Comparison of the subjective effects of Delta(9)-tetrahydrocannabinol and marijuana in humans.

RATIONALE: There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marijuana differ from the effects of its primary active ingredient, Delta(9)-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marijuana and THC using matched doses administered either by the smoked or the oral form. OBJECTIVE: Two studies were conducted to compare the subjective effects of pure THC to whole-plant marijuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking. METHODS: In each study, marijuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marijuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-carboxy-THC. RESULTS: In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marijuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marijuana). In both the oral study and the smoking study, THC-only and whole plant marijuana produced similar subjective effects, with only minor differences. CONCLUSION: These results support the idea that the psychoactive effects of marijuana in healthy volunteers are due primarily to THC.

An fMRI study of the effect of amphetamine on brain activity.

Functional magnetic resonance imaging was used to evaluate the effects of oral d-amphetamine on brain activation elicited by auditory and simple motor tasks in ten normal right-handed subjects. We measured the percent signal change and number of voxels activated by a tone discrimination task and a right hand finger-tapping task after 20 mg of d-amphetamine and after placebo. Compared to placebo, amphetamine significantly increased the number of activated voxels in the left and right primary auditory cortices during the tone discrimination task and increased the number of activated voxels in the ipsilateral primary sensorimotor cortex and right middle frontal area during the motor task. Although highly specific vascular effects of drug cannot be ruled out as an explanation, these results could also mean that amphetamine increases the neuronal activity associated with each of these two tasks.

Lack of effect of intravenous hydrocortisone on mood in humans: a preliminary study.

Patients receiving therapy with hydrocortisone often report that this drug produces stimulant-like effects or feelings of well-being. However, little is known about the mood-elevating effects of hydrocortisone after acute administration. Four healthy volunteers (two men and two women) received intravenous doses of hydrocottisone (0, 25, 50, 100 or 200 mg) on five separate sessions. Plasma levels of cortisol and adrenocorticotropic hormone (ACTH) were obtained, vital signs were monitored, and subjects completed a series of standardized subjective effects questionnaires. Despite large increases in circulating levels of cortisol, hydrocortisone did not produce any detectable stimulant-like effect on mood or vital signs. To the contrary, hydrocortisone had a mild sedative-like effect, decreasing 'arousal'. These preliminary data indicate that acute increases in cortisol do not have either subjective stimulant-like or mood-elevating effects.

Delta9-tetrahydrocannabivarin as a marker for the ingestion of marijuana versus Marinol: results of a clinical study.

Delta9-tetrahydrocannabinol (THC), the main psychologically active ingredient of the cannabis plant (marijuana), has been prepared synthetically and used as the bulk active ingredient of Marinol, which was approved by the FDA for the control of nausea and vomiting in cancer patients receiving chemotherapy and as an appetite stimulant for AIDS patients. Because the natural and the synthetic THC are identical in all respects, it is impossible to determine the source of the urinary metabolite of THC, 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid (THC-COOH), in a urine specimen provided in a drug-testing program. Over the last few years there has been a need to determine whether a marijuana positive drug test is the result of the ingestion of marijuana (or a related product) or whether it results from the sole use of Marinol. We have previously proposed the use of delta9-tetrahydrocannabivarin (THCV, the C3 homologue of THC) as a marker for the ingestion of marijuana (or a related product) because THCV is a natural component of most cannabis products along with THC and does not exist in Marinol. We have also reported that THCV is metabolized by human hepatocytes to 11-nor-delta9-tetrahydrocannabivarin-9-carboxylic acid (THCV-COOH); therefore, the presence of the latter in a urine specimen would indicate that the donor must have used marijuana or a related product (with or without Marinol). In this study, we provide clinical data showing that THCV-COOH is detected in urine specimens collected from human subjects only after the ingestion of marijuana and not after the ingestion of Marinol (whether the latter is ingested orally or by smoking). Four subjects (male and female) participated in the study in a three-session, within-subject, crossover design. The sessions were conducted at one-week intervals. Each subject received, in separate sessions and in randomized order, an oral dose of Marinol (15 mg), a smoked dose of THC (16.88 mg) in a placebo marijuana cigarette, or a smoked dose of marijuana (2.11% THC and 0.12% THCV). Urine samples were collected and vital signs were monitored every 2 h for a 6-h period following drug administration. Subjects were then transported home, were given sample collection containers and logbooks, and were instructed to record at home the volume and time of every urine collection for 24 h, and once a day for the remainder of a week (6 days). Subjects were also instructed to freeze the urine samples until the next session. All urine samples were analyzed by GC-MS for THC-COOH and THCV-COOH using solid-phase extraction and derivatization procedure on RapidTrace and TBDMS as the derivative. The method had a limit of detection of 1.0 ng/mL and 1.0 ng/mL for THCV-COOH and THC-COOH, respectively.

