The metabotropic glutamate 2/3 receptor agonist LY404039 reduces alcohol-seeking but not alcohol self-administration in alcohol-preferring (P) rats

Metabotropic glutamate (mGlu) receptors have been shown to mediate a number of behaviors including emotionality and responsivity to stress as demonstrated by efficacy in preclinical and clinical studies. The objective of this study was to assess the effects of the mGlu2/3 receptor agonist LY404039 (LY) on operant ethanol (EtOH) self-administration during alcohol seeking (pavlovian spontaneous recovery, PSR), alcohol relapse (alcohol deprivation effect, ADE), and maintenance responding for alcohol. Adult alcohol-preferring (P) rats were trained in 2-lever operant chambers to self-administer 15% EtOH (v/v) and water on a concurrent fixed-ratio 5-fixed-ratio 1 (FR5-FR1) schedule of reinforcement in daily 1h sessions. After at least 10 weeks of daily 1 h sessions, rats underwent seven extinction sessions, followed by 2 weeks of no manipulation, and then rats were tested for the expression of an EtOH PSR for four sessions. Rats were then given a week in their home cage before being returned to the operant chambers with access to EtOH and water (alcohol relapse). Finally, the effects of LY upon maintenance EtOH and water responding were assessed once stable responding was reestablished. The mGlu2/3 receptor agonist LY404039 reduced responding on the EtOH in the PSR test. LY also reduced the expression of an alcohol deprivation effect (ADE) during relapse, but did not reduce EtOH responding under maintenance conditions. The results of this study demonstrate that activating mGlu2/3 receptors inhibits the expression of alcohol seeking and relapse behavior without altering alcohol self-administration behavior.     

Distinct subsets of nucleus accumbens neurons encode operant responding for ethanol versus water

Subsets of nucleus accumbens (NAc) neurons process information about operant responses for drugs as well as natural rewards (food and water) by excitations and inhibitions in firing rate time-locked to the operant response. The degree to which ensembles of neurons exhibit similar firing patterns when encoding cues and operant responses across different reinforcer conditions will provide critical information regarding the functional organization of this nucleus. The present experiment evaluated the relative contribution of subsets of accumbens neurons that encode distinct features of lever press responding for ethanol vs. water. Electrophysiological recordings (n = 153 neurons) were made in the accumbens of rats trained on concurrent reinforcement schedules for ethanol and water throughout a self-administration session. During operant responding, 52% of neurons exhibited patterned discharges characterized by significant increases or decreases in firing rate of +/- 1 s relative to lever presses for ethanol and/or water. Of these phasic cells, 85% discriminated between presses for ethanol and water (i.e. exhibited firing patterns unique to one reinforcer type), while 15% exhibited identical firing patterns relative to lever presses for both reinforcers. Notably, the data revealed that both high ethanol preference and spatially distinct lever positions contributed to the reinforcer specificity. Together, these data demonstrate that subsets of NAc neurons encode conditioned and instrumental aspects of ethanol vs. water reinforcement in well-trained rats, and that reinforcer preference and spatial cues are important components of this differential information processing.     

Anticonvulsant effects of ipsilateral but not contralateral microinjections of the dopamine D2 agonist LY 171555 into the nucleus accumbens of amygdala-kindled rats.

Recent radioligand binding studies demonstrated an increase in the density of dopamine D2 receptors in the nucleus accumbens ipsilateral to the stimulating electrode in amygdala- or hippocampal-kindled rats. In the present study we examined the anticonvulsant effect of dopamine agonists by unilateral microinjections into the nucleus accumbens in rats kindled from the right basolateral amygdaloid nucleus. Microinjections of the D2 agonist LY 171555 into the ipsilateral nucleus accumbens 15 min prior to the kindling stimulation in fully kindled rats decreased significantly kindling parameters such as seizure severity, seizure duration and afterdischarge duration, whereas the D1 agonist SKF 38393 had no anticonvulsant effects. After ipsilateral microinjection of 40 pmol LY 171555 focal and generalized kindled seizures were totally blocked in almost 50% of the rats. The anticonvulsant effect of LY 171555 could be completely antagonised by systemic administration of the D2 antagonist sulpiride. Microinjection of the D1 or D2 agonist into the nucleus accumbens contralateral to the stimulating electrode had no anticonvulsant effects. In accordance with other reports our data indicate a possible topographic limitation of D2 receptor mediated anticonvulsant effects to specific regions of the basal ganglia.     

