d-Ala-met-enkephalin injection into the ventral tegmental area: effect on investigatory and spontaneous motor behaviour in the rat

The mesolimbic dopamine (DA) system, originating in the ventral tegmental area and projecting to limbic forebrain regions, plays a crucial role in mediating several important aspects of behaviour. Proximal to these DA neurons are enkephalin-containing nerve fibers. In an attempt to characterize the behavioural role of enkephalinergic transmission in the VTA, the present experiment examined in detail the investigatory and motor responses to microinfusion of d-ala-met-enkephalin (DALA), a long lasting analogue of enkephalin, into the ventral tegmental area (VTA). Injections into the substantia nigra (SN) and the hippocampus (HPC) were also performed as controls for site specificity. The behavioural apparatus consisted of an eight-hole box monitored by a video camera. Four doses of DALA were injected in the VTA (0.05, 0.1, 1 and 2.5 g/l bilaterally in 1 l volume) and one dose in the SN and HPC (0.1 g/l bilaterally in 1 l volume). The effect of DALA injections in the VTA was characterized by an inverted U-shape dose-effect curve. The low doses (0.05 and 0.1) induced an increase in the frequency of hole visits accompanied by a decrease in the mean duration of visits, whereas the highest doses induced a decrease in hole visit frequency. Low doses of DALA had no effect on strategy or organization of exploration, whereas the high doses produced decreased switching between holes. After low doses of DALA, locomotor activity at the periphery of the testing box was not significantly affected but locomotor activity in the centre was increased. After high doses of DALA, locomotor activity in the center and at the periphery of the box were decreased. Frequency of rearing was either not affected or decreased by DALA treatment. DALA injected in the SN resulted in a small increase in frequency of hole visits and did not affect rearing and locomotor activity. DALA injection in the HPC had no effect on investigatory and spontaneous motor behaviour. The results are discussed in terms of a modulatory role of endogenous enkephalin on mesolimbic dopamine neurons.     

Behavioral analysis of the effect of substance P injected into the ventral mesencephalon on investigatory and spontaneous motor behavior in the rat

In the present experiments the behavioral response to substance P (SP) microinfusion into the ventral tegmental area (VTA), substantia nigra (SN), and sensorimotor cortex (CX) was investigated in detail. The experiments were carried out using an eight-hole box to measure exploratory behavior and a video monitor for the analysis of spontaneous motor behavior. When infused into the VTA, SP (0.125, 0.5, 3.0 g) augmented the frequency and total duration of hole-pokes, and tended to diminish the mean duration of hole-pokes. The strategy and organization of responses, as measured by the order of hole-visits and hole-switching, were unchanged by SP and there was no indication of stereotypy, measured by the number of hole-pokes per hole-visit. The open-field analysis revealed a marked increase in locomotion and rearing, both in the periphery and center of the arena; grooming was decreased by SP. The behavioral profile following SN infusions of SP (3.0 g) was similar to that elicited by VTA infusions, with the exception that center rearing was not enhanced. SP administration into cortex (3 g) had no significant effect on any behavioral measures. It is hypothesized that SP infused into the ventral mesencephalon results in an enhancement of approach response tendencies, suggesting that endogenous SP in this region may regulate spontaneous behavior. The possibility of an interaction between SP and meso-telencephalic dopamine neurons is discussed.     

Endogenous neurotensin in the ventral tegmental area contributes to amphetamine behavioral sensitization.

Studies showing psychostimulant-like effects of exogenous neurotensin (NT) infused into the ventral tegmental area (VTA) prompted us to examine the role in the VTA of the endogenous NT in behavioral sensitization to amphetamine. Rats were sensitized to amphetamine by means of a subcutaneous amphetamine (1 mg/kg) injection, and the same dose was injected 7 days later to evaluate the expression of sensitization. The highly selective NT-receptor antagonist SR 142948A was injected into the VTA prior to the first and/or second amphetamine administration. SR 142948A (5 pmol/side) given before the first amphetamine exposure prevented the induction of behavioral sensitization, but did not alter the acute response to amphetamine. SR 142948A given with the second amphetamine administration did not affect the expression of behavioral sensitization. In contrast to administration into the VTA, intraperitoneal administration of SR 142948A (0.03, 0.1, or 0.3 mg/kg) had no detectable effect on the induction of amphetamine sensitization. These results suggest that activation of VTA NT receptors by endogenous NT may contribute to the neuroadaptations underlying behavioral sensitization to amphetamine.     

