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Post-traumatic stress disorder (PTSD) is an anxiety disorder of considerable prevalence in individuals who have experienced a traumatic event. Studies of the neural substrate of this disorder have focused on the role of areas such as the hippocampus, the amygdala and the medial prefrontal cortex. We show that the ventral tegmental area (VTA), which directly modulates these areas, is part of this circuitry. Using a rat model of PTSD, we show that a brief but intense foot shock followed by three brief reminders can cause long-term behavioral changes as shown by anxiety-like, nociception, and touch-sensitivity tests. We show that an intraperitoneal injection of a dopamine (DA) antagonist or a bilateral inactivation of the VTA administered immediately before the traumatic event decrease the occurrence or intensity of these behavioral changes. Furthermore, we show that there is a significant decrease of baseline VTA dopaminergic but not GABAergic cell firing rates 2 weeks after trauma. Our data suggest that VTA DA neurons undergo long-term physiological changes after trauma and that this brain area is a crucial part of the circuits involved in PTSD symptomatology.

Recreational abuse of toluene-containing volatile inhalants by adolescents is a significant public health problem. The mechanisms underlying the abuse potential of such substances remain unclear, but could involve increased activity in mesoaccumbal dopamine (DA) afferents innervating the nucleus accumbens (ACB). Here, using in vitro electrophysiology, we show that application of behaviorally relevant concentrations of toluene directly stimulates DA neurons in the ventral tegmental area (VTA), but not surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-DA neurons, the magnitude of VTA DA neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in vivo microdialysis, we show that perfusion of toluene directly into the VTA increases DA concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACB. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA DA neurons, thereby enhancing DA release in the ACB. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA DA neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse.

Inhalant abuse remains a significant health problem among the younger segment of society. In fact, the use of inhalants in this population trails only that of nicotine, alcohol, and marijuana. Toluene is a common ingredient in many of the substances sought out for inhalation abuse, apparently for its euphorigenic and hallucinogenic effects. Because drugs of abuse share the common property of altering the activity of mesolimbic dopamine neurons, it is reasonable to suspect that toluene-induced changes in this CNS pathway may underlie its abuse potential. Here we will provide in vivo and in vitro electrophysiological data and behavioral evidence linking toluene exposure in rats to activation of mesolimbic dopamine neurons. Exposure of rats to 11,000 ppm of inhaled toluene produced time-dependent activation of dopamine neurons within the midbrain ventral tegmental area (VTA). In the rat brain slice preparation, perfusion with toluene (23-822 microM) also evoked an increase in activity of both dopamine and nondopamine neurons within the VTA. These excitatory effects could not be found in adjacent non-VTA nuclei, nor were they sensitive to the glutamate antagonists CGS19755 or CNQX. In behavioral studies, systemic administration of toluene produced a dose-dependent locomotor hyperactivity that was attenuated by either pretreatment with the D2 dopamine receptor antagonist remoxipride or by 6-hydroxydopamine lesions of the nucleus accumbens. These findings show that toluene can activate dopamine neurons within the mesolimbic reward pathway, an effect that may underlie the abuse potential of inhaled substances containing toluene.