Acute hydrocortisone administration does not affect subjective responses to d-amphetamine in humans.

RATIONALE: Stress and glucocorticoids facilitate and reinstate psychostimulant self-administration in rodents. However, the effects of stress and glucocorticoids on the subjective and behavioral effects of psychostimulants have not been well studied in humans. OBJECTIVES: To examine the effects of acute hydrocortisone pretreatment on the subjective and behavioral effects of d-amphetamine. METHODS: Hydrocortisone (100 mg) and d-amphetamine (20 mg) were administered orally to 16 healthy male and female volunteers in a four-session, placebo-controlled, within-subject, crossover design. To prevent stomach irritation, subjects received rantidine hydrochloride before each experimental session. Dependent measures included self-reported mood and subjective effects (Addiction Research Center inventory, the profile of mood states, and a series of visual analogue scales), vital signs, salivary cortisol, and psychomotor performance. RESULTS: Hydrocortisone elevated salivary cortisol levels, produced modest dysphoria, and reduced subjects' reports of wanting more drug. However, hydrocortisone pretreatment did not affect any of the physiological, behavioral, or subjective effects of d-amphetamine. CONCLUSIONS: In contrast to the effects of glucocorticoids in rodent studies, these results indicate that an acute increase in cortisol does not enhance the psychostimulant effects of d-amphetamine in humans.

Naltrexone does not block the subjective effects of oral Delta(9)-tetrahydrocannabinol in humans.

Delta(9)-tetrahydrocannabinol (THC) and opioids have many common effects. In addition, some THC effects in laboratory animals can be blocked or attenuated by opioid antagonists. This suggests that opioid systems mediate or modulate some THC effects. To determine whether opioid systems mediate THC effects in humans, the effects of the opioid antagonist naltrexone on subjective responses to THC were examined in 14 marijuana users. Subjects participated in a double-blinded, cross-over design in which each subject received all combinations of naltrexone (0 or 50 mg) and THC (0, 7.5, or 15 mg). THC increased heart rate and self-reported drug effects, such as euphoria and marijuana-like effects, and decreased psychomotor performance. Naltrexone increased heart rate and decreased self-reported measures of vigor and hunger but did not alter any of the effects of THC. These results suggest that the subjective, physiological, and behavioral effects of THC in humans are not mediated through opioid systems.

Biochemical and anatomical characterization of forepaw adjusting steps in rat models of Parkinson's disease: studies on medial forebrain bundle and striatal lesions.

Deficits in forepaw adjusting steps in rats have been proposed as a non-drug-induced model of the akinesia associated with Parkinson's disease. The present study examined the relationship between contralateral forepaw adjusting steps and dopamine depletion after medial forebrain bundle lesions with 6-hydroxydopamine. Depletion of striatal dopamine by >80% resulted in dramatic reductions in the ability of rats to make adjusting steps, but rats with < 80% dopamine depletion had no detectable deficit. The deficit in forepaw adjusting steps was evident by three days after lesions and did not recover for up to 13 weeks. Compared to apomorphine-induced rotation, the deficit in adjusting steps was evident at milder dopamine depletion. Discrete striatal lesions were also utilized to localize the striatal subregions that mediate forepaw adjusting steps. Forepaw adjusting steps were reduced after lesions of dorsolateral, ventrolateral or ventrocentral striatum, but not after lesions of dorsomedial, dorsocentral or ventromedial striatum. The reductions in adjusting steps after the discrete striatal lesions were not as severe as after medial forebrain bundle lesions. Furthermore, none of the discrete striatal lesions resulted in rotation after apomorphine administration, although a few resulted in increase in amphetamine-induced rotation. Administration of L-3,4-dihydroxyphenylalanine partially reversed the reductions of forepaw adjusting steps in both sets of lesion experiments. Together, these results suggest that forepaw adjusting step deficits in the rat provide a good model for the akinesia of Parkinson's disease both in medial forebrain bundle and striatal lesions, and would be a useful tool for investigating the efficacy of various therapeutic strategies.

Subjective and behavioral effects of repeated d-amphetamine in humans.

