In utero Exposure to Anesthetics Alters Neuronal Migration Pattern in Developing Cerebral Cortex and Causes Postnatal Behavioral Deficits in Rats.

During fetal development, cerebral cortical neurons are generated in the proliferative zone along the ventricles and then migrate to their final positions. To examine the impact of in utero exposure to anesthetics on neuronal migration, we injected pregnant rats with bromodeoxyuridine to label fetal neurons generated at embryonic Day (E) 17 and then randomized these rats to 9 different groups receiving 3 different means of anesthesia (oxygen/control, propofol, isoflurane) for 3 exposure durations (20, 50, 120 min). Histological analysis of brains from 54 pups revealed that significant number of neurons in anesthetized animals failed to acquire their correct cortical position and remained dispersed within inappropriate cortical layers and/or adjacent white matter. Behavioral testing of 86 littermates pointed to abnormalities that correspond to the aberrations in the brain areas that are specifically developing during the E17. In the second set of experiments, fetal brains exposed to isoflurane at E16 had diminished expression of the reelin and glutamic acid decarboxylase 67, proteins critical for neuronal migration. Together, these results call for cautious use of anesthetics during the neuronal migration period in pregnancy and more comprehensive investigation of neurodevelopmental consequences for the fetus and possible consequences later in life.

mGluR5 is necessary for maintenance of methamphetamine-induced associative learning.

Conditioned place preference (CPP) reflects the significance of contextual cues that are associated with rewarding effects of abused drugs such as methamphetamine (Meth). Glutamate neurotransmission is augmented following exposure to stimulants and associated cues. Activation of group I metabotropic glutamate receptors (mGluR) is critical for the acquisition and expression of stimulant-induced CPP. We hypothesized that the maintenance of Meth-induced CPP would also require activated mGluR, and that the role of mGluR1 vs. mGluR5 group I subtypes may differ. To test this hypothesis, negative allosteric modulators (NAMs) of these receptors were administered following the development of Meth-induced CPP. NAMs exert their functional effects by displacing agonist from agonist-occupied receptors, thus NAMs selectively target brain regions with glutamate release. Conditioning with Meth every other day for six days resulted in significant preference for the Meth-paired compartment. Two once-daily injections of the mGluR1 NAM, JNJ16259685 (0.3mg/kg, i.p.) or its vehicle on days 13 and 14 after Meth-conditioning did not influence the maintenance of Meth-induced CPP; however, administration of the mGluR5 NAMs MTEP (3mg/kg, i.p.) and MPEP (30 mg/kg, i.p.) inhibited maintenance processes necessary for CPP to be expressed. These findings suggest a subtype-specific role of mGluR5 receptors in the maintenance of place preference memory and potential of mGluR5 NAMs as a useful target for Meth addiction therapy.

Pramipexole- and methamphetamine-induced reward-mediated behavior in a rodent model of Parkinson's disease and controls.

Pramipexole (PPX) is a dopamine agonist that is FDA-approved for treatment of motor dysfunction in Parkinson's disease and restless leg syndrome. In a subpopulation of treated patients, PPX can lead to impulsive-compulsive disorders including behavioral addictions and dopamine dysregulation syndrome, a phenomenon that mirrors drug addiction. Regardless of this clinical picture, the capacity of PPX to regulate reward-mediated behaviors remains unclear and has not been evaluated in an animal model of Parkinson's disease. To fill this gap, we examined the rewarding potential of PPX in parkinsonian-like rats using conditioned place preference (CPP) and also evaluated associated motor behaviors. Methamphetamine (meth) and saline served as positive and negative controls, respectively. To model Parkinson's disease, the neurotoxin 6-OHDA was injected bilaterally into the dorsolateral striatum. The resulting lesions were verified functionally using a forelimb adjusting step and post mortem immunohistochemical staining of striatal tyrosine hydroxylase. Three pairings of meth (1mg/kg, ip), paired with a unique context, induced CPP in both 6-OHDA-treated and sham-operated rats; saline pairings had no effect. Three pairings of (±)PPX at 2mg/kg ip (equal to 1mg/kg of the active racimer) induced CPP in 6-OHDA-treated rats, but a higher dose (4 mg/kg, ip (±)PPX) was needed to induce CPP in sham rats. In all rats, acute administration of 2mg/kg (±)PPX decreased locomotor activity; the behavior was normalized by the third (±)PPX administration. In summary, these findings reveal that (±)PPX has motor and rewarding effects and suggest the parkinsonian brain state may be more sensitive to the rewarding, but not motoric effects.