Effects of dopamine agonists on excitatory inputs to nucleus accumbens neurons from the amygdala: modulatory actions of cholecystokinin

The interaction of the cholecystokinin octapeptide (CCK-8) with dopamine (DA) and dopamine agonists on neurons in the nucleus accumbens was investigated using single unit recording and iontophoretic techniques in urethane-anaesthetized rats. Neurons in the nucleus accumbens were activated by single pulse stimulation of amygdala. Using seven-barrel microelectrodes, the effects of iontophoretic application of CCK-8, DA, dopamine D1 and/or D2 receptor agonists (SKF 38393 and LY 171555 respectively) were compared. The iontophoretic application of DA, LY 171555 and LY 171555 + SKF 38393 attenuated by 50-60% the excitatory responses of accumbens neurons to electrical stimulation of basolateral amygdala whereas SKF 38393 attenuated the response by less than 30%. The iontophoretic application of CCK reduced these attenuating effects of DA, LY 171555 and SKF 38393 + LY 171555. With CCK there was a rather small reduction of the attenuating effect of SKF 38393. These observations provide additional electrophysiological evidence of the interaction of CCK and dopamine and suggest that the interaction is associated mainly with dopamine D2 mechanisms.     

Anticonvulsant effects of ipsilateral but not contralateral microinjections of the dopamine D2 agonist LY 171555 into the nucleus accumbens of amygdala-kindled rats

Recent radioligand binding studies demonstrated an increase in the density of dopamine D₂ receptors in the nucleus accumbens ipsilateral to the stimulating electrode in amygdala- or hippocampal-kindled rats. In the present study we examined the anticonvulsant effect of dopamine agonists by unilateral microinjections into the nucleus accumbens in rats kindled from the right basolateral amygdaloid nucleus. Microinjections of the D₂ agonist LY 171555 into the ipsilateral nucleus accumbens 15 min prior to the kindling stimulation in fully kindled rats decreased significantly kindling parameters such as seizure severity, seizure duration and afterdischarge duration, whereas the D₁ agonist SKF 38393 had no anticonvulsant effects. After ipsilateral microinjection of 40 pmol LY 171555, focal and generalized kindled seizures were totally blocked in almost 50% of the rats. The anticonvulsant effect of LY 171555 could be completely antagonised by systemic administration of the D₂ antagonist sulpiride. Microinjection of the D₁ or D₂ agonist into the nucleus accumbens contralateral to the stimulating electrode had no anticonvulsant effects. In accordance with other reports our data indicate a possible topographic limitation of D₂ receptor mediated anticonvulsant effects to specific regions of the basal ganglia.     

Role of mu, delta and kappa opioid receptors in ethanol-reinforced operant responding in infant rats

We recently observed that naloxone, a non-specific opioid antagonist, attenuated operant responding to ethanol in infant rats. Through the use of an operant conditioning technique, we aimed to analyze the specific participation of mu, delta, and kappa opioid receptors on ethanol reinforcement during the second postnatal week. In Experiment 1, infant rats (PDs 14-17) were trained to obtain 5, 7.5, 10, or 15% ethanol, by operant nose-poking. Experiment 2 tested blood ethanol levels (BELs) attained by operant behavior. In Experiment 3, at PDs 16-18, rats received CTOP (mu antagonist: 0.1 or 1.0mg/kg), naltrindole (delta antagonist: 1.0 or 5.0mg/kg) or saline before training. In Experiment 4, rats received nor-binaltorphimine (kappa antagonist: 10.0 or 30.0mg/kg, a single injection after completion of PD 15 operant training), spiradoline mesylate (kappa agonist: 1.0 or 5.0mg/kg; at PDs 16-18) or saline (PDs 16-18), before the conditioning. Experiments 5 and 6 assessed possible side effects of opioid drugs in locomotor activity (LA) and conditioned taste aversion (CTA). Ethanol at 7.5 and 10% promoted the highest levels of operant responding. BELs were 12-15mg/dl. In Experiment 3 naltrindole (dose-response effect) and CTOP (the lowest dose) were effective in decreasing operant responding. Nor-binaltorphimine at 10.0mg/kg and spiradoline at 5.0mg/kg also blocked ethanol responding. The effects of opioid drugs on ethanol reinforcement cannot be explained by effects on LA or CTA. Even though particular aspects of each opioid receptor require further testing, a fully functional opioid system seems to be necessary for ethanol reinforcement, during early ontogeny.     