Inhalant abuse is a common, potentially lethal, form of drug abuse. Although the putative psychotropic compo- nent of some popularly abused inhalants appears often to be the organic solvent toluene, its effects on midbrain neurones which comprise reward pathways have not been established. Therefore, the present study was designed to assess the response of ventral tegmental dopamine neurones during toluene inhalation. Electrophysiological determinations were made using extracellular single-unit recordings in ketamine anaesthetized rats that were exposed to acute (1-15.3 rnin.) concentrations of toluene vapor (1 1,500 ppm) similar to those consumed by inhalant abusers. Toluene exposure through a tracheal breathing tube elicited two distinctly different patterns of response in dopamine neurons. One pattern consisted of an initial stimulation of neuronal firing (+221%,t72%; 8.5 min.). The other pattern consisted of only an inhibition of firing regardless of the length of exposure. Furthermore, the changes in firing rates were paralleled by changes in number of action potentials contained in bursts. Blood samples taken at the time of the dopamine recordings revealed comparable toluene concen- trations (4-79 pg/ml, n=24) regardless of the patterns of response. These results suggest that mesolimbic dopamine neurotransmission can be changed by an exposure paradigm comparable to that used by human abusers, and that these changes may be integral to the reinforcing effects underlying inhalant abuse. The widespread abuse of inhalants (i.e., spray paints, glues, and lacquers) is a significant and potentially lethal problem among youth. An epidemiological study showed that in 1995, 23% of the adolescents in the United States were ex- perimenting with inhalants (Mathias 1996). Notably, up- wards of 38% of users may die during their first inhalant experience (Flanagan & Ives 1994). Although inhalant use may also lead to the abuse of other substances, a significant percentage of users prefer and continue to abuse inhalants to the point of irreversible neurotoxic consequences (Delva et ul. 1997). Although the overall incidence of inhalant abuse is extensive there is little experimental data implicat- ing the abuse liability of solvents such as toluene with a specific CNS site or mechanism of action. The acute consumption of inhalants produces a variety of psychotropic effects including an initial euphoria, intoxi- cation, slurred speech, ataxia, numbness of the extremities, amnesia, hostile behaviour, and hallucinations. As inhal- ation continues, seizures, tinnitus, diffuse somatic pain, tremor, and death can occur (Flanagan & Ives 1994). Sev- eral reports also link chronic "huffing" to permanent liver, kidney, heart and cranial nerve damage, cerebral, cerebellar, and brainstem atrophy, neuropathies, dependence, and psy- chosis (for a review see Arlien-S~rborg 1992). Many consider the organic solvent toluene the essential psychotropic com- ponent found in the more commonly abused inhalants. Even non-human primates lever press for bursts of toluene

Ibogaine, an indole containing alkaloid, has been shown to reduce the rate of injection of morphine and cocaine in self-administration protocols. Since morphine- and cocaine-induced modulation of dopamine release is impulse dependent and essential for their reinforcing effects, disruption of dopamine neuronal activity by ibogaine could explain its purported 'antiaddictive' properties. Therefore, the present study was designed to determine: (1) the acute effects of ibogaine on the activity of VTA dopamine neurons, and (2) whether ibogaine pretreatment causes a persistent modification of the dopamine neuronal response to morphine and cocaine. Extracellular recordings in anesthetized animals found that intravenous ibogaine markedly excited VTA dopamine neuronal firing. However, ibogaine pretreatment (6-8 hr and 19 hr before) failed to alter either the spontaneous activity of VTA neurons, or the response of these dopamine neurons to morphine or cocaine. Thus, ibogaine's excitatory effect on VTA neurons is not long-lasting nor does it persistently alter cocaine- or morphine-induced changes in dopamine neuron impulse activity. Therefore, other mechanisms must be explored to account for the proposed antiaddictive properties of ibogaine.

Phencyclidine (PCP) and PCP-like drugs increased firing rates and the amount of burst activity of A10 dopamine neurons recorded extracellularly in anesthetized rats. These effects correlated to their potency as noncompetitive N-methyl-D-aspartate (NMDA) antagonists but not to their affinity for the sigma-receptor. In contrast, the direct acting NMDA antagonists, CGS 19755, (+)CPP and NPC 12626, produced no alterations in either firing rate or burst patterns. However, pretreatment with either CGS 19755 or (+)CPP effectively attenuated the excitatory effects of PCP. In contrast to the findings obtained in the whole animal, PCP in the midbrain slice preparation did not activate dopamine neurons, even though PCP selectively blocked the excitations induced by NMDA but not those of the nonNMDA agonists, kainate and AMPA. In the self-administration test system a progressive-ratio schedule of reinforcement was used to assess the reinforcing strength of PCP and the PCP congeners, TCP and BTCP. In comparison to BTCP, which produced breaking points comparable to those occurring with equivalent doses of cocaine, PCP and TCP had considerably less reinforcing efficacy. These behavioral differences appeared to reflect the affinity of the compounds for the dopamine reuptake site versus the PCP binding site on the NMDA-ion channel complex. Thus, PCP's psychotomimetic effects and abuse liability properties may result from the differential mechanisms by which it affects limbic and cortical dopamine neurotransmission.

