Search

Sex differences in ethanol intake in rats suggest that there may be sex differences in brain dopamine systems believed to mediate ethanol's reinforcing properties. To test this hypothesis, we used in vivo microdialysis to examine changes in nucleus accumbens and striatal dopamine, DOPAC and HVA following acute administration of several doses of ethanol in male and female Long-Evans rats. Following dialysis, rats were trained to bar press for oral ethanol reinforcement. In nucleus accumbens, females showed greater increases in dopamine than males at low to intermediate doses. In striatum, both sexes showed increased dopamine at the low to intermediate doses. In addition to showing increased responsiveness to ethanol-induced mesolimbic dopamine stimulation, females consumed more ethanol than males during behavioral testing. Correlations between neurochemical measures and subsequent ethanol consumption indicated that among males, both basal and peak ethanol-induced nucleus accumbens dopamine levels were inversely related to later ethanol intake. No such relationship was observed for females. Striatal neurochemical measures were not significantly related to ethanol intake. These findings supported the hypothesis of sex differences in mesolimbic responses to ethanol and suggested that the relationship of those responses to subsequent ethanol intake may differ for males and females.

Because an increase in extracellular levels of dopamine in the nucleus accumbens has been associated with the reinforcing effects of addictive drugs, we investigated whether U50,488, a selective kappa opioid receptor agonist, would alter cocaine-induced increases in extracellular dopamine in the nucleus accumbens using in vivo microdialysis in awake and freely moving rats. Cocaine (20 mg/kg i.p.) produced a 10-fold increase in extracellular dopamine levels. Pretreatment (20 min beforehand) with U50,488 (10 mg/kg i.p.), which alone caused a modest decrease in dopamine levels, produced a 50% decrease in the effect of cocaine on dopamine levels. This attenuation was completely reversed by administration of a kappa opioid receptor antagonist, nor-binaltorphimine (10 mg/kg s.c.), 20 min before the agonist challenge. Treatment with nor-binaltorphimine alone induced a brief increase in dopamine levels. These findings indicate that activation of kappa receptors attenuates cocaine's effects and that kappa opioid receptor agonists may, therefore, be useful as functional cocaine antagonists.

Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addiction to opioid and stimulant drugs and has been reported to decrease morphine and cocaine self-administration in rats. The present study sought to determine if other iboga alkaloids, as well as the chemically related harmala alkaloid harmaline, would also reduce the intravenous self-administration of morphine and cocaine in rats. Because both ibogaine and harmaline induce tremors, an effect that may be causally related to neurotoxicity in the cerebellar vermis, the temorigenic activities of the other iboga alkaloids were assessed. Lastly, in view of the involvement of the dopaminergic mesolimbic system in the actions of drugs of abuse, the effects of some of the iboga alkaloids on extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum were determined. All of the tested alkaloids (i.e., ibogaine, tabernanthine, R- and S-coronaridine, R- and S-ibogamine, desethylcoronaridine, and harmaline) dose-dependently (2.5-80 mg/kg) decreased morphine and cocaine intake in the hour after treatment; decreases in morphine and cocaine intake intake were also apparent the day after administration of some but not all of these alkaloids (i.e., ibogaine, tabernanthine, desethylcoronaridine, and the R-isomers of coronaridine and ibogamine). In some rats, there were persistent decreases in morphine or cocaine intake for several days after a single injection or after two or three weekly injections of one or another of these alkaloids; R-ibogamine produced such effects more consistently than any of the other alkaloids.(ABSTRACT TRUNCATED AT 250 WORDS)

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer cocaine could be identified. Estimated extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer cocaine intravenously. There were several significant relationships between dopamine and dopamine metabolite (3,4-dihydroxyphenylacetic acid and homovanillic acid) levels and rates of cocaine self-administration during both acquisition and asymptotic phases of testing. Dopamine levels in the nucleus accumbens were non-monotonically related to rates of self-administration during both phases: low to moderate dopamine levels were positively correlated with self-administration rates whereas moderate to high dopamine levels were negative correlated with self-administration rates. Dopamine, DOPAC (3,4-dihydroxyphenylacetic acid) and HVA (homovanillic acid) levels in the striatum were inversely correlated with self-administration rates during the acquisition phase. DOPAC and HVA levels in the left and right sides of the medial prefrontal cortex were positively and negatively correlated, respectively, with self-administration rates during the asymptotic phase; left/right asymmetrics in cortical metabolite levels were also correlated with asymptotic rates. There were no significant relationships between any neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the activity of brain dopamine systems.(ABSTRACT TRUNCATED AT 250 WORDS)