Evidence for opiate-dopamine cross-sensitization in nucleus accumbens: Studies of conditioned reward

We investigated opiate-amphetamine interactions within the nucleus accumbens in responding for conditioned reward. Separate groups of animals received 4-day intra-accumbens treatment with either saline, morphine (0.5 microgram/0.5 microliter), [D-Ala2 NMe-Phe4 Gly-ol5]-Enkephalin (DAMGO; 1.0 micrograms/0.5 microliter), or [D-Pen2,5]-Enkephalin (DPEN; 2.0 micrograms/0.5 microliter). One two subsequent test days, these rats were given a challenge of d-amphetamine (2.0 and 10.0 micrograms/0.5 microliter) and responding for conditioned reward was measured. In the conditioned reinforcement (CR) procedure, food-deprived animals were trained in an initial phase to associate a food reward (primary reinforcement) with a compound stimulus (light/click). In the next phase, a lever was introduced and responding on the lever produced the compound stimulus alone (secondary reinforcement). Previous evidence shows that psychostimulants but not opiates markedly potentiate responding for conditioned reward. In the present design, animals previously treated with either morphine or DAMGO (preferential mu agonists) showed potentiated lever responding following amphetamine challenges, relative to either DPEN- or saline-treated animals. These findings show that prior exposure of nucleus accumbens neurons to mu-selective opiates induces sensitization to the effects of amphetamine. The results are discussed in terms of opioid effects on dopamine transmission and second messenger systems.     

Oral operant ethanol self-administration in 5-HT1b knockout mice.

The present experiment examined oral ethanol self-administration in 5-HT1b knockout (KO) mice and 5-HT1b wide-type (WT) control mice using a continuous access operant procedure. After lever press training, adult 5-HT1b KO and 5-HT1b WT mice were placed in operant chambers on a 23 h per day basis with access to food (FR1), 10% v/v ethanol (FR4), and water from a sipper tube. KO mice displayed higher rates of responding on the ethanol-associated lever compared to WT mice. KO mice also consumed greater amounts of water. Food responding was the same in both genotypes. Following 30 sessions, ethanol concentration was altered every 5 days. Response patterns were determined using 0, 5, and 20% v/v ethanol concentrations. Ethanol responding (0, 5, 10, and 20% v/v) was also examined after the addition of 0.15% saccharin. KO mice and WT mice showed similar response rates for all ethanol concentrations. Since KO mice showed greater levels of ethanol responding only for unsweetened 10% v/v ethanol, and showed modest ethanol self-administration overall, the present results are not consistent with the notion that 5-HT1b KO have a generally greater preference for ethanol than 5-HT1b WT mice.     

Individual response profiles of male Wistar rats in animal models for anxiety and depression

