Nucleus accumbens opioid, GABAergic, and dopaminergic modulation of palatable food motivation: Contrasting effects revealed by a progressive ratio study in the rat.

The current studies were designed to evaluate whether incentive motivation for palatable food is altered after manipulations of opioid, GABAergic, and dopaminergic transmission within the nucleus accumbens. A progressive ratio schedule was used to measure lever-pressing for sugar pellets after microinfusion of drugs into the nucleus accumbens in non-food-deprived rats. The mu opioid agonist D-Ala2, NMe-Phe4, Glyol5-enkephalin and the indirect dopamine agonist amphetamine induced a marked increase in break point and correct lever-presses; the GABAA agonist muscimol did not affect break point or lever-presses. The data suggest that opioid, dopaminergic, and GABAergic systems within the accumbens differentially modulate food-seeking behavior through mechanisms related to hedonic evaluation of food, incentive salience, and control of motor feeding circuits, respectively. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mu opioid agonists potentiate amphetamine- and cocaine-induced rotational behavior in the rat

Opioids modulate brain dopaminergic function in various experimental paradigms. This study used the rotational model of behavior in rats with unilateral 6-hydroxydopamine-induced lesions of the nigrostriatal pathway to investigate this interaction. Doses of two presynaptically acting dopaminergic drugs, amphetamine and cocaine, were coadministered with several doses of the mu opioid agonist, morphine. Morphine, at 3.0 mg/kg, potentiated rotational behavior induced by each dose of the stimulants. To determine the receptor specificity of the actions of morphine, the mu opioid agonists buprenorphine, fentanyl, levorphanol, meperidine, and methadone, and dextrorphan, the non-opioid isomer of levorphanol, were administered alone and with 1.0 mg/kg amphetamine. Each of these drugs, as well as morphine, produced circling behavior on its own. All of the mu opioid agonists and dextrorphan increased amphetamine-induced turning; the coadministration of dextrorphan, levorphanol, meperidine, methadone and morphine with amphetamine produced turning greater than predicted by simple additivity. To determine whether an opioid receptor was involved in these interactions, the opioid antagonist, naltrexone, was administered before the amphetamine/mu opioid receptor agonist combination. Naltrexone blocked the potentiating effects of morphine, but not those of the other drugs. Moreover, naltrexone alone dose-dependently increased amphetamine-induced rotational behavior. These studies show that some mu opioid receptor agonists can potentiate stimulant-induced rotational behavior and that blockade of opioid receptors can also produce a potentiation. The role of mu opioid receptors in these effects remains unclear.     

Avoiding labor problems during vaginal birth after cesarean delivery

Dopamine has been proposed to mediate some of the behavioral effects of caffeine. This review discusses cellular mechanisms of action that could explain the role of dopamine in the behavioral effects of caffeine and summarizes the results of behavioral studies in both animals and humans that provide evidence for a role of dopamine in these effects. Caffeine is a competitive antagonist at adenosine receptors and produces a range of central and physiological effects that are opposite those of adenosine. Recently, caffeine has been shown to enhance dopaminergic activity, presumably by competitive antagonism at adenosine receptors that are colocalized and interact functionally with dopamine receptors. Thus, caffeine, as a competitive antagonist at adenosine receptors, may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors, thus stimulating dopaminergic activity. Consistent with this interpretation, preclinical behavioral studies show that caffeine produces behavioral effects similar to classic dopaminergically mediated stimulants such as cocaine and amphetamine, including increased locomotor activity, increased turning behavior in 6-hydroxydopamine-lesioned animals, stimulant-like discriminative stimulus effects, and self-administration. Furthermore, caffeine potentiates the effects of dopamine-mediated drugs on these same behaviors, and some of caffeine's effects on these behaviors can be blocked by dopamine receptor antagonists. Although more limited in scope, human studies also show that caffeine produces subjective, discriminative stimulus and reinforcing effects that have some similarities to those produced by cocaine and amphetamine.     