Nullifying drug-induced sensitization: behavioral and electrophysiological evaluations of dopaminergic and serotonergic ligands in methamphetamine-sensitized rats.

Repeated exposure to methamphetamine produces a persistent enhancement of the acute motor effects of the drug, commonly referred to as behavioral sensitization. Behavioral sensitization involves monoaminergic projections to several forebrain nuclei. We recently revealed that the ventral pallidum (VP) may also be involved. In this study, we sought to establish if treatments with antagonists or partial agonists to monoaminergic receptors could "reverse" methamphetamine-induced behavioral and VP neuronal sensitization. Behavioral sensitization was obtained in rats with five once-daily s.c. injections of 2.5mg/kg methamphetamine, an effect that persisted for at least 60 days. After the development of sensitization, 15 once-daily treatments of mirtazapine (a 5-HT(2/3), alpha(2) and H(1) antagonist), SKF38393 (D(1) partial agonist) or SCH23390 (dopamine D(1) antagonist) nullified indices of motor sensitization as assessed by measuring the motoric response to an acute methamphetamine challenge 30 days after the fifth repeated methamphetamine treatment. VP neurons recorded in vivo from methamphetamine-sensitized rats at the 30-day withdrawal time also showed a robust downward shift in the excitatory responses observed to an acute i.v. methamphetamine challenge in non-sensitized rats. This decreased excitatory effect was reversed by mirtazapine, but not by other antagonists that were tested. These data suggest a potential therapeutic benefit for mirtazapine in the treatment of methamphetamine addiction, and point to a possible role for the VP in the sensitization process to methamphetamine.

Cross-sensitization to morphine in cocaine-sensitized rats: behavioral assessments correlate with enhanced responding of ventral pallidal neurons to morphine and glutamate, with diminished effects of GABA.

Common neurobiological substrates contribute to the progressively increased behavioral effects (i.e., sensitization) that occur with repeated intermittent treatments of cocaine and morphine. Consequently, repeated exposure to cocaine can augment responding to morphine (termed cross-sensitization). Drug-induced sensitization in rats may model aspects of the dysfunction in motivation that are imposed by addiction. The ventral pallidum (VP) is involved in motivated behaviors and its function is altered by acute administration of cocaine and morphine, but the effects of repeated drug exposure remain unknown. Targeting this paucity, the present study evaluated electrophysiological changes in the VP of rats exposed to five once-daily cocaine treatments (15 mg/kg i.p.). This regimen also induced behavioral-sensitization that was expressed 3 days later when the rats received either an acute injection of cocaine (15 mg/kg i.p.) or morphine (10 mg/kg i.p.). VP neurons recorded in vivo 3 days after the repeated cocaine treatment regimen demonstrated increased excitatory responding to microiontophoretic applications of morphine and glutamate. The maximal effect (E(max)) was increased without altering potency, suggesting a change in the functional efficacy of the respective receptor systems. This did not represent a potentiation in transmission in general, for the effects of GABA were diminished. The results provide the first evidence for cellular adaptation in the VP after a sensitizing drug treatment paradigm and reveal that cross-sensitization of drug-induced behaviors temporally correlates with changes in VP neuronal responding. These findings advance an emerging theme that alterations in the VP may contribute to the increased motivation for drug seeking that occurs in drug-withdrawn addicts.

Short-term, D2 receptor blockade induces synaptic degeneration, reduces levels of tyrosine hydroxylase and brain-derived neurotrophic factor, and enhances D2-mediated firing in the ventral pallidum.