Abstinence following 'binge' use of psychostimulants is hypothesized to be related to a depletion of synaptic dopamine (DA) in the nucleus accumbens. The present study, therefore, tested the pharmacological responsiveness of the mesolimbic DA system to d-amphetamine injections, measured by in vivo chronoamperometry with stearate-modified graphite paste electrodes, during voluntary abstinence when rats were given prolonged free availability to d-amphetamine. Rats self-administered i.v. d-amphetamine (FR-1 time out 30 s; 0.25 mg/kg per inf) in three sessions, each separated by approximately 24 h, (1) to a criterion of 12 infusions; (2) for 24 h and (3) for 48 h. During the third session, when self-administration had ceased for at least 1.5 h (abstinence), and DA levels were near, or below, pre-drug baseline values, rats received passive i.v. injections of d-amphetamine or vehicle in a pattern that mimicked self-administration patterns during the first hour of the 48 h session. In contrast to the significant increases in DA efflux observed during the first hour of self-administration, d-amphetamine injections during abstinence did not increase DA oxidation currents. Furthermore, the length of the abstinence period was correlated with the time required for DA to return to pre-abstinence values. Together, these results suggest that the mesolimbic DA system is pharmacologically unresponsive to the actions of d-amphetamine during abstinence, and that resumption of drug use is associated with 'recovery of function' in the mesolimbic DA system.     

CCK-8 modulates D2 receptor agonist-induced hypermotility in the nucleus accumbens

The influence of CCK-8 on locomotor effects associated with independent D2 receptor stimulation was studied. To selectively stimulate mesolimbic D2 receptors LY 171555 was injected into the nucleus accumbens of awake rats. Locomotor activity was measured in the open-field test. LY 171555 induced a biphasic effect: low doses stimulated, whereas higher doses inhibited locomotor activity. CCK-8 injected into the posteromedial part of the nucleus accumbens suppressed hyperlocomotion induced by LY 171555. The CCK-8 effect was prevented by the CCK-antagonist L 364,718. Our results indicate that CCK-8 modulates D2 receptor-mediated effects in the mesolimbic system.     

Altered responsiveness of regional brain dopamine and DOPAC levels to systemic administration of quinpirole, a dopamine D2 agonist, in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that administration of quinpirole (LY171555), a potent and highly selective dopamine (DA) D2 receptor agonist, to conscious Sprague-Dawley rats produces increases in arterial pressure through the activation of sympathetic outflow and vasopressinergic activity. To test the hypotheses that quinpirole inhibits in vivo release of DA from central dopaminergic neurons by activation of DA receptors in the central nervous system (CNS) and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we examined the effects of quinpirole on stores of DA and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in brain regions of 4-week DOCA/NaCl-hypertensive rats and their normotensive controls. Levels of DA and DOPAC were measured in brain regions by HPLC 15 min after the i.v. administration of quinpirole (1 mg/kg). Quinpirole resulted in a significant increase in DA stores and decrease in DOPAC stores in most brain regions examined in both DOCA/NaCl-hypertensive rats and normotensive controls, presumably by inhibiting DA release through a presynaptic mechanism. In the vehicle-treated groups, DA stores in the anterior hypothalamus and DOPAC stores in the nucleus accumbens were lower in DOCA/NaCl-hypertensive rats than in H2O controls. Following quinpirole administration, DA stores in the anterior hypothalamus increased significantly in DOCA/NaCl-treated rats but not in H2O controls and DOPAC stores in the nucleus accumbens decreased significantly in H2O control rats but not in DOCA/NaCl-treated rats. These observations provide further evidence for the presence of inhibitory DA D2 receptors which modulate the activity of dopaminergic neurons in the CNS.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced response to the inhibitory action of LY171555, a dopamine D2-agonist, on in vivo striatal dopamine release in DOCA/NaCl-hypertensive rats