In vitro extracellular single-unit recordings from rat midbrain slices were used to assess the effects of excitatory amino acid agonists on the activity of A10 dopamine neurons. N-methyl-D-aspartic acid (NMDA), kainic acid (KA), and β-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) elicited dose-dependent increases in firing rates. The relative potencies for the 3 compounds was AMPA > KA > NMDA. None of the excitations was accompained by burst firing, but frequently periods of nonrecordable activity occurred following pronounced stimulation. Concurrent application of the excitatory amino acid antagonist CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) selectively blocked the excitations elicited by NMDA but not by KA or AMPA. Likewise the selective non-NMDA antagonist NBQX [2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline] blocked only the excitatory effects of AMPA and KA but not those elicited by NMDA. NBQX appeared to be less optent at antagonizing KA than AMPA. These results suggest that mesolimbic-mesocortical dopamine neurons possess both NMDA and non-NMDA receptors, and possibly distinct AMPA and KA recognition sites. © 1993 Wiley-Liss, Inc.

The binding of phencyclidine (PCP) within the channel gated by the NMDA-receptor complex can be positively or negatively modulated by compounds which facilitate or prevent the interaction of glutamate to the NMDA recognition site. In the present study extracellular recordings were used to evaluate the possibility that the negative modulation of NMDA channel function by the competitive NMDA antagonists (+/-)-CPP (3-((+/-)2-carboxypiperazin-4- yl)propyl-1-phosphonate) and CGS 19755 (cis-4-phosphonomethyl-2-piperidine carboxylate) could affect the response of A10 dopamine neurons to PCP. Pretreatment with 40 mg/kg of (+/-)-CPP or CGS 19755 completely blocked the low-dose excitatory effects of PCP, whereas 10 mg/kg of CGS 19755 produced only a partial blockade. However, neither CGS 19755 or (+/-)-CPP affected the amount of attenuation of A10 firing occurring with large doses of PCP. (+/-)-CPP and CGS 19755 pretreatment also failed to alter the morphine-induced stimulation of dopamine activity. These findings not only provide further evidence that the low-dose PCP-induced activation of A10 neurons is mediated through the NMDA-ion channel complex, but suggest that some physiological or behavioral effects evoked by PCP might be prevented by treatment with competitive NMDA receptor blockers.

The response of ventral tegmental (VTA) A10 dopamine neurons to a series of compounds covering the spectrum from high-affinity phencyclidine receptor ligands (MK-801, PCP) to high-affinity σ-receptor ligands ((+)-pentazocine, DTG) was measured using single-unit extracellular recording techniques in the rat. Dose-response comparisons revealed that MK-801 was 3, 6, 19 and 119 times more potent at activating A10 neurons than PCP, (+)-SKF-10,047, ketamine and (+)-pentazocine, respectively. DTG (1,3-di-o-tolylguanidine), the most selective σ-ligand, and U50,488H, a κ-opiate, failed to produce any stimulation of firing. Also, pretreatment with haloperidol, a potent σ-receptor ligand, did not prevent MK-801-induced excitations. Thus, the activation of the A10-mesolimbic-mesocortical dopamine pathways by PCP, PCP-like drugs and σ-psychotomimetics is mediated by the PCP receptor, not the haloperidol-sensitive σ-receptor, with potencies directly correlated to their activity as non-competitive N- methyl- d -aspartate (NMDA) antagonists.