Repeated treatments with neuroleptics are associated with biochemical and morphological alterations in forebrain neurons as well as an upregulation of D2-mediated changes in neuronal function. The present study evaluated the histological and physiological effects of three once-daily treatments with two chemically divergent neuroleptics, haloperidol (1 mg/kg i.p./day) and eticlopride (3 mg/kg i.p./day), measured in rats 24 h after the last injection. It was determined that this short-term antagonism of D2-like receptors induced fiber and terminal degeneration and significantly decreased tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF) immunoreactivity in the ventral pallidum (VP), as determined by optical density measurements. While other forebrain regions demonstrated changes in TH and BDNF, the neurodegeneration profile was unique to the VP. This was accompanied by an enhancement in the efficacy of the D2 agonist quinpirole to increase spiking rate of VP neurons recorded in chloral hydrate-anesthetized rats. These data indicate that short-term treatments with D2 antagonists are sufficient to induce changes in the biochemical and morphological profiles uniquely within the VP. Moreover, the functional ramifications of these changes appear to include profound alterations in the way dopamine regulates neuronal activity in this region.

Regulation of limbic information outflow by the subthalamic nucleus: excitatory amino acid projections to the ventral pallidum.

The subthalamic nucleus (STN), a component of the basal ganglia motor system, sends an excitatory amino acid (EAA)-containing projection to the ventral pallidum (VP), a major limbic system output region. The VP contains both NMDA and AMPA subtypes of EAA receptors. To characterize the physiology of the subthalamic pathway to the VP, and to determine the influence of EAA receptor subtypes, in vivo intracellular recordings, and in vivo extracellular recordings combined with microiontophoresis, were made from VP neurons in anesthetized rats. Of the intracellularly recorded neurons, 86% responded to STN stimulation, and these displayed EPSPs with an onset of 8.7 msec, consistent with a monosynaptic input. The EPSPs evoked in spontaneously firing neurons were nearly twice the amplitude of those in nonfiring cells (13.1 vs 6.8 mV, respectively). As neurons were depolarized by current injection, the latency for spiking decreased from 24.2 to 14.2 msec, although EPSP latency was unaffected. Eighty-seven percent of the extracellularly recorded VP neurons responded to STN stimulation with a rapid and robust enhancement of spiking; the response onset, like the EPSP onset, equaled 8.7 msec. Firing rate was enhanced by NMDA in 94% of the STN-excited cells, and AMPA increased firing in 94% as well. The NMDA-selective antagonist AP-5 attenuated 67% of the STN-evoked excitatory responses, and the AMPA-selective antagonist CNQX attenuated 52%. Both antagonists attenuated 33% of responses, and 78% were attenuated by at least one. This evidence suggests that a great majority of VP neurons are directly influenced by STN activation and that both NMDA and non-NMDA receptors are involved. Moreover, the VP response to STN stimulation appears to be strongly dependent on the depolarization state of the neuron.

6-hydroxydopamine-induced lesions of dopaminergic neurons alter the function of postsynaptic cholinergic neurons without changing cytoskeletal proteins.

The neuropathological hallmarks of many neurodegenerative diseases are intraneuronal inclusions containing cytoskeletal proteins such as neurofilaments in Lewy bodies in Parkinson's disease and tau in neurofibrillary tangles in Alzheimer's disease. Dysfunction in dopaminergic and cholinergic systems also exist in both Alzheimer's disease and Parkinson's disease. Because the primary pathology in Parkinson's disease is localized to the dopaminergic system, we set out to determine if perturbations in cholinergic systems are a consequence of dopaminergic neuron loss. Therefore, following intracerebral microinjections of 6-hydroxydopamine in rats, the activity of cholinergic neurons was measured by hemicholinium binding in cholinergic terminal fields and perturbations in cytoskeletal proteins were examined in dopaminoceptive neurons using immunocytochemistry. The 6-hydroxydopamine injections robustly reduced the number of monoaminergic cell bodies in the lateral midbrain and dramatically decreased dopamine and its major metabolites in dopaminergic projection sites. This treatment increased hemicholinium binding in the prefrontal cortex (200%) and amygdala (284%); however, despite previous reports to the contrary, there were no increases in immunoreactivity for phosphorylated neurofilaments, microtubule-associated protein (MAP) 2, tau or paired helical filament (PHF) tau. This lack of an increase in cytoskeletal proteins was observed following either injections of moderate doses of the toxin directly into the medial forebrain bundle or after high doses were administered intracerebroventricularly. These results suggest that removal of dopaminergic inputs to the forebrain results in hyperactivity of the cholinergic systems but is not sufficient to induce postsynaptic perturbations in cytoskeletal proteins which occur in neurodegenerative diseases.