Behavioral sensitization is thought to be an important determinant of drug-taking and drug-seeking behaviors. Although there is abundant research characterizing behavioral sensitization in animals, there is little evidence for this phenomenon in humans. The aim of the present study was to determine if repeated oral d-amphetamine administration enhances self-reported mood and other behavioral indices of d-amphetamine effects in humans. Sixteen healthy volunteers, with no prior stimulant use, received two doses of d-amphetamine (20 mg) and two doses of placebo, in alternating order, on 4 consecutive days, under double-blind conditions. Mood and behavioral effects were measured using standard self-report questionnaires. Heart rate, blood pressure, psychomotor performance, and tapping speed were also monitored. d-Amphetamine elicited prototypical increases on several measures including self-reported drug effects, mood, and physiological responses. However, except for a slight reduction in 'feel drug' scores during the first hour of the second d-amphetamine session, the majority of effects were not altered on the second session. These results indicate that the subjective effects of d-amphetamine display only an apparent mild tolerance after a single exposure 48 h earlier.

Role of aromatic L-amino acid decarboxylase for dopamine replacement by genetically modified fibroblasts in a rat model of Parkinson's disease.

Investigations of gene therapy for Parkinson's disease have focused primarily on strategies that replace tyrosine hydroxylase. In the present study, the role of aromatic L-amino acid decarboxylase in gene therapy with tyrosine hydroxylase was examined by adding the gene for aromatic L-amino acid decarboxylase to our paradigm using primary fibroblasts transduced with both tyrosine hydroxylase and GTP cyclohydrolase I. We compared catecholamine synthesis in vitro in cultures of cells with tyrosine hydroxylase and aromatic L-amino acid decarboxylase together versus cocultures of cells containing these enzymes separately. L-DOPA and dopamine levels were higher in the cocultures that separated the enzymes. To determine the role of aromatic L-amino acid decarboxylase in vivo, cells containing tyrosine hydroxylase and GTP cyclohydrolase I were grafted alone or in combination with cells containing aromatic L-amino acid decarboxylase into the 6-hydroxydopamine-denervated rat striatum. Grafts containing aromatic L-amino acid decarboxylase produced less L-DOPA and dopamine as monitored by microdialysis. These findings indicate that not only is there sufficient aromatic L-amino acid decarboxylase near striatal grafts producing L-DOPA, but also the close proximity of the enzyme to tyrosine hydroxylase is detrimental for optimal dopamine production. This is most likely due to feedback inhibition of tyrosine hydroxylase by dopamine.

Double transduction with GTP cyclohydrolase I and tyrosine hydroxylase is necessary for spontaneous synthesis of L-DOPA by primary fibroblasts.

Gene transfer of tyrosine hydroxylase (TH) in animal models of Parkinson's disease (PD), using either genetically modified cells or recombinant virus vectors, has produced partial restoration of behavioral and biochemical deficits. The limited success of this approach may be related to the availability of the cofactor, tetrahydrobiopterin (BH4), because neither the dopamine-depleted striatum nor the cells used for gene transfer possess a sufficient amount of BH4 to support TH activity. To determine the role of BH4 in gene therapy, fibroblast cells transduced with the gene for TH were additionally modified with the gene for GTP cyclohydrolase l; an enzyme critical for BH4 synthesis. In contrast to cells transduced with only TH, doubly transduced fibroblasts spontaneously produced both BH4 and 3, 4-dihydroxy-L-phenylalanine. To examine further the importance of GTP cyclohydrolase I in gene therapy for PD, in vivo micro-dialysis was used to assess the biochemical changes in the dopamine-denervated striatum containing grafts of genetically modified fibroblasts. Only denervated striata grafted with fibro-blasts possessing both TH and GTP cyclohydrolase I genes displayed biochemical restoration. However, no significant differences from controls were observed in apomorphine-induced rotation. This is partly attributable to a limited duration of gene expression in vivo. These differences between fibroblasts transduced with TH alone and those additionally modified with the GTP cyclohydrolase I gene indicate that BH4 is critical for biochemical restoration in a rat model of PD and that GTP cyclohydrolase I is sufficient for production of BH4.

The dopamine D1 receptor antagonist SCH 23390 can exert D1 agonist-like effects on rat nucleus accumbens neurons.