Toluene, a volatile hydrocarbon found in a variety of chemical compounds, is misused and abused by inhalation for its euphorigenic effects. Toluene's reinforcing properties may share a common characteristic with other drugs of abuse, namely, activation of the mesolimbic dopamine system. Prior studies in our laboratory found that acutely inhaled toluene activated midbrain dopamine neurons in the rat. Moreover, single systemic injections of toluene in rats produced a dose-dependent increase in locomotor activity which was blocked by depletion of nucleus accumbens dopamine or by pretreatment with a D2 dopamine receptor antagonist. Here we examined the effects of seven daily intraperitoneal injections of 600 mg/kg toluene on the content of serotonin and dopamine in the caudate nucleus (CN) and nucleus accumbens (NAC), substantia nigra, and ventral tegmental area at 2, 4, and 24 h after the last injection. Also, the roles of nitric oxide, peroxynitrite, and the production of 3-nitrosotyrosine (3-NT), in the CN and NAC were assessed at the same time points. Toluene treatments increased dopamine levels in the CN and NAC, and serotonin levels in CN, NAC, and ventral tegmental area. Measurements of the dopamine metabolite dihydroxyphenylacetic acid (DOPAC) further suggested a change in transmitter utilization in CN and NAC. Lastly, 3-NT levels also showed a differential change between CN and NAC, but at different time points post-toluene injection. These results point out the complexity of action of toluene on neurotransmitter function following a course of chronic exposure. Changes in the production of 3-NT also suggest that toluene-induced neurotoxicity may mediate via generation of peroxynitrite.

The abuse of volatile inhalants remains a prominent, yet poorly understood, form of substance abuse among youth. Nevertheless, the identification of a mechanism underlying the reinforcing properties of inhalants has been hampered by the lack of a clearly identifiable neural substrate upon which these chemicals act. One ingredient that is common to many abused inhalants is toluene, an organic solvent that is self-administered by nonhuman primates and rodents. Most drugs of abuse have been found to elicit forward locomotion in rats, an effect owing to the activation of mesoaccumbal dopamine (DA) pathways. Thus, the present study was undertaken using two different approaches to determine whether toluene-induced locomotor hyperactivity is also ultimately dependent upon DA neurotransmission in the mesolimbic nucleus accumbens (NAC). Here we report on the effects of 6-hydroxydopamine (6-OHDA) lesions of the NAC or pretreatment with the metabotropic mGlu2/3 receptor agonist LY379268 on toluene-induced locomotor activity. Both procedures, which are known to alter neurotransmission within the NAC, significantly attenuated toluene's locomotor stimulatory effects. These results provide strong support for a central mechanism of action of inhalants, which in the past has been more typically attributed to general nonspecific mechanisms throughout the brain. Moreover, as with other drugs of abuse, the NAC may be the final common pathway subserving toluene's abuse liability.

Inhalant abuse remains a significant health problem among the younger segment of society. In fact, the use of inhalants in this population trails only that of nicotine, alcohol, and marijuana. Toluene is a common ingredient in many of the substances sought out for inhalation abuse, apparently for its euphorigenic and hallucinogenic effects. Because drugs of abuse share the common property of altering the activity of mesolimbic dopamine neurons, it is reasonable to suspect that toluene-induced changes in this CNS pathway may underlie its abuse potential. Here we will provide in vivo and in vitro electrophysiological data and behavioral evidence linking toluene exposure in rats to activation of mesolimbic dopamine neurons. Exposure of rats to 11,000 ppm of inhaled toluene produced time-dependent activation of dopamine neurons within the midbrain ventral tegmental area (VTA). In the rat brain slice preparation, perfusion with toluene (23-822 microM) also evoked an increase in activity of both dopamine and nondopamine neurons within the VTA. These excitatory effects could not be found in adjacent non-VTA nuclei, nor were they sensitive to the glutamate antagonists CGS19755 or CNQX. In behavioral studies, systemic administration of toluene produced a dose-dependent locomotor hyperactivity that was attenuated by either pretreatment with the D2 dopamine receptor antagonist remoxipride or by 6-hydroxydopamine lesions of the nucleus accumbens. These findings show that toluene can activate dopamine neurons within the mesolimbic reward pathway, an effect that may underlie the abuse potential of inhaled substances containing toluene.

