhibition of dopamine receptor agonist-induced behaviour by the tachykinin NK 1 receptor antagonist CP-99,994 in guinea-pigs

Evidence that tachykinin NK 1 receptors selectively modulate activity in the mesolimbic dopamine pathway suggests an antipsychotic potential for tachykinin NK 1 receptor antagonists. We investigated the ability of the antagonist CP-99,994 (and the less active enantiomer CP-100,263) to block dopamine receptor agonist-induced behaviour in guinea-pigs. The active dose rangwe CP-100,263 were without effect. In contrast, both CP-99,994 (20 or 30 mg/kg) and CP-100,263 (10–30 mg/kg) antagonised behavioural stimulation induced by the dopamine receptor agonists amphetamine (1mg/kg i.p.) or (+)-PHNO ((+)-4-propyl-9-hydroxy-naphthoxazine hydrochloride; 0.1 mg/kg s.c.). Lower doses of CP-99,994 or CP-100,263 were not active. These findings do not support the proposal that tachykinin NK 1 receptors in the terminal projection area of the mesolimbic system can modify dopamine-mediated behaviour.

Alterations in striatal neurotrophic activity induced by dopaminergic drugs

The administration of dopaminergic drugs induces a variety of compensatory responses ostensibly designed to reinstate normal dopamine (DA) tone. We have hypothesized that drug-induced alterations in striatal-derived neurotrophic activity contributes to these compensatory processes. This phenomenon has been studied by examining the growth of mesencephalic cultures incubated with cell-free extracts of striatal tissue taken from patients or rats treated with various drugs. Our results reveal that reducing striatal DA tone by administering the DA antagonist haloperidol, the DA neurotoxin 6-hydroxydopamine, or as occurs naturally in Parkinson's disease, increases striatal trophic activity. Conversely, increasing striatal DA tone by administering the indirect DA agonists amphetamine or levodopa reduces trophic activity in the striatum. Kainic acid lesions of the striatum similarly reduce this trophic activity. The implications of these drug-induced alterations in trophic activity are discussed and reviewed.

The relationship between diabetes mellitus and Parkinson's disease.

It has been reported that 50% to 80% of patients with Parkinson's disease have abnormal glucose tolerance which may be further exacerbated by levodopa therapy. Little is known about the impact of chronic hyperglycemia on the severity of the motor manifestations and the course of the disease as well as its impact on the efficacy of levodopa or other dopaminergic drugs. This issue, which has been largely ignored, is of clinical relevance since animal studies indicate that chronic hyperglycemia decreases striatal dopaminergic transmission and increases the sensitivity of postsynaptic dopamine receptors. In addition, evidence from experimental animal studies indicates that diabetic rats are resistant to the locomotor and behavioral effects of the dopamine agonist amphetamine. The resistance to the central effects of amphetamine is largely restored with chronic insulin therapy. In the present communication, I propose that in Parkinson's disease diabetes may exacerbate the severity of the motor disability and attenuate the therapeutic efficacy of levodopa or other dopaminergic agents as well as increase the risk of levodopa-induced motor dyskinesias. Thus, it is advocated that Parkinsonian patients should be routinely screened for evidence of glucose intolerance and that if found aggressive treatment of the hyperglycemia may improve the response to levodopa and potentially diminish the risk of levodopa-induced motor dyskinesias.

Differential effects of serotonergic and catecholaminergic drugs on ingestive behavior.

The serotonergic agonists fenfluramine and fluoxetine and the catecholaminergic agonists amphetamine and phenylpropanolamine are well known to cause a reduction in intake in rats. In the studies reported here we investigated the effects of these drugs on the microstructure of licking behavior of the rat ingesting 0.4 M sucrose. The purpose was to examine the similarities in the behavioral effects within and between these two classes of anorectic agents. The serotonergic agonists fenfluramine and fluoxetine caused a reduction in intake primarily by reducing the size of bursts and clusters of licking within the test meal without affecting the duration of the meal, suggesting a reduction in the palatability of the test solution. The catecholamine agonists amphetamine and phenylpropanolamine reduced intake primarily by reducing the number of bursts and clusters without affecting their size, suggesting a fractionation in the organization of the normal pattern of ingestion. The differences between the two serotonin and the two catecholamine agonists on the microstructure of the licking behavior suggest a different effect of the two neurotransmitters on the motor system that controls ingestive behavior. The similarities between the two different agonists within each class suggests a common neurotransmitter mechanism responsible for these two different effects on the behavior of the animals.