Effects of serotonergic 5-HT1A and 5-HT1B ligands on ventral pallidal neuronal activity.

To clarify the role of the 5-HT system in limbic outputs, the present study compared the effects of the 5-HT1A agonist 8-OH-DPAT and the 5-HT1B agonist CP-94253 with the non-selective 5-HT agonist TFMPP on the firing rate of ventral pallidal (VP) neurons recorded in chloral hydrate-anesthetized rats. 8-OH-DPAT (0.25-256 microg/kg i.v.) dose-dependently enhanced (9/26 neurons) or suppressed (8/26) activity, and the 5-HT1A antagonist (+)WAY-100135 often attenuated these responses. TFMPP (0.011-1.453 mg/kg i.v.) dose-dependently reduced the firing rate of 7/8 VP neurons tested. In contrast, CP-94253 (0.013-12.8 mg/kg i.v.) had little or no effect. In sum, these data suggest that the 5-HT1A receptor appears to be particularly important in influencing limbic outputs mediated via the VP.

Ventral pallidal injections of a mu antagonist block the development of behavioral sensitization to systemic morphine.

Acute activation of opioid receptors in the ventral pallidum increases motor behaviors in rats. The present study was designed to investigate the possibility that the ventral pallidum influences motor responses induced by chronic opiate treatments and to examine the receptors that may be involved in such an effect. For five consecutive days, ambulations were quantified after rats received once-daily intraperitoneal (i.p.) injections of morphine (10 mg/kg) or saline following bilateral intra-ventral pallidal injections of either saline (0.5 microl/hemisphere), the mu antagonist CTOP (2. 1 microg/0.5microl/hemisphere), or the D1 antagonist SCH23390 (0.25 microg/0.5microl/hemisphere). Behavioral sensitization to an acute morphine challenge (10 mg/kg i.p.) was assessed 72 h after terminating the repeated treatment regimen. Rats who repeatedly received the intra-ventral pallidal saline + i.p. morphine exhibited increases in ambulations during the chronic treatment protocol and this effect was greatly enhanced (i.e., sensitized) following the post withdrawal acute morphine challenge. Rats repeatedly treated with intra-ventral pallidal CTOP + i.p. morphine did not display a motor response either during the chronic treatment regime or to the acute morphine challenge; an effect not seen when CTOP was injected into brain structures located dorsal to the ventral pallidum. The rats repeatedly treated with intra-ventral pallidal injections of SCH23390 + i.p. morphine demonstrated a motor response during the chronic protocol but the magnitude of this response was not significantly enhanced by the acute morphine challenge. These results demonstrate that: 1) mu opioid and D1-like dopamine receptors in the ventral pallidum influence the increase in locomotion that occurs during repeated morphine treatments; and 2) mu opioid (but not D1) receptors in the ventral pallidum are important in the postwithdrawal sensitized response to morphine. Such observations indicate that the ventral pallidum plays a critical role in morphine-induced behavioral sensitization.

Opioid modulation of ventral pallidal inputs.

While the ventral pallidum (VP) is known to be important in relaying information between the nucleus accumbens and target structures, it has become clear that substantial information processing occurs within the VP. We evaluated the possibility that opioid modulation of other transmitters contained in VP afferents is involved in this process. Initially, we demonstrated that opioids hyperpolarized VP neurons in vitro and suppressed spontaneous firing in vivo. The ability of opioids to modulate other transmitters was determined using microiontophoretically applied ligands and extracellular recordings of VP neurons from chloral hydrate-anesthetized rats. With neurons that responded to iontophoresed opioid agonists, the ejection current was reduced to a level that was below that necessary to alter spontaneous firing. This "subthreshold" current was used to determine the ability of mu opioid receptor (microR) agonists to alter VP responses to endogenous (released by electrical activation of afferents) and exogenous (iontophoretically applied) transmitters. microR agonists decreased the variability and enhanced the acuity (e.g., "signal-to-noise" relationship) of VP responses to activation of glutamatergic inputs from the prefrontal cortex and amygdala. By contrast, microR agonists attenuated both the slow excitatory responses to substance P and GABA-induced inhibitions that resulted from activating the nucleus accumbens. Subthreshold opioids also attenuated inhibitory responses to stimulating midbrain dopaminergic cells. These results suggest that a consequence of opioid transmission in the VP is to negate the influence of some afferents (e.g., midbrain dopamine and accumbal GABA and substance P) while selectively potentiating the efficacy of others (e.g., cortical and amygdaloid glutamate). Interpreted in the context of opiate abuse, microR opioids in the VP may serve to diminish the influence of reinforcement (ventral tegmental area and nucleus accumbens) in the transduction of cognition (prefrontal cortex) and affect (amygdala) into behavior. This may contribute to drug craving that occurs even in the absence of reward.