Non-amphetaminic mechanism of stimulant locomotor effect of modafinil in mice

Previously established dose-response curves indicated that modafinil 20-40 mg/kg i.p. elicited in mice an obvious stimulation of locomotor activity roughly similar to that induced by (+)amphetamine 2-4 mg/kg. The effects of various agents modifying dopamine transmission were compared on the locomotor response to both drugs. The preferential D2 dopamine receptor antagonist haloperidol 37.5-150 micrograms/kg i.p. suppressed the stimulant effect of (+)amphetamine in a dose dependent manner, but not that of modafinil. The D1 dopamine receptor antagonist SCH 23390 (7.5-30 micrograms/kg s.c.) reversed the (+)amphetamine but not the modafinil induced hyperactivity. The tyrosine hydroxylase inhibitor alpha-methyl-para-tyrosine (200 mg/kg) suppressed the hyperactivity induced by 4 mg/kg dexamphetamine but not that induced by 20 mg/kg modafinil. Associating L-DOPA 150 mg/kg and benserazide 37.5 mg/kg with (+)amphetamine 2 mg/kg resulted in stereotyped climbing behavior, that was not observed with modafinil 10-80 mg/kg. The profound akinesia induced by reserpine (4 mg/kg s.c.; 5 h before testing) was reversed by (+)amphetamine 2 mg/kg but not by modafinil 40 mg/kg. Finally, on synaptosomes prepared from mouse striata preloaded with [3H]dopamine, modafinil 10(-5) M did not increase the spontaneous [3H]dopamine release whereas (+)amphetamine, at the same concentration, doubled it. From all these differences between the two drugs, it is concluded that the mechanism underlying the modafinil induced stimulant locomotor effect differs completely from that of (+)amphetamine.     

Amphetamine-induced incentive sensitization of sign-tracking behavior in adolescent and adult female rats.

Age-specific behavioral and neural characteristics may predispose adolescents to initiate and escalate use of alcohol and drugs. Adolescents may avidly seek novel experiences, including drugs of abuse, because of enhanced incentive motivation for drugs and natural rewards, perhaps especially when that incentive motivation is sensitized by prior drug exposure. Using a Pavlovian conditioned approach (PCA) procedure, sign-tracking (ST) and goal-tracking (GT) behavior was examined in amphetamine-sensitized and control adolescent and adult female Sprague–Dawley rats, with expression of elevated ST behavior used to index enhanced incentive motivation for reward-associated cues. Rats were first exposed to a sensitizing regimen of amphetamine injections (3.0 mg/kg/ml d-amphetamine per day) or given saline (0.9% wt/vol) once daily for 4 days. Expression of ST and GT was then examined over 8 days of PCA training consisting of 25 pairings of an 8-s presentation of an illuminated lever immediately followed by response-independent delivery of a banana-flavored food pellet. Results showed that adults clearly displayed more ST behavior than adolescents, reflected via both more contacts with, and shorter latencies to approach, the lever. Prior amphetamine sensitization increased ST (but not GT) behaviors regardless of age. Thus, when indexed via ST, incentive motivation was found to be greater in adults than adolescents, with a prior history of amphetamine exposure generally sensitizing incentive motivation for cues predicting a food reward regardless of age. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Emergency coronary artery surgery after failed PTCA: myocardial protection with continuous coronary perfusion of beta-blocker-enriched blood