Our previous studies have demonstrated that LY171555 (quinpirole), a specific dopamine (DA) D₂-receptor agonist, has a pressor effect in the conscious rat which is accompanied by increased sympathetic outflow and arginine vasopressin release. To test the hypothesis that LY171555 inhibits in vivo release of DA and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), from central dopaminergic neurons of the conscious, freely moving rat by activation of presynaptic DA receptors in the central nervous system and that this mechanism may be altered in the desoxycorticosterone acetate (DOCA)/NaCl model of hypertension, we used the in vivo push-pull perfusion method to study the effect of LY171555 on central DA release in normotensive and DOCA/NaCl-hypertensive rats. Levels of the DOPAC and HVA were measured in striatal perfusates by HPLC before and after administration of LY171555 (1 mg/kg, i.v.) of conscious, unrestrained 4-week DOCA/NaCl hypertensive and uninephrectomized H₂O control rats. There were no significant differences in basal striatal HVA (80 ± 12 vs 89 ± 11 pg/min; DOCA/NaCl vs control) or DOPAC levels (37 ± 5 vs 17 pg/min; DOCA/NaCl vs control) during the entire 240-min collection period. LY171555 significantly reduced HVA and DOPAC levels in perfused striatum in both normotensive control and DOCA/NaCl-hypertensive rats. The LY 17555-induced suppression in HVA levels was significantly greater in DOCA/NaCl rats (Δ = 60.7 ± 3.6%) than in H₂O controls (Δ = 49.0 ± 3.5%, P < 0.05). Pretreatment with metoclopramide (10 mg/kg, i.v.), a specific central and peripheral DA D₂-receptor antagonist, completely blocked the suppressive effects of LY171555 on HVA and DOPAC levels. These observations provide direct evidence for the presence of functionally significant presynaptic inhibitory DA D₂-receptors which modulate dopaminergic neuro-transmission in the striatum of conscious, freely moving rats. This regulatory mechanism appears to be altered in the DOCA/NaCl model of hypertension. These results support the concept that DOCA/NaCl-hypertensive rats have altered central dopaminergic activity.     

Selective anorexigenic effects of corticotropin releasing hormone in the rhesus monkey

1. Rhesus monkeys were equipped with a novel intracerebroventricular (i.c.v.) cannula system and trained to respond under operant schedules of food presentation or termination of stimuli associated with the delivery of shock (escape). 2. CRH decreased food-maintained behavior in a dose-related manner over the range of (0.3-10 micrograms/kg) but did not affect escape responding, demonstrating a selective effect on food-maintained responding. 3. This selective effect was related to the tendency for responding to stop after delivery of a food pellet when higher doses of CRH were given, consistent with the notion that a conditioned aversion to food was established in the presence of CRH. 4. This may suggest that in hyperaroused clinical states such as depression and anorexia nervosa, focus is shifted away from appetitive tasks as a result of increased levels of CRH.     

A comparison of the effects of intra-accumbens injections of amphetamine and morphine on reinstatement of heroin intravenous self-administration behavior

In rats previously trained to self-administer heroin intravenously, the application of morphine directly to the ventral tegmental area (VTA) has been shown to reinstate responding after a period of extinction, suggesting that the activation of mesolimbic dopamine neurons might underlie the priming effects of i.v. injections of opiates and stimulants found previously. In the present experiments rats were trained to self-administer heroin intravenously. Following extinction training, and after a period of at least 30 min of no responding, bilateral microinjections of either 0.5 microliter saline or 10 micrograms/0.5 microliter (+)-amphetamine sulfate were made into the N. accumbens. Amphetamine, but not saline reinstated self-administration behavior for about 1 h. In contrast, bilateral intra-accumbens injections of either 5 or 10 micrograms/0.5 microliter morphine sulfate to these same animals led to only infrequent responses late in the 90 min session. Both drugs increased locomotor activity measured in independent tests. Because the locomotor activity produced by intra-accumbens morphine occurs independent of the mesolimbic dopamine system, unlike that produced by VTA morphine and intra-accumbens amphetamine, and because it does not show sensitization, it is argued that the reinstatement effects of opiates and stimulants on self-administration behavior are mediated by the mesolimbic dopamine system, and may be related to the ability of opiates and stimulant drugs to cause sensitization within that system.     

Session-long modulations of accumbal firing during sucrose-reinforced operant behavior

The nucleus accumbens is involved in the selection and expression of motivated behaviors. Attempts to understand how activity of single neurons in the accumbens relates to behavior have largely concentrated on brief modulations in accumbal firing that occur in the seconds around events during operant sessions. However, a small number of studies have reported modulations that last the entire duration of a behavioral session. In all of these reports, the operant session was a drug self-administration session. The present study tested the hypothesis that session-long modulations, like phasic firing patterns, are components of normal accumbal activity during periods of instrumental behavior. Eight rats were chronically implanted (unilaterally) with microwire arrays in the nucleus accumbens, and trained to lever press on a Fixed-Ratio 1 schedule of sucrose reinforcement. Activity of 51 single units was recorded, and both session-long increases (n = 14) and session-long decreases (n = 13) were observed. These findings show that session-long modulations are a normal component of the response of accumbal neurons during periods of operant behavior. Moreover, although session-long modulations during cocaine self-administration sessions might reflect pharmacological actions, aspects of the modulations might additionally or alternatively correspond to afferent-driven responses. Further characterization of the firing patterns may elucidate novel mechanisms that mediate accumbal contributions to behavior.     