The effects of cocaine and the amphetamines on brain and behavior: a conference report.

A Chicago City-Wide Mini-Conference on Cocaine and the Amphetamines was held on the 13 May 1996 at Loyola University Chicago. The purpose of the one day symposium was to facilitate the dissemination of recent research findings of investigators in the Chicago area working in drug abuse research. The speakers discussed recent concepts relating to the consequences of the amphetamines and cocaine on different biologic processes including the development of neuronal pathways, adaptational responses to chronic administration and neurotoxicity. Some of the specific areas discussed were: (a) psychostimulant-induced effects on brain serotonin and dopamine systems, (b) amphetamine-induced neurotoxicity, (c) the long-term consequences of prenatal exposure to cocaine, (d) effects of cocaine withdrawal on hormone responses, and (e) mechanisms underlying drug-taking behavior and dependence. The potential clinical consequences of the research findings and how they impact on medications-development and community efforts in dealing with the problems of drug abuse were also discussed. Progress on these issues, which was presented at the First Annual Follow-Up Meeting, held on the 17 July 1997, are also included in this report.

Substance P attenuates and DAMGO potentiates amygdala glutamatergic neurotransmission within the ventral pallidum.

The amygdala (AMG), nucleus accumbens (NA) and ventral pallidum (VP) influence goal-oriented behaviors. However, the nature of the interactions among these regions has not been well characterized. Anatomical studies indicate that excitatory amino acids are contained in VP inputs from the AMG, and the NA is a primary source of VP substance P (SP) and opioids. The present study was designed to functionally characterize the NA and AMG projections to the VP, and to assess if opioids and SP can modulate AMG-mediated excitatory neurotransmission within the VP. To do so, extracellularly recorded electrophysiological responses of single VP neurons to electrical activation of VP afferents were monitored during microiontophoretic application of treatment ligands in chloral hydrate-anesthetized rats. The anatomically described glutamatergic inputs from the AMG, and SP inputs from the NA, were pharmacologically verified. It also was determined that even though iontophoretically applied SP increased the spontaneous activity of VP neurons, at ejection current levels that were below those necessary to produce this effect (termed sub-threshold), the tachykinin attenuated AMG stimulation-evoked glutamatergic neurotransmission. SP failed to modulate the excitations induced by iontophoretically applied glutamate suggesting that SP modulation of AMG-evoked excitations were mediated via a decrease in the pre-synaptic release of glutamate. Like SP, the effects of sub-threshold ejection currents of micro opioid agonist DAMGO on AMG-evoked responses were not predicted by the opioid's effects on spontaneous VP neuronal activity; DAMGO inhibited spontaneous firing but potentiated AMG-evoked glutamatergic neurotransmission. The opioid also potentiated effects of exogenous glutamate implying an interaction at a post-synaptic site. These results indicate that tachykinin and opioid neuropeptides contained in NA projection neurons can differentially modulate AMG glutamatergic inputs to the VP.

GABA- and glutamate-evoked responses in the rat ventral pallidum are modulated by dopamine.