MK-801 (dizocilpine), a noncompetitive N-methyl-D-aspartate antagonist, induces dystonia in monkeys at doses of 0.08 mg/kg. This syndrome was tested with the dopamine D1 receptor antagonist NNC 756, the DA D2 receptor antagonist raclopride, the atypical antipsychotic clozapine, the dopamine D1 receptor agonist SKF 81297, the dopamine D2/D3 receptor agonist quinpirole, the anticholinergic biperiden, amphetamine, and the benzodiazepine midazolam in 7 Cebus apella monkeys previously treated with dopaminergic agents. NNC 756 (0.004 and 0.01 mg/kg), raclopride (0.004 and 0.01 mg/kg), SKF 81297 (0.3 and 0.6 mg/kg), quinpirole (0.1 and 0.2 mg/kg), amphetamine (0.25 and 0.5 mg/kg), and biperiden (0.125 and up to 1.0 mg/kg), had no significant effect on MK-801-induced dystonia. In contrast, both clozapine (2.0 mg/kg) and midazolam (0.4 and 1.0 mg/kg) reduced the dystonia caused by MK-801. Dystonia induced by dopamine D1 and D2 antagonists is easily antagonized by biperiden and dopamine agonists, whereas these drugs had no significant effect on MK-801-induced dystonia. It has been proposed that dystonia may be caused by a sudden drop in the output from the basal ganglia that is primarily GABAergic. Midazolam's enhancing effect on the GABAergic tone is consistent with this hypothesis. The effect of clozapine is more difficult to explain, but this drug has a rich pharmacology and suggests an agonistic glutamatergic effect.     

Amphetamine-like discrimination stimulus effects of ephedrine and its stereoisomers in pigeons.

This study assessed the discriminative stimulus effects of (±)-ephedrine and its stereoisomers in pigeons discriminating 1.0 mg/kg of amphetamine from saline. Amphetamine, (±)-, (-)-, and (+)-ephedrine, and cocaine occasioned greater than 80% drug-key responding with the following rank order of potency: amphetamine > cocaine > (-)-ephedrine ≥ (±)-ephedrine ≥ (+)-ephedrine. Neither the α-adrenergic antagonist, phentolamine, nor the β-adrenergic antagonist, propranolol, antagonized the effects of amphetamine or (±)-ephedrine. In contrast, the dopamine receptor antagonist, haloperidol, antagonized the discriminative stimulus effects of amphetamine and (±)-ephedrine as well as those of (-)- and (+)-ephedrine. These results indicate that, like cocaine, (±)-ephedrine and its stereoisomers share discriminative stimulus effects with amphetamine. Moreover, these effects appear to be the result of increased activity in dopaminergic systems. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dopamine agonists in Parkinson's disease: a look at apomorphine

Apomorphine is a D1 and D2 dopamine receptor agonist with anti-parkinsonian properties qualitatively similar to those seen with L-dopa. It was first used in the treatment of Parkinson's disease by Schwab in the 1950s but owing to its short duration of action, the need for parenteral administration, and adverse reactions including nausea, vomiting, postural hypotension and sedation, it was not widely prescribed. In the early 1970s, Cotzias confirmed its potent anti-parkinsonian effects and that some of its secondary effects were diametrically opposite to those seen with L-dopa. The advent of peripheral dopamine receptor antagonist drugs, which counteract the unwanted effects of apomorphine, and the development of new drug delivery systems including insulin pens and ambulatory mini pumps have led to the resurrection of apomorphine for the treatment of Parkinson's disease. Over the last five years in Europe, the drug has proved to be a major advance in the treatment of refractory "on-off" oscillations in Parkinson's disease. It has also been used as a diagnostic test for dopaminergic responsiveness in Parkinson syndromes and tremors of uncertain aetiology. The drug has also proved particularly useful in dealing with certain "off-period" disabilities, including pain, bladder dysfunction, dystonia and gastro-intestinal symptoms. Continuous steady state infusion of apomorphine by mini-pump may reduce the severity of "on" phase dyskinesias over time. The drug has also proved useful in the clinical pharmacological investigation of the pathophysiology of the motor response to dopaminergic drugs in Parkinson's disease and the occurrence of involuntary movement sequences. Neuropsychiatric side-effects are relatively infrequent when compared with ergolene dopamine agonists.(ABSTRACT TRUNCATED AT 250 WORDS)     

Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.     