Behavioral concomitants of regional changes in the brain's biogenic amines after apomorphine and amphetamine

Behavioral and neurochemical changes were analyzed in rats after systemical injections of the dopamine receptor agonist apomorphine (0.5 mg/kg) or the indirect agonist amphetamine (1.0 mg/kg). As expected, amphetamine led to an increase in locomotion, whereas apomorphine resulted in decreases in locomotion, rearings, and grooming. The analysis of biogenic amines in tissue samples showed that amphetamine decreased 3,4-dihydroxy-phenylacetic acid (DOPAC) levels and DOPAC/dopamine ratios in the neostriatum, and resulted in a lower 5-hydroxyindole-3-acetic acid (5-HIAA)/5-hydroxytryptamine (5-HT) ratio in the ventral mesencephalon. Apomorphine decreased the dopamine metabolites [DOPAC, homovanillic acid (HVA), 3-methoxytyramine (3-MT)] and their respective metabolite/transmitter ratios and increased dopamine levels in the neostriatum. Similar decreases in dopamine metabolites or their ratios were found in the ventral mesencephalon, septum, and frontoparietal cortex but not the thalamus. In addition to its effects on dopamine, apomorphine decreased norepinephrine in the ventral neostriatum and 5-HT and 5-HIAA in the cortex. Correlations between behavioral activity and neurochemical metabolism (using the metabolite-transmitter ratios for the latter) revealed relationships between locomotion and serotonergic activity in the thalamus of animals treated with amphetamine. Evidence for a relationship between locomotion or rearings and dopaminergic activity was found in all six brain areas analyzed. Here, the pattern of correlation was dependent on the kind of treatment and the behavioral and neurochemical measures. These results support earlier findings on the neurochemical effects of apomorphine and amphetamine in the neostriatum and ventral mesencephalon, and add new evidence for an action on the septal area, thalamus, and frontoparietal cortex.

The effects of amphetamine, apomorphine, SKF 38393, quinpirole and bromocriptine on responding for conditioned reward in rats.

The present study investigated the effects of the dopamine (DA) D1 selective agonist, SKF 38393, and the D2 selective agonists, quinpirole and bromocriptine, on responding for conditioned reward. The nonselective DA agonist apomorphine and the indirect agonist amphetamine, were also evaluated. Male rats (n = 302) were tested in a procedure consisting of three distinct phases. During the pre-exposure phase the rats were exposed to an operant chamber containing two levers; one lever produced a lights-off stimulus (3s) and the other a tone stimulus (3s). This was followed by 4 conditioning sessions during which the levers were removed and rats received pairings of the lights-off stimulus (80 per day) and food, presented according to a variable time 45s schedule. Two test sessions followed during which the levers were present and the number of responses made on each lever was calculated as a ratio of the number of responses made during pre-exposure. Drugs were administered prior to each test session. A saline group showed a higher ratio of responding for the lights-off stimulus than the tone stimulus, indicating that the lights-off stimulus had become a conditioned reward. Amphetamine (0.01-2.0mg/kg) and to a lesser extent, quinpirole (0.01-5.0mg/kg) and bromocriptine (0.05-10.0mg/kg) dose-dependently increased responding and specifically enhanced responding on the lever producing the conditioned reward. Apomorphine (0.1-5.0mg/kg) increased responding on both levers at higher doses but the conditioned reward effect was lost. SKF 38393 (0.1-10.0mg/kg) appeared to impair the acquisition of responding for conditioned reward. The results were interpreted as indicating that responding for conditioned reward may be dependent on a D1 receptor-mediated reward signal.

Possible serotonergic and dopaminergic mediation of the N-ethyl-3,4-methylenedioxyamphetamine discriminative stimulus

Eight male rats previously trained to discriminate 2.0 mg/kg N-ethyl-3,4-methylenedioxyamphetamine (MDE) from its vehicle in a two-lever, food motivated task were utilized to characterize the stimulus properties of MDE. The 5-HT receptor agonists l-(m-trifluoromethylphenyl)piperazine (TFMPP), quipazine and 6-methoxy-l,2,3,4 tetrahydro-β-carboline were able to generalize to the stimulus produced by MDE. However, the 5-HT receptor agonists m-chlorophenylpiperazine (mCPP), buspirone and norfenfluramine, the dopamine receptor agonist amphetamine, as well as the acetylcholine receptor agonist arecoline did not completely generalize. In addition, the simultaneous administration of norfenfluramine and amphetamine generalized to MDE. Pretreatment with the serotonin receptor antagonists cinanserin and metergoline or the dopamine receptor antagonist haloperidol failed to completely inhibit the discriminative stimulus produced by MDE. Multiple p-chlorophenylalanine (PCPA) pretreatments significantly reduced MDE discrimination, whereas vehicle discrimination was unaffected. Five days following cessation of PCPA pretreatment, MDE discrimination returned to criterion levels and remained at that level. These results suggest that the stimulus produced by MDE involve a complex interaction of various neurotransmitters, with both serotonergic and dopaminergic components.