LSD-induced alterations of locomotor patterns and exploration in rats

A free exploration test was used to examine the effects of LSD on investigatory responding and locomotor activity in a novel environment. Rats were injected with 20–30 g/kg LSD or saline prior to being placed in a home cage. After 10 min, a door was opened permitting entry into a larger holeboard chamber where crossovers, rearings, hole pokes, and routes of locomotion were monitored. When administered either 10 or 30 min prior to testing, LSD reduced the time spent in the holeboard chamber only during the first half of a 1-h session, resulting in a corresponding reduction in all holeboard activity measures. In the subsequent 30 min, LSD-treated rats maintained a steady level of responding, in contrast to the continual derement exhibited by controls. Despite their initial avoidance of the holeboard, LSD-treated rats made consistently longer hole pokes into floor holes and showed a more diversified pattern of locomotion than did controls throughout the 1-h session. Most striking was the failure of LSD-treated rats to establish the stereotyped excursion routes, characteristic of controls, from the home cage to various parts of the holeboard. It is suggested that LSD potentiates both neophobic (avoidance) and investigatory responses to a novel environment by retarding the rate of behavioral habituation.     

In vitro modulation of the firing rate of dopamine neurons in the rat substantia nigra pars compacta and the ventral tegmental area by antipsychotic drugs

An in vitro experimental midbrain slice preparation is described which allows simultaneous extracellular recordings of the (spontaneous) electrical activity of dopamine neurons in the rat substantia nigra (SN) and the ventral tegmental area (VTA). Under identical in vitro circumstances the mean firing frequency of the SN dopamine neurons was higher than that of the VTA dopamine neurons (2.1 vs. 1.4Hz). With this slice preparation, modulation of the electrical activity of SN and VTA dopamine neurons by (new) drugs can be quickly determined. Experiments with the selective D2 receptor agonist quinpirole and the selective D2 receptor antagonist (-)-sulpiride indicated that dopamine neurons in the SN and VTA hardly differ in their pharmacological properties for the D2-like (auto)receptor. (-)-Sulpiride and to a lesser extent risperidone induced a small increase in firing rate in SN and VTA neurons, which was reversible upon wash-out. Olanzapine-induced increase in firing rate was persistent in SN and VTA neurons, whereas the clozapine-induced increase in firing rate was only completely recovered upon wash-out in SN neurons. The difference in firing rates of SN and VTA dopamine neurons could have consequences for the effectiveness of dopaminergic drugs acting at the D2-like dopamine (auto)receptor on these neurons.     

Chronic methylphenidate modulates locomotor activity and sensory evoked responses in the VTA and NAc of freely behaving rats

Repeated exposure to psychostimulants leads to behavioral sensitization. The mode of action of brain circuitry responsible for behavioral sensitization is not well understood. There is some evidence that psychostimulants, such as amphetamine and cocaine, activate the ventral tegmental area (VTA) and nucleus accumbens (NAc). However, little is known about the effect of methylphenidate (MPD) on the electrophysiological properties of VTA and NAc neurons. The study was designed to investigate the chronic effects of MPD administration on sensory evoked field potentials of VTA and NAc in freely behaving rats previously implanted with permanent electrodes. On experimental day 1, locomotor behavior was recorded for 2 h post-saline injection followed by sensory evoked field potential recordings after saline and three different escalating (0.6, 2.5, and 10.0 mg/kg) MPD doses. After completion of the last recording, the rat was returned to its home cage. To induce behavioral sensitization, animals were injected for five days with 2.5 mg/kg MPD. Following a rechallenge with saline and identical MPD doses as those given on experimental day 1, locomotor recording of the rat was also performed on experimental days 2, 6 and 11. Results showed that repeated administration of MPD increased locomotion in dose-response manner and elicited behavioral sensitization, while the amplitude of the sensory evoked field responses of the VTA and NAc exhibited dose-response attenuation on both recording days (days 1 and 10). In addition, repeated administration of MPD resulted in attenuating the baseline amplitudes of sensory input on experimental day 10, while MPD administration on experimental day 10 elicited further attenuation of the VTA and NAc sensory evoked responses. Such further attenuation can be interpreted as electrophysiological sensitization.     