Multiple strains of Saccharomyces cerevisiae on a single grape vine

The opioid system plays an important role in feeding. In general, opioid agonists typically increase feeding and opioid antagonists decrease feeding in non-food restricted animals. In food restricted animals the effects of these drugs are substantially reduced. Opioid antagonists have shown a marked effectiveness at reducing consumption of sweet foods. Explanations for this robust effect have typically focused on drug induced changes in taste, taste perception, or palatability. The current study relates the effects of the opioid antagonist naloxone on motivation to obtain different sucrose concentrations to the drug's effects on unrestricted sucrose solution consumption. Changes in motivation to respond were assessed under a progressive ratio reinforcement schedule (PR) which required increased response cost for each successive unit of sucrose solution. Motivation, as measured by the PR, increased as sucrose concentration increased and naloxone produced a dose-dependent decrease in motivation to respond for a given sucrose concentration. Thus, the effectiveness of naloxone was indirectly related to strength of the sucrose concentration. Under unrestricted access to sucrose solutions, naloxone reduced consumption greatest under the higher concentrations. The data suggest at least part of naloxone's effects on sweet tasting food may be mediated through endogenous opioid reward systems that are reflected in measures of motivation.     

Inhibition of tuberoinfundibular dopaminergic neural activity during suckling: involvement of mu and kappa opiate receptor subtypes

Previous studies have shown that mu (mu) and kappa (kappa) opioid antagonists inhibit suckling-induced prolactin release. Prolactin responses elicited by pup suckling or opioid administration are mediated, at least in part, by suppression of dopamine (DA) release from tuberoinfundibular dopaminergic (TIDA) neurons in the hypothalamus. We examined the effects of the mu opiate receptor antagonist, beta-funaltrexamine (beta-FNA), and the kappa opiate receptor antagonist, nor-binaltorphimine (nor-BNI) on the activity of TIDA neurons in lactating rats. TIDA neuronal activity was determined by measuring DOPA accumulation in the caudate putamen (CP) and median eminence (ME). The effects of opioid antagonist treatment were determined in pup-deprived (low circulating prolactin levels) or pup-suckled rats (high circulating prolactin levels). The accumulation of 5-hydroxytryptophan (5-HTP) in the medial preoptic area (MPOA), the anterior hypothalamus (AH) and the median eminence (ME) was quantified as an index of serotonergic activity in the same animals for comparative purposes. In vehicle treated rats, suckling caused a significant and selective decrease in DOPA accumulation in the ME. beta-FNA (5 micrograms, i.c.v.) pretreatment significantly increased DOPA accumulation in the ME of pup-deprived and pup-suckled rats. beta-FNA pretreatment also prevented the suckling-induced suppression of DOPA accumulation in the ME. In contrast to the actions of beta-FNA, pretreatment with nor-BNI (8 micrograms, i.c.v.) did not significantly affect the activity of the TIDA neurons in pup-deprived or pup-suckled rats. Suckling alone did not alter 5-HTP accumulation in any of the brain regions examined, and neither opioid antagonist had appreciable effects on 5-HTP accumulation. These results demonstrate that the EOP tonically inhibit the TIDA neurons in both pup-deprived and pup-suckled, post-partum female rats by acting through the mu, but not the kappa, opiate receptor subtype. Furthermore, the suckling-induced inhibition of TIDA neurons is also mediated through the EOP acting at mu, but not kappa opioid receptors.     

Mutations in the adenovirus-encoded single-stranded DNA binding protein that result in altered accumulation of early and late viral RNAs

Indorenate (TR3369, 5-methoxytryptamine b-methylcarboxylate HCl) is a 5-HT1-like receptor agonist with hypotensive activity. Here, we describe that indorenate also decreases food intake (ED50 26.1 mg/kg) without an appreciable effect in water intake (the estimated ED50 for water was 589.8 mg/kg). The anorectic activity of indorenate was compared to the effects of amphetamine and other serotonin agonists; the effect of indorenate was smaller than those of the other compounds; however, the effect of indorenate was specific to food, whereas all the other drugs also produced significant decrements in water intake. The serotonin antagonists cinanserin, cyproheptadine, methergoline and methysergide effectively prevented the decrease in food intake produced by indorenate and fenfluramine. Haloperidol, a dopaminergic antagonist, was ineffective in preventing the effect of indorenate although it prevented the anorectic effect of amphetamine. The present results suggest the participation of serotoninergic, but not dopaminergic mechanisms, in the decrease in food intake produced by indorenate.     