Delta-9-tetrahydrocannabinol (delta9-THC), the principal psychoactive ingredient in marijuana elicits a variety of physiological effects in animals and humans, and with repeated exposure tolerance develops to most of its effects. However, studies in humans found that tolerance did not occur to the pleasurable marijuana "high". Since ventral tegmental dopamine neurons play a pivotal role in drug reinforcement and reward, and possibly in the euphorigenic quality of marijuana, the present study sought to determine whether tolerance develops to the neurophysiological response elicited in these neurons by delta9-THC. Using single-unit extracellular recordings the activity of midbrain ventral tegmental (VTA) and substantia nigra pars compacta (SNpc) dopamine neurons was measured in animals that had received twice-daily injections of 5 mg/kg delta9-THC for 14 days. Cannabinoid-induced changes in body temperature, locomotion, and catalepsy were also assessed in the same animals. After 2 weeks tolerance had developed to delta9-THC-induced hypothermia, catalepsy and reduction in locomotor activity. In naive animals and in animals that had received twice-daily vehicle injections for 14 days, delta9-THC increased VTA neuronal firing by 52% and 46%, respectively, while SNpc neurons showed increases of 23% and 30%, respectively. Following chronic cannabinoid treatment, however, SNpc neurons were significantly less responsive to delta9-THC with a maximum increase in rate of only 3%, while VTA neurons continued to show a robust increase in firing rate (+45%) when challenged with THC. These results suggest that VTA and SNpc dopamine neurons develop a differential response to delta9-THC following long-term cannabinoid exposure. This finding may be relevant to the observation that in humans tolerance occurs to many of marijuana's physiological effects but not to its euphorigenic actions.

The behavioral hyperactivity elicited by most drugs of abuse has been linked to changes in mesolimbic dopamine neurotransmission. However, the locomotor stimulant effects of toluene, a constituent in many abused inhalants, has not been clearly associated with this site of action. The present study was designed to examine the hypothesis that toluene-induced hyperactivity is also dependent upon intact dopamine neurotransmission. Using photocell-equipped cages, 600-1200 mg/kg toluene produced an inverted U-shaped dose response. However, in the presence of 5 mg/kg remoxipride, a selective D2-dopamine antagonist toluene-induced hyperactivity was reduced by 57%. The effects of remoxipride appear to be selective as a pretreatment, as it did not reduce either spontaneous locomotor activity or the stimulatory effects of the muscarinic antagonist scopolamine. These results clearly show that toluene induces locomotor hyperactivity through a dopamine-dependent mechanism. Because the mesolimbic dopamine system has been shown to play a role in the rewarding properties of drugs of abuse, its activation by toluene may also underlie the abuse potential of this and other inhalants.

Behavioral, biochemical and recent electrophysiological data have increasingly implicated the involvement of dopamine in the central actions of cannabinoid compounds. However, the site and mechanism by which cannabinoids stimulate dopamine systems has been somewhat controversial. Central opioid systems have also been suggested to play a role in some cannabinoid-induced behaviors as evidenced by their attenuation in the presence of the opioid antagonist naloxone. However, recent studies using the cannabinoid receptor-selective antagonist SR141716A suggest that the central actions of psychoactive cannabinoids are mediated principally through activation of CB1 receptors. Using single cell electrophysiological recordings in the rat we assessed the effects of both SR141716A and naloxone on delta9-tetrahydrocannabinol (THC)-induced activation of ventral tegmental dopamine neurons. While dopamine cell firing was dose-dependently increased following cumulative dosing with delta9-THC it was partially or completely inhibited following pretreatment with 0.5 and 2 mg/kg SR141716A, respectively. However, 1 and 10 mg/kg naloxone failed to alter the response to delta9-THC. These data provide the first evidence that delta9-THC-induced changes in mesolimbic dopamine neuronal activity are mediated by the CB1 cannabinoid receptor, but a causal link for the involvement of opioid systems could not be established.

Extracellular recordings were used to determine the effects of cannabinoids on the activity of dopamine neurons within the ventral tegmental area (VTA) and substantia nigra pars compacta (SNC). Systemic administration of the natural psychoactive cannabinoid delta 9-tetrahydrocannabinol (delta 9-THC) and the synthetic cannabimimetic aminoalkylindole WIN 55,212-2 produced dose-dependent increases in firing rate and burst firing in both neuronal populations. These effects appear to be specific as the non-psychoactive cannabidiol and the inactive enantiomer WIN 55,212-3 failed to alter either parameter of neuronal excitability. Furthermore, dopamine neurons in the VTA were more sensitive than those in the SNC to the stimulatory actions of delta 9-THC. These results may provide a mechanism by which psychoactive cannabinoids increase extracellular dopamine levels in mesolimbic and striatal tissues, and thereby contribute to the reinforcing effects of marijuana.