Neuroanatomical site specific modulation of spontaneous motor activity by neurotensin

Immunohistofluorescent neurotensin (NT) is found in the ventral tegmental area (VTA), and bilateral injection of NT into the VTA produces an increase in exploratory behaviours. The VTA also contains dopaminergic cell bodies with axonal projections to the nucleus accumbens. In this study it was shown that bilateral microinjection of NT (4.0 μg/side) into the nucleus accumbens blocked the behavioral hyperactivity produced by intra-VTA injection of NT (2.5 μg/side).     

Neurokinin-alpha injected into the ventral tegmental area elicits a dopamine-dependent behavioral activation in the rat

Neurokinin-alpha (NKA) and substance P (SP), neuropeptides of the tachykinin family, have been identified in dopaminergic areas of rat brain. It has previously been shown that SP microinjected into the ventral tegmental area (VTA), site of the dopaminergic A10 (DA-A10) cell bodies, causes a behavioral activation characteristic of dopamine agonists. The present experiment measured open field behavior following bilateral VTA injections of NKA (0.02, 0.2, 2.0 micrograms/0.5 microliters). NKA induced a dose-dependent behavioral activation at lower concentrations of NKA than previously reported with SP. Medium and high doses of NKA produced significant increases in locomotion and rearing in both the center and periphery of the open field. Grooming decreased with dose, although this effect was not significant. In a second experiment, the behavioral activation by NKA (2.0 micrograms) was blocked by pretreatment with haloperidol (0.2 mg/kg), confirming that the NKA-induced effect is mediated by dopamine. Although the VTA contains both SP and NKA, receptors binding NKA exist here in greater density than those binding SP. Thus NKA may be the tachykinin in this region that preferentially interacts with DA-A10 neurons mediating behavioral arousal.     

Modulation of Locomotor Activation by the Rostromedial Tegmental Nucleus

The rostromedial tegmental nucleus (RMTg) is a strong inhibitor of dopamine neurons in the ventral tegmental area (VTA) reported to influence neurobiological and behavioral responses to reward omission, aversive and fear-eliciting stimuli, and certain drugs of abuse. Insofar as previous studies implicate ventral mesencephalic dopamine neurons as an essential component of locomotor activation, we hypothesized that the RMTg also should modulate locomotion activation. We observed that bilateral infusions into the RMTg of the gamma-aminobutyric acid A (GABA_A) agonist, muscimol, indeed activate locomotion. Alternatively, bilateral RMTg infusions of the GABA_A receptor antagonist, bicuculline, suppress robust activations of locomotion elicited in two distinct ways: (1) by disinhibitory stimulation of neurons in the lateral preoptic area and (2) by return of rats to an environment previously paired with amphetamine administration. The possibility that suppressive locomotor effects of RMTg bicuculline infusions were due to unintended spread of drug to the nearby VTA was falsified by a control experiment showing that bilateral infusions of bicuculline into the VTA produce activation rather than suppression of locomotion. These results objectively implicate the RMTg in the regulation of locomotor activation. The effect is important because much evidence reported in the literature suggests that locomotor activation can be an involuntary behavioral expression of expectation and/or want without which the willingness to execute adaptive behaviors is impaired.     

Stress produces opioid-like effects on investigatory behavior

Stimulation of opioid systems with opiate agonists produce characteristic alterations in the investigatory behavior exhibited by rats in a novel environment. As numerous reports now indicate that opioid systems can be activated by exposure to stress, the following study examined whether exposure to stressors could produce opiate-like alterations of investigatory behavior. Naive rats were exposed to one of three stressors (restraint, tailpinch pressure, high intensity white noise) or to control procedures, and were observed in a novel environment. The frequency and duration of a wide range of behavioral activities were recorded. All three stressors were found to produce morphine-like alterations of investigatory behavior. The average time an animal spent per contact with stimuli in the environment was decreased significantly by stress, with greater reductions being associated with locomotor hypoactivity. The stress-induced reductions of investigatory behavior were blocked by very low doses of the opiate antagonist naloxone (0.1-0.25 mg/kg). These results are consistent with an activation of opioid systems underlying some of the changes in investigatory behavior produced by exposure to stress.     