Dopaminergic-cholinergic interactions in the striatum: the critical significance of calcium concentrations in brain microdialysis

Brain microdialysis experiments were performed to assess the effects of calcium (1.2 mmol/l and 3.4 mmol/l) in the perfusion solution on a variety of pharmacological treatments known to affect the release of dopamine (DA) and/or acetylcholine (ACh). Intrastriatal infusion of the muscarinic receptor agonist oxotremorine (100 microM), the selective dopamine D-2 receptor agonist (-)-N-0437 (1 microM), and the indirect DA agonists (+)amphetamine (10 microM) and nomifensine (1 microM) via the dialysis probe did not affect the overflow of ACh when the perfusion fluid contained 3.4 mmol/l calcium. In contrast, these compounds produced pronounced decreases in the overflow of ACh at 1.2 mmol/l calcium. Intrastriatal infusion of the muscarinic receptor antagonist atropine (1 microM) increased the output of ACh both at 1.2 mmol/l and 3.4 mmol/l calcium. The selective DA D-2 receptor antagonist (-)-sulpiride (1 microM) did not affect the overflow of ACh at either calcium concentration. Infusion of oxotremorine and atropine had no effect on the overflow of DA at either 1.2 mmol/l at 3.4 mmol/l calcium. (-)-N-0437 decreased and (-)-sulpiride increased DA overflow, both effects being independent of the calcium concentration in the perfusion fluid. Nomifensine and (+)amphetamine caused relatively (but not absolutely) larger increases in the overflow of DA at 1.2 mmol/l calcium. These findings emphasize the critical importance of the calcium concentration of the perfusion fluid in determining the nature of pharmacological responses in microdialysis experiments, and demonstrate that locally applied dopaminergic drugs can modulate striatal cholinergic function.

Interaction between recovery from behavioral asymmetries induced by hemivibrissotomy in the rat and the effects of apomorphine and amphetamine.

Spontaneous and drug-induced turning behavior and thigmotactic scanning were tested either acutely (4-6 hr) or chronically (9 days) after unilateral removal of vibrissae in rats. Rats that were tested acutely scanned more with the intact vibrissae side. This asymmetry was reduced in rats that were tested chronically, indicating behavioral recovery. The indirect dopamine agonist amphetamine induced a reversed asymmetry after 9 days because the animals then scanned more with the side lacking the vibrissae. Postsynaptic doses of apomorphine administered to acutely tested rats induced more scanning with, and more turning toward, the intact vibrissae side. A negative correlation was found in the chronically tested rats between the asymmetry in spontaneous scanning and the asymmetry after apomorphine. Nonrecovered rats showed indications of a reversal after apomorphine. The results are discussed in relation to mechanisms of neural plasticity in the basal ganglia, such as receptor supersensitivity and changes in nigrostriatal afferents.

Preferential stimulation of D1 or D2 receptors disrupts food-rewarded operant responding in rats

Rats were trained to lever-press for food on a variable interval 30-sec schedule. Following stabilization of response rates, separate groups of rats were treated with saline, the nonselective DA agonists amphetamine or apomorphine, the D1 agonist SKF 38393, or the D2 agonist quinpirole prior to placement in the operant chamber. Treatment with SKF 38393 or quinpirole produced dose-dependent reductions in overall response rates which were similar to those observed with either amphetamine or apomorphine. In addition, treatment with the D2 agonist produced a gradual decline in responding within each test session. These data suggest that preferential stimulation of either D1 or D2 receptors is sufficient in disrupting food-reinforced lever-pressing; furthermore, the extinction-like intrasession decline in responding induced by the D2 agonist suggests that this drug, unlike the others, may have disrupted responding by reducing the reinforcing efficacy of the food.

Dopamine and sexual behavior in the male rat: a reevaluation.

In castrated male rats treated with a low dose of testosterone propionate (0.40 mg/kg per week), the dopamine agonists amphetamine and amfonelic acid reduced mount latency without affecting other aspects of sexual behavior. Apomorphine, in doses between 0.05 and 0.15 mg/kg, and 1-DOPA 5-45 mg/kg + carbidopa 50 mg/kg, lacked effect on sexual behavior. Both amphetamine and amfonelic acid increased locomotor activity in a dose-dependent manner. Apomorphine, in the lowest dose, produced a reduction whereas the higher doses of this drug as well as all doses of 1-DOPA lacked effect on this behavior. In castrated animals implanted with a testosterone-filled Silastic capsule, showing a level of sexual activity indistinguishable from that of intact animals, amphetamine and amfonelic acid did not affect sexual behavior. The dopamine receptor antagonists haloperidol and cis(Z)-flupentixol reduced sexual behavior, whereas pimozide was without effect in the dose range used. The doses of haloperidol and flupentixol that were required to reduce sexual activity were such that they also affected motor execution measured in a treadmill test. It is suggested that increased dopaminergic neurotransmission may stimulate sexual behavior in an indirect way, augmenting behavioral arousal. The inhibitory effects of dopamine antagonists could be explained either by a reduced arousal level or by motor deficiencies.