The effects of local perfusion of the ventral tegmental area (VTA) with N-methyl-D-aspartic acid (NMDA) on extracellular dopamine concentrations in the nucleus accumbens were investigated by using in vivo microdialysis in halothane anaesthetized rats. The electrophysiological response of VTA dopamine neurons to NMDA were also assessed in an in vitro rat brain slice preparation. In both preparations NMDA elicited a biphasic response. Exposure of the VTA to low doses of NMDA (100 microM) elicited increases in dialysate dopamine levels in the nucleus accumbens and increases in the firing rate of VTA dopamine neurons. Larger doses (100 microM) resulted in profound reductions in both dopamine release in the accumbens and firing in the VTA. A strong correlation between the ability of NMDA to influence dopamine release in the accumbens and the firing rate in the VTA was observed. Perfusion with the non-competitive NMDA receptor antagonist PCP eliminated the NMDA-induced increases in extracellular dopamine in the accumbens. These data suggest that dopamine release in the accumbens and the firing rate of dopamine neurons can be both increased or decreased depending upon the magnitude of glutamatergic stimulation within the VTA.

The aim of the present study was to assess the effects of l -glutamate ( l -GLU) on the neurophysiology of ventral tegmental A10 dopamine neurons in rat midbrain slices using extracellular and intracellular recording methods. l -Glutamate perfusion of 10–100 μM concentrations produced dose-dependent increases in firing rate, with no changes in pattern of firing, while higher concentrations led to a loss of activity reminiscent of depolarization inactivation. The extracellular changes were relfected by the pronounced membrane depolarizations observed through intracellular recordings. The effects of low doses (≦ 30 μM) of l -GLU on firing rate and membrane potential were completely antagonized by co-perfusion with the noncompetitive NMDA blocker, phencyclidine, or the selective competitive NMDA receptor antagonist, CGS 19755, but not by the selective non-NMDA blocker NBQX. However, at concentrations of ≧ 300 μ M l -GLU's effects could not be completely blocked without the presence of both CGS 19755 and NBQX. Moreover, the magnitude of l -GLU-induced depolarizations became attenuated at membrane potentials more negative than −70 mV. These results suggest that in physiological-like conditions that low extracellular levels of glutamate excite midbrain dopamine neurons via a preferential activation of NMDA receptors, and that only at higher concentrations of l -GLU are non-NMDA receptors brought into play.

Extracellular single-unit recordings were used to assess the effects of PCP and PCP-like drugs (MK-801 and TCP) on the burst firing of ventral tegmental A10 dopamine neurons in the rat. The effects of these noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists were compared to the potent and competitive NMDA antagonists CGS 19755 and (+/-)CPP, and to BTCP, a PCP-derivative possessing little affinity for the PCP binding site within the ion channel gated by NMDA. PCP, MK-801, and TCP produced dose-dependent increases in the firing rate, which were accompanied by increases in the amount of burst activity, the number of action potentials within a burst, and the conversion of nonbursty cells to bursty. However, the coefficient of variation, a measure of the regularity of firing, was not significantly altered. These predominately excitatory effects contrast with the inhibition of firing, decrease in bursting, and regularization of pattern produced by BTCP. CGS 197555 and (+/-)CPP failed to alter any of the measured parameters. Thus, the increase in firing rate and amount of burst activity of dopamine neurons produced by PCP and PCP-like drugs, and the resultant hyperdopaminergia within the mesolimbic-mesocortical regions, could underlie the psychotomimetic properties of these compounds. Moreover, this effect would not appear to be related to a loss of activity at the NMDA recognition site, as evidenced by the lack of effect of the competitive NMDA antagonists.