Neurotensin,substance P,neurokinin-α, and enkephalin: injection into ventral tegmental area in the rat produces differential effects on operant responding

The neuropeptides neurotensin, substance P, neurokinin- (substance K), and met-enkephalin are present endogenously in the ventral tegmental area (VTA), site of the A10 dopaminergic (DA) cell bodies. In the present study these four peptides were injected bilaterally into the VTA in the rat, and the effects on operant behavior were assessed. Cannulae aimed at the VTA were implanted in four groups of animals, which had been trained to bar-press for food reward on a fixed-interval, 40-s schedule. A fifth group, in which the effects of systemically administered amphetamine were assessed, was also tested. Response rate across the interval was measured, and the index of quarter-life was taken as an indication of the temporal pattern of resonding. In addition, a rate-dependency analysis was carried out for all data. Neurotensin (NT, 0.0175, 0.175, 0.5 g in 1 l) dose-dependently decreased response rates without affecting quarter-life, and reduced the number of reinforcements obtained. Substance P (SP, 0.1, 1.0, 3.0 g) did not affect responding, and neurokinin- (NKA, 0.1, 1.0, 3.0 g) induced a small increase in responding. Quarter-life was not affected by SP or NKA, but responding on the nonreinforced lever was significantly increased by both peptides. d-Ala-met-enkephalin (DALA, 0.01, 0.1, 1.0 g) induced a dose-dependent increase in responding which was also rate-dependent, and reduced quarter-life. DALA effects were similar to the classic pattern of responding observed after systemic amphetamine. These results suggest that although all these peptides elicit behavioral activation and may affect DA neuronal activity, the behavioral responses can be differentiated with respect to operant behavior.     

Spatial and temporal patterning distinguishes the locomotor activating effects of dizocilpine and phencyclidine in rats

A behavioral pattern monitor was used to assess the effects of dizocilpine (MK-801) and phencyclidine on the spatial and temporal patterns of locomotion and investigatory behavior in rats. The monitor provided both quantitative measures of crossovers, rearings and holepokes and qualitative measurement of the spatial and temporal patterns of locomotion. Dizocilpine (0.004-0.5 mg/kg) and phencyclidine (0.25-5.0 mg/kg) produced similar, dose-dependent increases in locomotor activity. At small doses, dizocilpine and phencyclidine increased investigatory holepokes, while at larger doses, both drugs significantly decreased the number of holepokes. Rearings were reduced similarly by the larger doses of each drug. Both dizocilpine and phencyclidine produced perseverative spatial patterns of locomotion, especially at larger doses. However, the locomotor patterns produced by these drugs were found to be dissimilar in spatial quality. After phencyclidine, animals frequently circled the perimeter of the monitor chamber or moved repetitively in horseshoe or figure-8 patterns. By contrast, rats given dizocilpine completed small rotations about either end of the chamber. Pretreatment with a small dose (0.02 mg/kg) of haloperidol, prior to either dizocilpine (0.5 mg/kg) or phencyclidine (5.0 mg/kg) had no effect on the increase in locomotor activity or the decreases in investigatory holepokes produced by the drugs. However, haloperidol altered the effects of phencyclidine on the spatial and temporal patterns of locomotion, suggesting that sigma receptors or other haloperidol-sensitive binding sites, may influence the quality but not the quantity of phencyclidine-induced hyperactivity.     

Antagonization of the behavioral activation produced by direct stimulation of forebrain dopamine receptors caused by intraaccumbens injections of neurotensin

A number of studies have shown that intracisternal, intracerebroventricular, or direct administration of neurotensin (NT) into the nucleus accumbens (ACC) can antagonize the arousal and excitement produced by activation of the mesolimbic dopamine (DA) system of rats. This study investigated where NT acts relative to DA neurons to exert this antagonistic effect. In this study we selectively removed the majority of limbic forebrain DA terminals by bilateral administration of 6-hydroxydopamine (6-OHDA) into the anterolateral hypothalamus of desipramine-pretreated rats. The 6-OHDA-treated rats subsequently developed DA receptor supersensitivity, as evidenced by behavioral supersensitivity to L-DOPA. The L-DOPA dose employed was subthreshold for behavioral excitation in control rats. The behavioral excitation to L-DOPA in 6-OHDA-treated rats consisted of increases in sniffing and increases in locomotion and/or rearing, along with decreases in resting and sleep. Following bilateral intra-ACC injections of NT, L-DOPA-induced sniffing, rearing, and locomotion decreased significantly, and resting and sleep increased significantly. These data suggest that intra-ACC NT, acting in or proximal to the ACC, can antagonize the behavioral effects of limbic DA stimulation and that this antagonism is postsynaptic to DA neurons.     