Role of endogenous dopamine in the neurochemical deficits induced by methcathinone

Multiple administrations of methcathinone caused persistent deficits in monoaminergic systems, as reflected by decreases in dopamine and 5-hydroxytryptamine uptake capacity, tissue content and associated rate-limiting synthetic enzyme activities. Because dopamine has been implicated in mediating such effects after administration of related amphetamine analogs, its role in effecting methcathinone-induced monoaminergic neuronal impairment was assessed. A single high-dose administration of methcathinone increased striatal dopamine release, as measured by microdialysis in conscious rats and reflected by increases in striatal neurotensin-like immunoreactivity. Dopaminergic deficits observed 18 hr after a multiple-dose treatment with methcathinone were prevented by pretreatment with the selective D1 antagonist SCH23390 and D2 receptor antagonist eticlopride, but 5-hydroxytryptaminergic deficits were not altered. 5-Hydroxytryptaminergic changes did not occur in animals depleted of striatal dopamine by 6-hydroxydopamine lesions. These results indicate that dopaminergic systems are profoundly affected by methcathinone administration and that dopamine likely contributes to the monoaminergic effects of this stimulant.     

Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species

Delta opioid peptide [D-Ala2,D-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.     

Spontaneous and drug-stimulated locomotor activity after the administration of pertussis toxin into the ventral tegmental area

Pertussis toxin (PTX) injected into the ventral tegmental area (VTA) produces an enhanced locomotor response to amphetamine. In the present study, we have evaluated the role of dopamine receptors on spontaneous locomotor activity and the enhanced locomotor response to dopaminergic agonists after the administration of PTX into the VTA. PTX injected into the VTA of rats produced a delayed increase in spontaneous locomotor activity with a latency of 4 d. This activity was markedly increased by day 6 and remained elevated for at least 28 d after PTX treatment. This increased spontaneous locomotor activity of PTX-treated animals was antagonized by the administration of the D1 receptor antagonist SCH23390 (0.03 and 0.1 mg/kg sc), but not by the D2 receptor antagonist eticlopride (0.1 and 0.3 mg/kg sc). After adaptation to the locomotor cages, the animals showed a markedly enhanced motor response to amphetamine (0.5 mg/kg ip) and apomorphine (5 mg/kg sc). The heightened locomotor responses to these dopaminergic agonists could be elicited for at least 2 mo after PTX administration. The enhanced response to amphetamine was antagonized by the administration of SCH23390 (0.03 and 0.1 mg/kg sc), but not by eticlopride (0.1 mg/kg). The increased response to apomorphine in PTX-treated animals was inhibited by SCH23390 (0.1 mg/kg sc) and partially inhibited by eticlopride (0.1 mg/kg sc). Both of these antagonists inhibited the spontaneous and the drug-induced locomotor responses in vehicle-treated control animals. These results suggest that the administration of PTX into the VTA leads to an increase in spontaneous and drug-induced locomotor activity in which D1 receptors seem to play an important role.     

Behavioral effects of amphetamine in rats with lesions in the corpus striatum.