Dopamine enhances terminal excitability of hippocampal-accumbens neurons via D2 receptor: role of dopamine in presynaptic inhibition

The effects of dopamine on the axonal terminals of hippocampal-nucleus accumbens (HIPP-ACC) neurons were investigated in urethane-anesthetized rats using extracellular single-unit recording techniques. Antidromic responses recorded in the ventral subiculum of the hippocampus were evoked by stimulation of the medial accumbens. Baseline terminal excitability of these neurons, established by threshold stimulation of the accumbens, was markedly enhanced by conditioning stimulation (10 Hz) of the ventral tegmental area (VTA), the origin of the mesolimbic dopaminergic neurons. Iontophoretic application of sulpiride, a selective D2 antagonist, onto the HIPP-ACC terminals attenuated the increased terminal excitability of these neurons produced by conditioning VTA stimulation, while intraperitoneal injection of SCH23390, a selective D1 antagonist, failed to attenuate this effect. Iontophoretic application of dopamine or its selective D2 agonist, LY171555, onto the terminals of the HIPP-ACC neurons mimicked the prolonged enhancement of the terminal excitability produced by VTA stimulation, whereas SKF38393, a D1 agonist, had no effect. The effects of VTA stimulation, dopamine and LY171555 application were similar after the accumbens had been pretreated with ibotenic acid, suggesting a direct action of dopamine on the axonal terminals of HIPP-ACC neurons, and that changes in terminal excitability were not mediated via interneurons or feedback pathways from the accumbens to the hippocampus. Since iontophoretic application of potassium, a depolarizing agent, also enhanced the terminal excitability of the HIPP-ACC neurons, it appears that dopamine depolarized, via D2 receptors, the axonal terminals of HIPP-ACC neurons.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sensitization to the effects of repeated amphetamine administration on intracranial self-stimulation: Evidence for changes in reward processes

The effects of daily administration of 1.0 mg/kg of d-amphetamine for 20 consecutive days on self-stimulation responding from the substantia nigra, and nucleus accumbens were evaluated at several current intensities. Raising current intensity increased rates of responding when electrodes were situated in these areas, and amphetamine significantly enhanced rates of responding from both brain regions. Moreover, the drug-induced response enhancements were facilitated further after repeated drug/test pairings. Although response sensitization was observed at several current intensities, it developed sooner at the lower current levels indicating that the sensitizing effect of repeated drug administration on self stimulation responding was not due to variations in locomotor activity or arousal levels induced by amphetamine treatment. Furthermore, sensitization was observed at current levels that engendered both high and low levels of responding, suggesting that the sensitization was unrelated to the rate dependent effects of the drug. Rather, it was argued that repeated amphetamine treatment sensitized animals to the rewarding properties of electrical brain stimulation. Possible neurochemical and behavioral mechanisms that may be involved in the development of reverse tolerance after repeated amphetamine treatment were discussed.     