Behavioral effects of neural transplants into the intact striatum

The behavioral effects of fetal brain tissue and adrenal medulla transplants into the intact striatum of rats were investigated. Following a bilateral injection of 1.5, 3 or 6 microliters of fetal striatal tissue, a volume-related weight loss was found in all transplanted groups, including the SHAM group, during the first 7 days after the surgery. Rearing behavior was changed in a transplant volume-related manner. Histological analysis suggested that the locomotor effects of transplants into the intact striatum are related to the volume of the transplants. Following bilateral transplantation of fetal cortex (CTX), substantia nigra (SN), striatum (STR), or adrenal medulla (AM) into the striatum, the different behavioral deficits were observed among these transplant groups. The SN group showed a decrease in spontaneous locomotion, significantly increased rearing activity in response to administration of amphetamine, reduction of food intake and water intake and a reduction in body weight. The CTX and AM groups showed a marked increase in spontaneous rearing activities. Hyporesponsiveness to the administration of apomorphine (1 mg/kg) and amphetamine (1 mg/kg) was evident in the CTX, STR, AM groups and SHAM groups. In contrast, the haloperidol-induced catalepsy scores of the CTX, STR, SN and AM were significantly higher than those of a normal control group. In addition, the CTX group showed a deficit in the delayed reward alternation test. These results indicated that the behavioral deficits produced by transplants into normal striatum may be related to both mechanical destruction due to transplant expansion and specific neurochemical interactions of each tissue type between the host and the transplant. Therefore, potential negative consequences of neural transplantation therapy should be considered as well as the beneficial effects.     

GABA stimulation and blockade in the hypothalamus and midbrain: effects on feeding and locomotor activity

Microinjections of the gamma-aminobutyric acid (GABA) antagonist, bicuculline methiodide (BM) (100 ng), into the anterolateral hypothalamus (LH) increased ingestion of sweet milk. A subsequent injection of BM 48 hrs. later produced a type of kindling effect consisting of feeding related automatisms, such as gnawing and biting. The behavioral effects of injections of 100 ng of GABA into the LH were variable. GABA injections into the ventromedial hypothalamus (VMH) reliably increased food intake. GABA injections into the origin of the nigrostriatal dopamine (DA) neurons in the substantia nigra (SN) suppressed it. Similar injections into the origin of the mesolimbic DA cells in the ventral tegmental area (VTA) had no effect on feeding behavior. Following BM injections into the SN, a moderate increase in tilt box activity was observed. A second injection of the GABA blocker 6 days later exaggerated this effect. Short latency extreme hyperactivation was accompanied by unidirectional barrel rolling which persisted until blocked by local injections of GABA.     

Behavioral characterization of morphine effects on motor activity in mice

A biphasic effect of morphine on locomotion has been extensively described. Nevertheless, the effects of this opioid on other behavioral parameters have been overlooked. The aim of the present study was to verify the effects of different doses of morphine on motor behaviors observed in an open-field. Adult female mice were injected with saline or morphine (10, 15 and 20 mg/kg, i.p.) and observed in an open-field for quantification of locomotor and rearing frequencies as well as duration of immobility and grooming. The lowest dose of morphine decreased locomotion (and increased immobility duration) while the highest dose increased it. All doses tested decreased rearing and grooming. Thus, the effects of morphine on locomotion do not parallel to its effects on rearing and grooming. Our results indicate that locomotion not always reflects the effect of drugs on motor activity, which can be better investigated when other behavioral parameters are concomitantly taken into account.     

Rewarding effects elicited by cocaine microinjections into the ventral tegmental area of C57BL/6 mice: involvement of dopamine D<Subscript>1</Subscript> and serotonin<Subscript>1B</Subscript> receptors

Rationale The role of ventral tegmental area (VTA) in mediating the rewarding effects of cocaine has not been extensively studied.Objectives We used the intracranial self-administration (ICSA) procedure to assess the involvement of the VTA in the rewarding effects of cocaine, and the effect of dopamine (DA) D₁- and serotonin (5-HT)_1B-receptor antagonists on ICSA of cocaine.Methods Adult male C57BL/6 mice were stereotaxically implanted, unilaterally, with a guide cannula either 1.5 or 2.3 mm above the VTA. After 1 week, mice were trained to discriminate between the two arms of a Y-maze over seven daily sessions, one arm being reinforced by intracranial cocaine microinjections. Starting from session 8, the D₁ and 5-HT_1B-receptor antagonists were injected IP pre-test each day over five consecutive sessions.Results Mice injected into the VTA rapidly exhibited a preference for the cocaine-reinforced arm, whatever the dose of cocaine available (30 pmol or 150 pmol per injection), reaching optimum ICSA performance within 5 days. In contrast, mice injected 0.8 mm above the VTA did not discriminate between the arms of the maze and performed at random, except for one subject. Once the ICSA response was acquired, systemic pre-injections of either the D₁ (SCH23390; 25 g/kg IP) or 5-HT_1B (GR127935; 0.5 mg/kg IP) antagonist disrupted this behavior. Replacement of each antagonist by vehicle led to the reinstatement of intra-VTA cocaine self-administration.Conclusions The results of the present study suggest that VTA neurons play a critical role in mediating the rewarding effects of acute cocaine and that both D₁ and 5-HT_1B receptors modulate these effects.     