Conducted 5 experiments, using a total of 132 male albino Sprague-Dawley rats. Lesions in the ventral striatum lowered forebrain dopamine and impaired avoidance behavior more severely than comparable lesions in the dorsal striatum. Ventral striatal damage also antagonized the effects of amphetamine on stereotyped behavior and on intertrial activity. Lesions in the dorsal striatum did not modify the effect of amphetamine in these tests. Neither dorsal nor ventral striatal lesions significantly depleted forebrain norepinephrine, and both failed to affect the facilitatory effects of amphetamine on exploratory activity in an open field. These observations support the hypothesis that some but not all of the behavioral effects of amphetamine may be due to the drug's action on dopaminergic components of the striatum. (32 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

No evidence for presynaptic opioid receptors on cholinergic, but presence of kappa-receptors on dopaminergic neurons in the rabbit caudate nucleus: involvement of endogenous opioids

The effects of various opioid receptor agonists and antagonists were studied in rabbit caudate nucleus slices preincubated with either [3H]dopamine or [3H]choline, superfused with medium (containing in most experiments the D2 receptor antagonist domperidone) and subjected to electrical field stimulation. The stimulation-evoked [3H]overflow from slices prelabeled with [3H]dopamine (evoked [3H]dopamine release) was significantly reduced by preferential kappa-opioid receptor agonists, like U-50,488 H, but not by mu- or delta-opioid receptor selective drugs. Opioid receptor antagonists shifted the concentration/response curve of U-50,488 H to the right (apparent pA2-value of the kappa-selective antagonist nor-binaltorphimine: 10.1) and enhanced the evoked dopamine release in the presence of a mixture of peptidase inhibitors. On the other hand, the [3H]overflow from rabbit caudate nucleus slices prelabeled with [3H]choline (evoked acetylcholine release) remained almost unaffected by any opioid receptor agonist, as long as the presynaptic D2 heteroreceptor was blocked with domperidone: in the absence of domperidone, U-50,488 H exhibited facilitatory effects. For comparison, the effects of the preferential delta-opioid receptor agonist DPDPE was also studied in slices of the rat striatum, where it clearly inhibited the evoked acetylcholine release. From our data we conclude that in the rabbit caudate nucleus the evoked dopamine release is inhibited by both exogenous and endogenous opioids via presynaptic kappa-opioid receptors, whereas the evoked release of acetylcholine is not, or only indirectly (via released dopamine) affected by opioids.     

An acute dose of delta 9-tetrahydrocannabinol affects behavioral and neurochemical indices of mesolimbic dopaminergic activity

Cannabinoid consumption has been reported to affect several neurotransmitter systems and their related behaviors. The present study has been designed to examine cannabinoid effects on certain behaviors, which have been currently located in the limbic forebrain, in parallel to their effects on mesolimbic dopaminergic neurons. To this end, male rats treated with an oral dose of delta 9-tetrahydrocannabinol (THC) or vehicle were used 1 h after treatment for two different behavioral tests or neurochemical analyses of mesolimbic dopaminergic activity. Treatments, behavioral tests and sacrifice were performed in the dark phase of photoperiod because it corresponds to the maximum behavioral expression in the rat. Behavioral tests were a dark-light emergence test, which allows measurements of emotional reactivity, and a socio-sexual approach behavior test, which allows measurements of sexual motivation and also of spontaneous and stereotypic activities. Neurochemical analyses consisted of measurements of dopamine (DA) and L-3,4-dihydroxyphenylacetic acid (DOPAC) contents, tyrosine hydroxylase activity, in vitro DA release and number and affinity of D1 receptors in the limbic forebrain. Results were as follows. THC exposure markedly altered the pattern executed by the animals in both tests. Concretely, THC-exposed animals exhibited a low number of visits to an incentive female in addition to high time spent in the vicinity of an incentive male, both observed in the socio-sexual approach behavior test, and an increased emergence latency to go out of a dark compartment in the dark-light emergence test. However, the fact that THC also decreased spontaneous activity and the frequency of rearing and self-grooming behaviors, in addition to the observations of either low total number of visits to both incentive sexual areas or high escape latency to go out of a light compartment, when the animal is placed in this compartment, also suggest the possible existence of an accompanying motor deficit. These behavioral effects were accompanied by increases in DA and DOPAC contents and in D1 receptor density in the limbic forebrain and to a slight decrease in the pattern of K(+)-evoked DA release in vitro from perifused limbic fragments, with no changes in the remaining neurochemical parameters. Collectively, these results allow us to conclude that acute THC markedly altered the behavioral pattern executed by the animals in a socio-sexual approach behavior test and in a dark-light emergence test, presumably indicating loss of sexual motivation and increased emotionality, although also accompanied by motor deficiencies.(ABSTRACT TRUNCATED AT 400 WORDS)     