Interactions between the selective dopamine D1-class receptor antagonist SCH 23390 and the dopamine D2-class receptor agonist quinpirole on nucleus accumbens neurons were investigated with extracellular single cell recording and microiontophoresis. Because dopamine D1 receptor stimulation enables many dopamine D2 receptor-mediated effects, SCH 23390 was expected to antagonize quinpirole-induced inhibition of activity. Although concurrent iontophoretic administration of SCH 23390 attenuated the inhibitory effects of quinpirole on most neurons, the antagonist further suppressed the firing of most neurons during attempts to reverse quinpirole-induced inhibition. SCH 23390 also reinstated (enabled) quinpirole-induced inhibition in rats acutely depleted of dopamine. These findings suggest that under certain conditions, SCH 23390 may exert dopamine D1 agonist-like effects.

L-3,4-dihydroxyphenylalanine-induced dopamine release in the striatum of intact and 6-hydroxydopamine-treated rats: differential effects of monoamine oxidase A and B inhibitors.

Administration of L-DOPA (50 mg/kg) elicits a significant increase in extracellular dopamine in striata of rats treated with the catecholaminergic neurotoxin 6-hydroxydopamine but not in striata of intact rats. To assess the role of dopaminergic nerve terminals in determining the effects of exogenous L-DOPA on extracellular dopamine levels in striatum, we examined the relative contributions of monoamine oxidase A and monoamine oxidase B to the catabolism of dopamine synthesized from exogenous L-DOPA. Extracellular concentrations of dopamine and its catabolite, 3,4-dihydroxyphenylacetic acid, were monitored with in vivo dialysis in striata of intact rats and of rats with unilateral 6-hydroxydopamine lesions of striatal dopamine. Clorgyline (2 mg/kg), an inhibitor of monoamine oxidase A, significantly increased dopamine and decreased 3,4-dihydroxyphenylacetic acid in intact but not in dopamine-depleted striata. Inhibition of monoamine oxidase B with either L-deprenyl (1 mg/kg) or Ro 19-6327 (1 mg/kg) did not significantly affect dopamine or 3,4-dihydroxyphenylacetic acid in striata of intact or dopamine-depleted rats. In intact rats, administration of clorgyline in conjunction with L-DOPA produced a > 20-fold increase in dopamine and prevented the L-DOPA-induced increase in 3,4-dihydroxyphenylacetic acid. Although both L-deprenyl and Ro 19-6327 administered in combination with L-DOPA elicited a small but significant increase in dopamine, levels of 3,4-dihydroxyphenylacetic acid were not affected. In rats pretreated with 6-hydroxydopamine, clorgyline had no significant effect on the increases in dopamine and 3,4-dihydroxyphenylacetic acid elicited by L-DOPA. Furthermore, neither L-deprenyl nor Ro 19-6327 affected L-DOPA-induced increases in dopamine and 3,4-dihydroxyphenylacetic acid in dopamine-depleted striata. The present findings indicate that deamination by monoamine oxidase A is the primary mechanism for catabolism of striatal dopamine, both under basal conditions and after administration of exogenous L-DOPA. Loss of dopaminergic terminals eliminates this action of monoamine oxidase A but does not enhance deamination by monoamine oxidase B. These data support a model in which exogenous L-DOPA elicits enhanced extracellular accumulation of dopamine in the dopamine-depleted striatum because some transmitter synthesis occurs at nondopaminergic sites and the dopamine terminals that normally take up and catabolize this pool of transmitter are absent.

Parametric and pharmacological analyses of the enhanced grooming response elicited by the D1 dopamine receptor agonist SKF 38393 in the rat.

The present report investigated several parametric and pharmacological aspects of the enhanced self-grooming behavior of rats following systemic administration of the selective D1 dopamine (DA) receptor agonist SKF 38393. The amount of time that rats spent grooming themselves was measured continuously for 30 min following drug administration to provide a quantitative measure of the drug-induced behavior. SKF 38393 increased the amount of grooming in a dose-dependent manner (0.5-16 mg/kg, SC). The onset of this effect required at least 5 min and it persisted for at least 60 min. The ability of SKF 38393 to enhance grooming was shared by R-SKF 38393, but not S-SKF 38393, consistent with the affinities of these enantiomers for the D1 DA receptor. Unlike SKF 38393, the peripheral D1 agonist fenoldopam (SKF82526) failed to cause an increased grooming response, suggesting a central site of action for elicitation of this behavior. The SKF 38393-induced increase in grooming was competitively antagonized by the D1 selective antagonist SCH 23390 (0.5 mg/kg, SC). Although the D2 DA receptor-selective antagonist eticlopride reduced SKF 38393-elicited grooming, this antagonism appeared to be of a physiological rather than pharmacological nature. When eticlopride was coadministered with the non-selective (mixed) D1/D2 agonist apomorphine, an increase in grooming behavior similar to that produced by SKF 38393 was observed. Inactivation of D1 and D2 DA receptors produced by pretreatment with the irreversible antagonist N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), at a dose which reduces D1 and D2 receptor density by > or = 50% (8.0 mg/kg, IP), reduced SKF 38393-induced grooming by approximately 50%.(ABSTRACT TRUNCATED AT 250 WORDS)