Microiontophoresis was used to investigate the influence of dopamine on GABA- and glutamate-induced responses from ventral pallidal neurons recorded extracellularly in chloral hydrate-anaesthetized rats. Modulation was determined by comparing dopamine-induced alterations in amino acid-induced activity ('signal') with dopamine-induced effects on spontaneous firing ('noise'). A dopamine ejection current-response curve was generated to determine the current levels that did not alter spontaneous firing ('subthreshold') and those that produced approximately 50% of the maximal dopamine-induced response (ECur50). Co-iontophoresis of dopamine with GABA generally diminished the inhibitory influence of GABA on pallidal neuron firing; 70% of neurons tested with ECur50 dopamine demonstrated a decrease in the signal-to-noise ratio whereas 10% displayed an increase. At subthreshold dopamine ejection currents, 59% of neurons responded with a decrease and 18% responded with an increase in the GABA signal-to-noise ratio. When ECur50 dopamine was co-iontophoresed with glutamate, 84% of the neurons displayed a decrease in the signal-to-noise ratio for glutamate-evoked excitations whereas 11% demonstrated an increase. Subthreshold dopamine ejection currents decreased the signal-to-noise ratio in 62% of the ventral pallidal neurons excited by glutamate and increased the ratio in 23%. These data illustrate that dopamine substantially alters GABA- and glutamate-evoked responses even at ejection currents that are below those necessary to change spontaneous firing. Thus, it appears that neuromodulation is an important means by which dopamine influences ventral pallidal neuronal activity.

Morphine modulation of GABA- and glutamate-induced changes of ventral pallidal neuronal activity.

Microiontophoresis was used to investigate the influence of morphine on the GABA- and glutamate-evoked responses of ventral pallidal neurons recorded extracellularly from chloral hydrate-anesthetized rats. Of the GABA-sensitive neurons (50 of 69 tested) in the ventral pallidum, all displayed a decreased firing rate when GABA was applied, whereas all of the glutamate-sensitive neurons (29 of 40 tested) increased neuronal activity in the presence of glutamate. The majority of ventral pallidal cells tested (65 of 83) were sensitive to iontophoretically applied morphine, and both increases and decreases in neuronal activity were observed. The ability of morphine to alter the ratio between amino acid-evoked activity ("signal") and spontaneous firing ("noise") was used as an indicator of morphine modulation. A morphine subthreshold ejection current, i.e. one that did not change spontaneous firing rate, and a morphine ejection current that produced approximately 50% of the maximum opioid-induced neuronal response were chosen for this evaluation. When morphine was co-iontophoresed with GABA or glutamate, attenuation of the amino acid signal-to-noise ratio was generally seen, though some potentiations were observed. These changes were independent of the direction of morphine-induced changes in spontaneous firing rate. Both sub- and suprathreshold ejection currents were capable of affecting GABA- and glutamate-evoked responses. These data suggest that morphine is a robust ventral pallidal neuromodulator. As ventral pallidal amino acid activity is important in the integration of sensorimotor information, opioid modulation of amino acid transmission in the ventral pallidum may have a profound effect on this integration.

Interactions between the mu opioid agonist DAMGO and substance P in regulation of the ventral pallidum.

Substance P (SP) increases, and the mu-specific opioid agonist DAMGO decreases neuronal firing within ventral pallidum (VP) of the basal forebrain. This study investigated a possibility that some VP neurons are oppositionally co-regulated by SP and DAMGO using microiontophoresis combined with the extracellular electrophysiological recordings from chloral hydrate-anesthetized rats. SP altered DAMGO's ejection current-response curve, decreasing Emax and slope, and increasing the Ecu50 (ejection current level at which 50% of the maximal response was obtained). The modulation was observed even at low ejection current levels that, when applied alone, were not sufficient to alter neuronal activity (i.e., subthreshold). Also, DAMGO altered the Emax and slope of SP's ejection current-response curve. DAMGO induced these effects even at subthreshold ejection current levels. The responses to each peptide were blocked by a receptor-specific antagonist. These findings demonstrate that SP and mu-activating opioids antagonize each other's effects on VP neuronal firing. Thus, they may interact as physiological antagonists in the regulation of VP-associated functions.

Contribution of the nucleus accumbens to cocaine-induced responses of ventral pallidal neurons.