D1 and D2 dopamine receptor mediation of amphetamine-induced acetylcholine release in nucleus accumbens

To assess the interaction of dopamine and acetylcholine systems in the rat nucleus accumbens in response to direct D-amphetamine administration, in vivo microdialysis measures of acetylcholine were used during reverse dialysis of amphetamine alone and in combination with D1 and D2 receptor antagonists SCH 23390 and sulpiride, respectively. During a 15-min exposure to amphetamine (50 microM) in the nucleus accumbens, acetylcholine increased to 33% above pre-infusion levels, became maximal at 15 min post-infusion (+41%) and gradually returned to baseline levels by 60 min post-amphetamine. Conversely, amphetamine (1 mM) administration caused a biphasic change in acetylcholine release with a trend toward a decrease (-14%) during exposure followed by a significant increase (+36%) at 30 min post-amphetamine that returned to baseline levels by 60 min after infusion. The increases observed during amphetamine (50 microM) exposure and during recovery from amphetamine (1 mM) were both blocked by co-administration with the D1 antagonist, SCH 23390 (10 microM), but not with the D2 antagonist, sulpiride (10 microM). Co-infusion of sulpiride eliminated the trend toward reduced acetylcholine release observed during 1 mM amphetamine whereas co-administration of SCH 23390 potentiated this decrease. A possible tonic D1 facilitation of nucleus accumbens acetylcholine release was indicated by the consistent reductions in acetylcholine release observed during infusion of SCH 23390. These results suggest that amphetamine administration in the nucleus accumbens induces a bidirectional change in acetylcholine release that is dependent on dose and opposing effects of nucleus accumbens D1 and D2 activation. In general, relatively low doses of amphetamine administered into the nucleus accumbens caused an increase in acetylcholine release that was dependent on dopamine D1 receptors whereas higher doses of amphetamine resulted in a D2-mediated decrease.     

Intermanual differences on motor and psychomotor tests in alcoholics: no evidence for selective right-hemisphere dysfunction

The effects of pharmacological manipulations of dopaminergic transmission on appetitive and consummatory aspects of male sexual behavior were investigated in castrated male Japanese quail treated with exogenous testosterone. Appetitive male sexual behavior was assessed by measuring a learned social proximity response and consummatory behavior was assessed by measuring copulatory behavior per se. The nonselective dopamine receptor agonist, apomorphine, inhibited in a dose-dependent manner both components of male sexual behavior. Two indirect dopamine agonists were also tested. Nomifensine, a dopamine re-uptake inhibitor, decreased appetitive sexual behavior but increased the frequency of mount attempts, a measure of consummatory sexual behavior. Amfonelic acid, a compound that enhances dopaminergic tone by a complex mechanism, increased aspects of both appetitive and consummatory behaviors. These data suggest that, in quail, as in rodents, increases in dopaminergic tone facilitate both appetitive and consummatory aspects of male sexual behavior. Apomorphine may be inhibitory in quail because it acts primarily on D2-like receptors, unlike in rats, where it stimulates sexual behavior and acts primarily on D1-like receptors at low doses but interacts with D2-like receptors at higher doses. This is supported by the observation that stereotyped pecking, a behavior stimulated selectively in quail by D2 agonists, was increased by apomorphine but not by the two indirect agonists. The observed partial dissociation between the effects of these dopaminergic agonists on appetitive and consummatory sexual behaviors suggests that these two components of male sexual behavior may be controlled by the action of dopamine through different neuronal systems.