Extracellular single-unit recordings in rat midbrain slices were used to assess the effects of phencyclidine (PCP) on the spontaneous and excitatory amino acid-induced firing of ventral tegmental (VTA) dopamine neurons. Perfusion with PCP concentrations from 10 nM to 100 μM resulted in only minimal decreases in firing rate. Neither excitatory effects nor changes in firing pattern were ever observed upon exposure to PCP. In contrast, PCP selectively antagonized the stimulatory effects of N-methyl-D-aspartate (NMDA), but did not alter α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)- or kainate (KA)-induced excitations. These results are discussed in relation to the low-dose stimulatory effects of PCP on ventral tegmental A10 dopamine neurons in the whole animal preparation.

Electrophysiological and behavioral methods were used to evaluate and compare the effects of the competitive N- methyl - d - aspartate (NMDA) receptor Mocker, NPC 12626, with the non-competitive NMDA antagonist, phencyclidine (PCP), on the activity of mesolimbic dopamine neurons. NPC 12626 (50 mg/kg, i.p.) produced a degree of locomotor hyperactivity comparable to that seen with PCP (5 mg/kg). However, 6-hydroxydopamine lesions of the nucleus accumbens blocked the PCP-induced hyperactivity but not the behavioral activation evoked by NPC 12626. Single-unit extracellular recordings from ventral tegmental A10 dopamine neurons also found marked differences between the competitive and non-competitive NMDA antagonists. Intravenous injections of NPC 12626 and CGS 19755 in doses up to 60 mg/kg failed to change A10 activity. This was in contrast to the striking bimodal dose-dependent increase-decrease in firing rate elicited by PCP. The absence of an effect of NPC 12626 on a10 neurons was not evidently related to a lack of access to central sites since NPC pretreatment (40 mg/kg, i.v.) completely antagonized the neurotoxicity caused by intrastriatal injection of quinolinic acid, an NMDA agonist, but not that caused by the non-NMDA compound, kainic acid. Thus, competitive NMDA antagonists do not share PCP's properties of activating mesolimbic dopaminergic systems, and as such they may be devoid of the potent psychotomimetic effects or the abuse liability associated with non-competitive NMDA receptor Mockers such as PCP.

This study evaluated with electrophysiological and behavioral techniques the ability of rimcazole, a novel putative antipsychotic and selective sigma-receptor ligand, to antagonize the stimulation of the mesocorticolimbic dopamine system by the sigma-agonist, (+)SKF 10,047. Rimcazole effectively blocked the (+)SKF 10,047-induced excitation of ventral tegmental dopamine neurons while having no effect on either spontaneous activity or apomorphine-elicited slowing of A10 firing. Rimcazole also antagonized the behavioral hyperactivity produced by (+)SKF 10,047, but not by d-amphetamine which is also mediated through the same mesolimbic dopamine pathway. These data provide further evidence that rimcazole's novel pharmacologic profile may involve a blockade of sigma-receptors on mesocorticolimbic dopamine neurons.

Administration of morphine sulfate (1–4 mg/kg i.v.) to cats produces changes in body temperature, with hyperthermia appearing with larger doses. Since the central neurotransmitters dopamine and serotonin have been implicated in thermoregulation, studies were done to determine whether morphine's action could be mediated via these transmitters. Temperature responses were measured in freely moving cats by means of rectal thermometer probes. Either pimozide, 0.5 mg/kg i.p., a specific DA receptor blocker, or fluoxetine HCl, 10 mg/kg i.p., a specific inhibitor of 5-HT uptake, was administered 2—3 h prior to morphine injection. Temperatures were monitored for 3.5 h after morphine administration. Both agents were found to enhance the hyperthermic response to morphine with the maximum morphine effect occurring in most cases by 2h. The results indicate that a balance in the ratio of 5-HT : DA may be involved in cat thermoregulation and that the hyperthermic responses in the cat to morphine may be affected by shifting this 5-HT : DA ratio.