The behavioral effects of CCK8 injected into the medial nucleus accumbens are dependent on the motivational state of the rat

The effects of CCK8 injected into the rat median nucleus accumbens on exploration and locomotion were measured in the four hole box and open-field tests. CCK8 (1 fmol to 100 pmol) induced hypoexploration in the four hole box (duration, frequency), with the pattern of the responses remaining unchanged compared to those of the control group. These effects were reversed by injection of the CCK antagonist proglumide (20 micrograms) into the nucleus accumbens. In the open-field test, CCK8 (100 pmol) only decreased locomotion and rearing when the rats were not habituated to the environment. These results show that the behavior of rats exposed to a novel external stimuli is highly sensitive to CCK8.     

Amphetamine,apomorphine and investigatory behavior in the rat: Analysis of the structure and pattern of responses

In the present experiments, the effects of a wide range of doses of d-amphetamine and apomorphine were studied on investigatory behavior in an automated eight-hole box. Amphetamine (0.125, 0.25, 0.5, 1.0, 3.0, 5.0 mg/kg) increased frequency and total duration of responses, and decreased mean duration in a dose-dependent manner. The strategy and organization of responses, as measured by the order of hole-visits and hole-switching, were unchanged at lower doses of amphetamine but were altered at higher doses. Perseverative hole-poking was observed at the highest dose (5.0) as indicated by increased number of hole-pokes per hole-visit. Apomorphine (0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 3.2 mg/kg) decreased mean duration of responses, but in contrast to amphetamine markedly diminished frequency. Locomotor activity was also measured at all doses of both drugs. Our observations indicate that these two stimulant drugs both of which increase motor activity, have markedly different effects on investigatory responses. It is likely that amphetamine increases prepotent response tendencies (i.e., hole-poking), although this does not necessarily reflect enhanced exploration. Further, the results obtained with amphetamine support predictions made by the Lyon-Robbins behavioral theory of amphetamine effects.     

Activation of glutamate neurotransmission in the prefrontal cortex sustains the motoric and dopaminergic effects of phencyclidine.

N-methyl-D-aspartate (NMDA) receptor antagonists such as phencyclidine (PCP) produce schizophrenia-like symptoms in healthy individuals, thus generating interest in understanding the mechanisms by which these drugs modify behavior. The hallmark of the behavioral effects of NMDA antagonists in the rodent is stereotyped motor activity. Although the major cellular correlate of this behavioral activation is thought to be an increase in dopamine neurotransmission in the nucleus accumbens (NAc), recent evidence suggests that NAc dopamine is neither necessary nor sufficient to elicit NMDA antagonist-induced motor effects. Based on our previous observation that NMDA antagonists increase glutamate efflux in the prefrontal cortex (PFC), and thus increase non-NMDA receptor glutamatergic neurotransmission in this region, we hypothesized that an increase in PFC efferent activity would activate motor pathways, independent of dopamine neurotransmission in the NAc. We tested this hypothesis by measuring dopaminergic and motoric effects of PCP while blocking non-NMDA receptors in the PFC, or in the ventral tegmental area (VTA) and NAc. Both VTA and NAc receive direct glutamatergic input from the PFC, and are implicated in the regulation of motor behavior. Blocking non-NMDA receptors in the PFC, NAc, or the VTA inhibited PCP-induced locomotion and stereotypy. This blockade was accompanied by an inhibition of PCP's effect on cortical dopamine release. However, the PCP-induced increase in NAc dopamine was not diminished, despite the behavioral inhibition. These findings suggest that the PFC may be a principal site for the regulation of PCP-induced stereotypy and hyperlocomotion, and that this regulation is independent of accumbal dopamine activity.