Modulation of acetylcholine release by D1, D2 dopamine receptors in rat striatum under freely moving conditions

Using in vivo brain dialysis under freely moving conditions, we have studied the effects of dopamine (DA) agonists and antagonists on acetylcholine (ACh) and DA release in rat striatum. The striatal infusion of the D1 DA receptor specific agonist, SKF38393, increased striatal ACh release in a dose-dependent manner (10(-6) to 10(-4) M), and 3 x 10(-5) M SKF38393 elicited a 60% augmentation in the level of ACh release. The level of ACh was increased with perfusion of 10(-4) M SCH23390, a D1 specific antagonist, but decreased with 10(-3) M SCH23390. The D2 specific agonist, LY171555, and the antagonist, sulpiride, slightly altered the level of ACh in the striatum. On the other hand the level of DA dramatically increased in a dose-dependent manner with SKF38393 or SCH23390 and decreased with LY171555. LY171555 inhibited the effect of 10(-4) M SKF38393 on ACh release, and enhanced the effect of SKF38393 on DA release. These results suggest that the D1 DA receptor mainly mediates ACh release and the D2 DA receptor modifies the effects of the D1 receptor.     

Inhibition of A9 and A10 dopamine cells by the cholecystokinin-B antagonist LY262691: Mediation through feedback pathways from forebrain sites

The diphenylpyrazolidinone cholecystokinin-B (CCK-B) antagonist LY262691 has been shown to decrease the number of spontaneously active dopamine (DA) cells in the ventral tegmental area (Al0) and substantia nigra (A9) of the anesthetized rat. In the present study, we examined the localization of the receptors mediating these effects of LY262691 on A9 and A10 DA cells. In one group of anesthetized rats, the effects of systemic administration of LY 262691 on the number of spontaneously active A9 or A10 DA cells was determined using extracellular, single-unit recordings after radio frequency lesions were placed in the nucleus accumbens, caudate-putamen, or medial prefrontal cortex. Lesions of the caudate-putamen blocked the effects of systemically administered LY262691 on the number of spontaneously active A9, but not A10, DA cells. Conversely, lesions of the n. accumbens blocked the effects of systemically administered LY262691 on A10, but not. A9, DA cells. Lesions of the medial prefrontal cortex blocked the effects of systemically administered LY262691 on both A9 and A10 DA cells. In a separate group of anesthetized rats, the number of spontaneously active A9 or A10 DA cells was determined after LY262691 was microinjected into the n. accumbens, caudate-putamen, or medial prefrontal cortex. Microinjection of LY262691 into the caudate-putamen led to a significant decrease in the number of spontaneously active A9, but not A10, DA cells. Conversely, microinjection of LY262691 into the n. accumbens or medial prefrontal cortex led to a significant decrease in the number of spontaneously active A10, but not A9, DA cells. Microinjection of a structurally related CCK-A antagonist (LY219057) into the n. accumbens or medial prefrontal cortex did not affect the number of spontaneously active A10 DA cells, and microinjection of LY219057 into the caudate-putamen did not affect the number of spontaneously active A9 DA cells. These results indicate that, consistent with known feedback pathways between forebrain structures and midbrain DA neurons, the effects of LY262691 on A9 cells are mediated, at least in part, by antagonism of CCK-B receptors in the caudate-putamen, whereas the effects of LY262691 on A10 cells are mediated, at least in part, by antagonism of CCK-B receptors in the n. accumbens and medial prefrontal cortex. © 1993 Wiley-Liss, Inc.     

Jaw muscle activity, the nucleus accumbens and dopaminergic agonists: A new approach

A method was developed to analyze electromyographic (EMG) signals in terms of power, viz., a measure for overall muscle activity, and number of seconds marked by distinct frequency ranges. With the help of this method, the effects of intraaccumbens administration of distilled water, the D1 receptor agonist SK&F 38393 (SKF; 5 micrograms), the D2 receptor agonist LY 171555 (LY; 10 micrograms), and their combination upon the EMG signals of the masseter and the digastric muscle were analysed in freely moving rats. Only the combined treatment affected the power: The noted increase was limited to the digastric muscle. The time/frequency analysis was limited to frequency ranges 3-4 Hz (class A), 4-5 and 5-6 Hz (class B), and 6-7, 7-8, ..., 12-13, and 13-14 Hz (class C). Apart from a small effect of SKF alone and of SKF in combination with LY on class B of the masseter muscle, neither SKF nor LY affected class A or B. SKF and LY increased and decreased, respectively, class C in both muscles. The data suggest that SKF and LY elicited both opposite and synergistic effects. The method is a new tool to analyze EMG signals in freely moving rats.