The present study characterized the responses of ventral pallidal (VP) neurons to intravenously (iv) administered cocaine (0.003, 0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg) in chloral hydrate-anesthetized rats. Eighty-four percent (16/19) of the tested neurons displayed rate changes following cocaine administration. Fifty-three percent responded by increasing firing rate, with an EMAX of 217 +/- 26% of basal activity and an ED50 of 0.07 +/- 0.03 mg/kg. Neurons that responded with a rate decrease (26%) had an EMAX of 14.3 +/- 9.0% of basal control and an ED50 of 0.04 +/- 0.02 mg/kg. One neuron (5%) displayed a biphasic response pattern. Haloperidol (0.2 mg/kg) attenuated cocaine-induced effects in 90% of the tested neurons. Given the responsiveness of VP neurons to cocaine, the extensive innervation of the VP by the nucleus accumbens (NAC), and the importance of the NAC in regulating cocaine-induced effects, it is likely that NAC activity may affect VP responses to cocaine. To test this possibility, the influence of NAC on cocaine-induced VP activity was evaluated. Unilateral inactivation of the NAC with microinjections of procaine (40 mu g/2 mu l/2 min) did not alter the proportion of VP neurons responsive to subsequent systemic administration of cocaine (0.1, 1.0 mg/kg iv) or the EMAX for those neurons showing a rate decrease. However, for the population of neurons showing a cocaine-induced rate increase, intra-NAC procaine significantly enhanced EMAX to 392 +/- 74% of control. These data suggest that the ability of VP neurons to respond to iv cocaine is independent of the NAC. However, the magnitude of the cocaine-induced effect appears to be dependent on NAC influences.

Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P.

The ventral pallidum of the basal forebrain contains a high concentration of substance P and receives a massive projection from the nucleus accumbens. The present study was designed to determine whether the accumbens serves as a source for substance P-containing fibers in the ventral pallidum and characterize the function of this tachykinin peptide within the ventral pallidum. By combining in situ hybridization for messenger RNA of the substance P prohormone, beta-preprotachykinin, with Fluoro-Gold retrograde labeling from iontophoretic deposits in the ventral pallidum, a population of substance P-containing neurons was demonstrated in the shell and core components of the nucleus accumbens and the ventromedial striatum. The function of substance P within the ventral pallidum was characterized at the level of the single neuron, and the behaving animal. Electrophysiological assessment revealed that approximately 40% of the 97 ventral pallidal neurons tested were readily excited by microiontophoretic applications of substance P or a metabolically stable agonist analog, DiMeC7 [(pGlu5, MePhe8, MeGly9)-substance P5-11]. Response characteristics were distinguished from glutamate-induced excitations by a slower onset and longer duration of action. Recording sites of tachykinin-sensitive neurons were demonstrated to be located throughout the ventral pallidum and within high densities of fibers exhibiting substance P-like immunoreactivity. When behaving rats received microinjections of DiMeC7 into this same region, the animals displayed an increase in motor activity, with a response threshold of 0.1nmol per hemisphere. These results verify the existence of a substantial substance P-containing projection from the nucleus accumbens to the ventral pallidum. The projection likely serves to excite ventral pallidal neurons for these neurons readily increased firing following local exposure to tachykinins. Furthermore, an increase in motor behavior appears to be a consequence of this neuronal response.

Partial and full dopamine D1 agonists produce comparable increases in ventral pallidal neuronal activity: contribution of endogenous dopamine.

Systemic administration of the partial DA D1 agonist SKF38393 often increases the firing rate of neurons in the VP of rats. This study extended this finding by comparing responses to (+/-)SKF38393 with those produced by two D1 agonists that have greater intrinsic efficacy, (+/-)SKF82958 and (+/-)DHX. The role of endogenous DA in D1 agonist-induced effects also was examined. Extracellular recordings of single VP neurons were obtained in chloral hydrate-anesthetized male rats, to which equimolar doses of SKF38393, SKF82958 or DHX were administered i.v. Each of the agonists increased firing rate in about 45% of the neurons tested. Moreover, each agonist produced the same maximal increase in activity (161% to 178% of spontaneous rate). Acute decreases in synaptic DA, produced by either GBL or combined treatment with reserpine and AMPT, potentiated the maximal increase in activity evoked by SKF38393 or SKF82958. These DA-depleting treatments did not alter the percentage of neurons that displayed this response to D1 agonist challenge. Low doses of the selective D1 antagonists SCH23390 or SCH39166 generally attenuated the agonist-induced changes in firing rate, supporting the conclusion that D1 receptors were activated by SKF38393, SKF82958 and DHX. Thus, these three D1 agonists, which produce different maximal increases in striatal adenylyl cyclase activity, had comparable efficacy to increase VP neuronal activity. A reduction in endogenous DA enhanced the D1 agonist-induced effects, possibly through a reduction in inhibitory influences on VP neurons that are mediated by other DA receptor subtypes.