[3H]Phencyclidine ([3H]PCP) binding to rat nucleus accumbens, hippocampal and striatal membranes, and PCP-induced locomotor hyperactivity were assessed following selective lesions of the mesolimbic dopaminergic system. 6-Hydroxydopamine (6-OHDA) injections into the A10 region of the ventral tegmental area or into the accumbens itself resulted in a blockade of PCP's stimulatory effects and a highly significant reduction in the number of [3H]PCP binding sites and dopamine content of the nucleus accumbens. However, destruction of the dopaminergic mesolimbic fibers did not significantly alter hippocampal or striatal [3H]PCP binding. The data suggest that PCP elicits its locomotor stimulating effects via an interaction with PCP binding sites located mostly on mesolimbic dopaminergic terminals within the nucleus accumbens.

The nucleus accumbens and medial prefrontal cortex contain high concentrations of phencyclidine (PCP) binding sites as well as supply inhibitory and excitatory inputs to the ventral tegmental area (VTA). Thus these two regions could be instrumental in mediating the unique bimodal response of A10 neurons to systemically administered PCP. Therefore we evaluated electrophysiologically the effects of lesions of these two areas on this pattern of response. In sham-lesioned controls, i.v. injections of PCP elicited a typical dose-dependent bimodal effect which was characterized by an activation of A10 firing at low dose (reaching a maximum of +44% at 1 mg/kg) followed by a slowing of this response with larger doses. However, in animals with kainic acid or radiofrequency lesions of the nucleus accumbens, PCP produced only a unimodal response resulting in sustained and elevated (+88% in kainate and +55% in radiofrequency lesioned groups) firing rates. Notably, neither basal activity nor the degree of activation of the A10's at doses of PCP less than 1 mg/kg were affected by the lesions. In contrast, excitotoxic destruction of the medial prefrontal cortex had no effect on the response of A10 neurons to PCP even though basal activity was slightly elevated in this group. These results suggest that the inhibitory component of the bimodal response of VTA neurons to systemic PCP is mediated via feedback pathways from the nucleus accumbens, but that the mesocortical prefrontal cortex does not appear to modulate any portion of this bimodal response.

The present study was primarily designed to explore the relationship between phencyclidine(PCP)-induced hyperactivity and the mesolimbic dopamine (DA) system. In addition, the motor-activating and behavioral effects of amphetamine (1.5 mg/kg), SKF-10,047 (25.0 mg/kg), scopolamine (1.0 mg/kg), and caffeine (10.0 mg/kg) were also measured and compared to PCP action. While all compounds produced a moderate to large degree of hyperactivity with varying time courses for effect, gross behavioral observations indicated a greater similarity between PCP and SKF-10,047 than between any of the other drugs. Following bilateral 6-hydroxydopamine lesions of the nucleus accumbens the robust locomotor-stimulating action of 5 mg/kg PCP was significantly reduced. Such lesions also successfully prevented amphetamine- and SKF-10,047-induced hyperactivity, but not the behavioral activation produced by scopolamine or caffeine. These results suggest that PCP and SKF-10,047, like amphetamine, elicit locomotor activity through presynaptic DA mechanisms within the mesolimbic system.

Metaphit, a derivative of phencyclidine (PCP) which irreversibly binds to a population of PCP receptor sites in rat brain, has been considered as a potentially specific PCP antagonist. In whole animal studies, however, metaphit has been shown to have either antagonist or PCP-like actions depending upon the animal species used and the experimental variable evaluated. In the present study, the ability of PCP to produce hyperactivity was assessed in rats following pretreatment with intravenous, intraventricular or intracerebral injections of metaphit. Whereas, intravenous and intraventricular metaphit pretreatment failed to alter the locomotor stimulatory effects of PCP, direct injections of metaphit into the nucleus accumbens resulted in a dose-dependent reduction of PCP-induced hyperactivity. This result also was mimicked by intra-accumbens injections of equimolar concentrations of PCP, but not by the local anesthetic procaine. Additionally, intra-accumbens metaphit prevented d-amphetamine-induced hyperactivity and also depleted significantly accumbens dopamine content; effects not seen after intracerebral PCP administration. These results suggest that metaphit produces a functional antagonism of PCP-induced locomotor activity through presynaptic mechanisms unrelated to specific blockade of PCP receptors.