Discriminative stimulus properties of haloperidol

AbstractRats (N = 9) were trained to discriminate the antipsychotic drug haloperidol (0.05 mg/kg i.p.) from drug vehicle (0.25% acetic acid in 0.9% saline) using a water‐reinforced, fixed‐ratio 10 response operant procedure. Acquisition of discrimination required a mean of 45 trainingsessions (median value of 38 sessions). The discriminative stimulus was dose‐dependent with an ED50 value of 0.008 mg/kg. The total number of responses per 10‐min test session was significantly reduced at all doses of haloperidol that produced haloperidol lever selection. The antipsychotic drug chlorpromazine substituted for the haloperidol discriminative stimulus (ED50 = 0.38 mg/kg). The indirect dopaminergic agonists amphetamine (1.0 mg/kg) and cocaine (10 mg/kg) fully blocked the haloperidol discriminative stimulus. Taken together, these initial results suggest that the discriminative stimulus produced by haloperidol is mediated, at least in part, by an interaction with dopamine receptors.

Nucleus accumbens opiate-dopamine interactions and locomotor activation in the rat: evidence for a pre-synaptic locus.

Locomotor activation produced by the indirect dopamine (DA) agonist amphetamine is reversed by the opiate-receptor antagonist naloxone. Since amphetamine-stimulated locomotion results from the release of DA within the nucleus accumbens (N.Acc.), it is possible that these effects of naloxone result either from a decrease in the pre-synaptic release of DA within the N.Acc. or from a disruption of the effects of DA at, or distal to, the post-synaptic DA receptor. In the present study, we investigated the effects of naloxone on the locomotor-activating properties of dopamine injected directly into the nucleus accumbens. Naloxone (0-2 mg/kg) had no significant effect of DA-stimulated locomotion; the lowest dose of naloxone tested (0.5 mg/kg) was shown to significantly disrupt the locomotor activation produced by amphetamine (0.5 mg/kg). In separate animals, very high doses of naloxone (5.0 mg/kg) had no significant effect on locomotor activation produced by the DA receptor agonist apomorphine in rats following 6-hydroxydopamine (6OHDA) denervation of the N.Acc. These results indicate that naloxone must disrupt amphetamine-stimulated locomotion through its action presynaptic to N.Acc. DA receptors.

The effects of haloperidol on amphetamine- and methylphenidate-induced conditioned place preferences and locomotor activity.

Place preferences induced by the indirect dopamine (DA) receptor agonists amphetamine (AMP) and methylphenidate (MPD) were investigated using an unbiased compartment procedure. In this procedure, prior to drug conditioning, rats did not exhibit preferences for either of the two compartments in a shuttle box. Both stimulants produced place preferences. Repeated testing of the MPD conditioned animals revealed an extinction-like decrease in preferences, suggesting that place preferences produced by MPD result from conditioning of MPD's reinforcing properties to environmental cues. During conditioning, the DA receptor antagonist haloperidol was administered prior to drug (S+) treatments, or prior to both drug and vehicle (S-) treatments. Haloperidol pretreatment blocked place preferences induced by AMP but not by MPD. In contrast, haloperidol blocked locomotor activity stimulated by either AMP or MPD. These results suggest that the reinforcing properties of MPD and AMP may be mediated by different mechanisms, while the locomotor stimulant effects of the two drugs have common neural substrates.

A comparison of CNS stimulants with phencyclidine on dopamine release using in vivo voltammetry

Pheneyelidine (PCP) produces some neurachemical and behavioral effects in rats similar to those produced by the indirectly acting dopamine (DA) agonists amphetamine and amfonelic acid, In view of these findings, the effects of PCP, d-amphetamine and amfonelic acid on the release of DA in the rat striatum were examined by in vivo voltammetry. Drug effects on DA release were determined using newly developed electrodes selective for catecholamines, PCP (5 and 10 mg/kg IP) produced a dosedependent decrease in the electrochemical signal that lasted for approximately 4 hr. In contrast, d-amphetamine (2.5 mg/kg, IP) and amfonelic acid (5.0 mg/kg, IP) both caused marked increases in electrochemical signals. The data provide evidence that PCP at the doses tested alters dopaminergic neurotransmission in a manner different from that of amphetamine and the non-amphetamine central nervous system stimulants by decreasing DA release from dopaminergic nerve terminals.