Lesions of the nigrostriatal dopamine projection increase the inhibitory effects of D1 and D2 dopamine agonists on caudate-putamen neurons and relieve D2 receptors from the necessity of D1 receptor stimulation.

Extracellular single unit recording and microiontophoretic techniques were used to determine the sensitivities and interactions of D1 and D2 dopamine (DA) receptors in the caudate putamen (CPu) of rats that were denervated of DA by intraventricular injections of the catecholamine neurotoxin 6-hydroxydopamine (6-OHDA). Seven to 10 d after the 6-OHDA injection, DA levels in the ipsilateral CPu were reduced to 11.8% of control. Current-response curves revealed that the inhibitory responses of CPu neurons to microiontophoretic administration of both the selective D1 receptor agonist SKF-38393 and the selective D2 receptor agonist quinpirole were significantly increased in 6-OHDA-pretreated rats, suggesting up-regulation of both receptor subtypes. Although our previous studies have established that D1 receptor activation is normally required for (enables) the inhibitory effects of selective D2 agonists in the CPu, this requirement was no longer evident in 6-OHDA-denervated rats. Whereas acute DA depletion [produced by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT)] attenuated the inhibitory effects of quinpirole on CPu neurons, long-term DA denervation (produced by 6-OHDA) enhanced the inhibitory effects of the D2 agonist. The enhanced effects of quinpirole in 6-OHDA-lesioned rats were not due to residual DA stimulating supersensitive D1 receptors (i.e., enabling) since further DA depletion (99.7%), produced by acute administration of AMPT in 6-OHDA-lesioned rats, failed to diminish the inhibitory efficacy of quinpirole. In addition to relieving D2 receptors from the need for D1 receptor-mediated enabling, 6-OHDA lesions also abolished the normal synergistic relationship between the receptor subtypes since low (subinhibitory) currents of SKF-38393 (4 nA) failed to potentiate the inhibitory effects of quinpirole on CPu neurons in lesioned rats. Similar findings (i.e., supersensitivity and loss of synergistic effects) were obtained from rats that had received repeated pretreatment with reserpine (2.5 mg/kg) for 4 d, indicating that these effects of 6-OHDA lesions were due to the depletion of synaptic DA rather than to the structural loss of DA terminals. Therefore, both the quantitative (potentiation) and the qualitative (enabling) synergistic effects between D1 and D2 receptors in the rat CPu were abolished when these receptors were functionally supersensitive. The present study provides electrophysiological support for previous behavioral studies indicating that the requirement of D1 receptor stimulation for D2 receptor-mediated functional effects (enabling) is not maintained in rats chronically depleted of DA by either 6-OHDA lesions or repeated reserpine.

D1 dopamine receptor stimulation enables the postsynaptic, but not autoreceptor, effects of D2 dopamine agonists in nigrostriatal and mesoaccumbens dopamine systems.

Possible functional interactions between D1 and D2 dopamine (DA) receptors were examined using extracellular single-cell recording with microiontophoretic application of selective D1 and D2 receptor agonists both postsynaptically, in the rat nucleus accumbens (NAc) and caudate-putamen (CPu), and presynaptically, at impulse-regulating somatodendritic DA autoreceptors in the ventral tegmental area (A10) and substantia nigra pars compacta (A9). In addition, synthesis-modulating nerve terminal DA autoreceptors were studied in both the CPu and NAc using the gamma-butyrolactone (GBL) neurochemical model of isolated nerve terminal autoreceptor function in vivo. In both the NAc and CPu, the inhibition of neurons produced by iontophoresis of the D2 receptor agonists quinpirole or RU-24213 was attenuated by acute DA depletion via the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT). However, during iontophoresis of the selective D1 DA receptor agonist SKF 38393, the inhibitory effects of the D2 agonists were again evident, suggesting that the attenuation of D2 agonist-induced inhibition was due to decreased D1 receptor activation. In contrast, the inhibitory effects produced by the non-selective D1/D2 agonist apomorphine or by SKF 38393 were unaffected by AMPT pretreatment. Thus, D1 receptor activation appears necessary for D2 receptor-mediated inhibition of NAc and CPu neurons, whereas D2 receptor activation is not required for the inhibition produced by D1 receptor stimulation. In contrast to postsynaptic D2 receptors, the ability of DA agonists to stimulate D2 DA autoreceptors was not altered by manipulations of D1 receptor occupation. Enhancing D1 receptor stimulation with SKF 38393 or reducing D1 receptor occupation with either the selective D1 receptor antagonist SCH 23390 or AMPT failed to alter the rate-inhibitory effect of i.v. quinpirole on A9 or A10 DA neurons. Similarly, iontophoresis of SKF 38393 failed to alter the inhibitory effects of iontophoretic quinpirole. SKF 38393 also failed to affect the inhibition of GBL-induced increases in DOPA accumulation (tyrosine hydroxylase activity) produced by quinpirole in either the NAc or CPu. Furthermore, reversal of GBL-induced increases in DOPA accumulation by apomorphine or quinpirole was unaffected by pretreatment with SCH 23390. Therefore, D1 receptor occupation appears to be necessary for the expression of the functional effects of postsynaptic D2 receptor stimulation but not presynaptic D2 DA autoreceptor stimulation.

Is stimulation of both D1 and D2 receptors necessary for the expression of dopamine-mediated behaviors?

Recent electrophysiological findings have indicated that D1 dopamine (DA) receptor stimulation by SKF 38393 enables the inhibitory effects of the D2 receptor agonist quinpirole on nucleus accumbens neurons. In the present study, a similar interaction was shown for quinpirole-induced stereotyped behaviors. In control rats, SKF 38393 enhanced the stereotyped responses induced by quinpirole, converting lower-level stereotypies (sniffing and rearing) to more intense oral behaviors (licking and gnawing). In rats depleted of DA (79% reduction) by the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine (AMPT), the behavioral effects of quinpirole were abolished. However, quinpirole-induced stereotyped responses were reinstated by SKF 38393 suggesting that D1 receptor stimulation by endogenous DA is necessary for D2 receptor-mediated stereotyped responses (sniffing, rearing). In support of this suggestion, stereotyped behaviors produced by the non-selective D1/D2 agonist apomorphine were not affected by AMPT pretreatment. In contrast to the effects of quinpirole, the ability of SKF 38393 to induce grooming responses was not abolished by AMPT pretreatment or by combined pretreatment with AMPT and reserpine (greater than 99% DA depletion). These results indicate that D1 receptor stimulation enables D2 receptor-mediated stereotyped responses, but that this relationship is not reciprocal since D2 receptor stimulation is not necessary for the grooming response elicited by SKF 38393.

Electrophysiological effects of BMY 14802, a new potential antipsychotic drug, on midbrain dopamine neurons in the rat: acute and chronic studies.

The present experiments compared the ability of a new potential antipsychotic drug, BMY 14802 (alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine- butanol), to alter the electrophysiological activity of midbrain dopamine (DA) neurons in the rat substantia nigra (A9) and ventral tegmental area (A10). Intravenous administration of BMY 14802 reversed the rate-suppressant effects of the DA agonist apomorphine on both A9 and A10 DA neurons; however, this reversal occurred at significantly lower doses in A10 than in A9. These effects of BMY 14802 appeared not to be mediated by DA receptors because, unlike the established antipsychotic drugs haloperidol and clozapine, BMY 14802 pretreatment failed to block apomorphine-induced suppression of A10 DA cells. Repeated s.c. administration (28 days) of BMY 14802 (2.5-10.0 mg/kg) reduced the number of spontaneously active A10 DA cells recorded per electrode track without affecting the number of A9 DA cells. This inactivation of A10 DA neurons was only partially reversed by the administration of apomorphine. Thus, it is uncertain as to whether this effect was produced by depolarization block as occurs during repeated administration of known antipsychotic drugs. These findings indicate that BMY 14802 influences DA neurotransmission by a nondopaminergic (perhaps sigma opioid) mechanism. The more potent effect of BMY 14802 on A10 DA neurons suggests that this novel compound may exert antipsychotic effects without producing significant extrapyramidal side effects.