It is common practice in microdialysis studies for probes to be "calibrated" in artificial CSF and in vitro recoveries determined for all substances to be measured in vivo. Dialysate concentrations of such substances are then "corrected" for in vitro recoveries to provide "estimates" of extracellular concentrations. At least for dopamine, in vitro and in vivo recoveries are significantly different and, therefore, an estimate of extracellular dopamine based on correction for in vitro recovery is likely to be erroneous. Generally, however, the relative relationships of such estimates among animals are of interest rather than the "true" extracellular values. Such relationships would be valid to the extent that estimated values are correlated with or predictive of true values. Using the "no net flux" procedure, the present study sought to determine, for both dopamine and its metabolite 3,4-dihydroxyphenylacetic acid (DOPAC), whether in vitro and in vivo recoveries would correlate with each other as well as whether respective estimated and true (no net flux) values of these substances would correlate with each other. Probes (3 mm; BAS/CMed MF-5393), previously calibrated, were lowered into both the nucleus accumbens and striatum of freely moving rats the day before sample collection was begun. In vitro and in vivo recoveries were not significantly correlated (r = 0.1-0.3), for either dopamine or DOPAC. For both dopamine and DOPAC, however, there were significant correlations (r = 0.7-0.8) between estimated and true values. Surprisingly, when using these commercial probes, absolute dialysate levels for both substances were even better correlated (r = 0.9-0.95) with true values.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of IP saline injections on basal dopamine (DA), homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC), and morphine-evoked levels of DA, DOPAC, and HVA in the striatum (STR) and nucleus accumbens (NAC) of female Sprague-Dawley rats was quantified, using in vivo microdialysis. In the STR, saline injections twice daily over 3 days, then once on day 4 (2x /day group), resulted in higher basal DOPAC and HVA levels compared to unhandled rats (naive group), or rats injected with saline once daily for 4 days (1x /day group). DOPAC and HVA were greater after IP injection of 30 mg/kg morphine in the saline 2x /day group compared to the saline 1x /day and naive groups. In the NAC, DOPAC was higher after injection of morphine in saline-pretreated rats, compared to naive rats. These results suggest that handling and/or IP saline injections affect basal and morphine-evoked changes in DA metabolites in the STR, and morphine-evoked DOPAC in the NAC.

Pregnant rats were given injections of saline (0.5 ml/kg) or cocaine (10 mg/kg, 20 mg/ml, s.c.) twice daily between gestational days 7-21. Offspring were examined by microdialysis between postnatal days 10-125 to study the effects of prenatal cocaine exposure on the nigrostriatal dopamine (DA) system. Twenty-min dialysis samples were collected and assayed for DA, DOPAC and HVA. After four baseline samples, the rat was exposed to 20 min of intermittent tail pinch and monitored for four samples; then each rat received an acute injection of cocaine (20 mg/kg, i.p.) and six additional samples were collected. Basal dialysate concentrations of all DA markers, estimated from pre-implantation calibration of the probes, were markedly reduced in young rats ('pups', 10-30 days old) as compared with adult rats (40-125 days old). Compared to control pups, basal DA, as well as DOPAC and HVA, were elevated in the prenatal-cocaine pups. Tail pinch (a mild stressor) produced a significant increase in DA only in the pups prenatally exposed to cocaine. The increase in basal DA induced by an acute cocaine injection (20 mg/kg) was also greater and more prolonged in the prenatal-cocaine pups. In older rats (40-125 days) there were no group differences in any of the DA parameters. Thus prenatal exposure to cocaine produces an activation of the DA system which persists after birth but returns to normal in older rats.

Exposure to stressors that are not controlled results in a variety of changes in behavior and in brain chemistry. Among these is the activation of dopamine-containing neuronal systems projecting to the medial prefrontal cortex (PFC), to a lesser extent the nucleus accumbens (NAC) and, in a few studies, the striatum. Previous data have shown that stressor evoked PFC activation is asymmetrical. The present experiments were designed to assess the effects of controlled and uncontrolled stressors on these DA systems using the procedures of the learned helplessness (LH) model. In a first experiment, 80 trials of either a controllable (ESC) or identical uncontrollable footshock stressor (YOK) caused an activation, as indicated by increased metabolite concentrations of DA in the PFC, NAC and striatum. In the PFC, YOK caused a bilateral DA depletion, relative to ESC and control animals, and a right > left increase in DOPAC/DA which was not seen in ESC animals. These findings suggested a preferential effect of YOK in the right PFC. A second experiment used rats that had been grouped according to their turning behavior, YOK right-biased rats showed an increase in DOPAC on the right side of the PFC and YOK left-biased rats displayed a similar increase on the left side in response to a brief (5 min) controllable footshock stressor. Since right-turning rats had been shown to be more sensitive to a LH behavioral phenomenon, the data suggested that right PFC activation is responsible for the greater LH sensitivity. A final experiment evaluated the neurochemical and behavioral responses to a prolonged footshock stressor 24 h after uncontrolled footshock. Right-biased YOK animals displayed depressed footshock escape behavior and a right > left depletion in PFC DA and HVA. Across-groups footshock escape performance was correlated with DA and HVA concentrations on the right but not on the left side of the PFC. Thus a disturbance of right PFC DA utilization was again associated with compromised coping behavior. The data suggest that the inability to control a stressor causes a lateralized alteration of PFC DA and this results in a disruption of the ability to respond to a new stressor. These findings indicate that the two sides of the PFC are differentially specialized for responding to a stressor.

Systemic administration of ibogaine (40 mg/kg, i.p.) has been reported to induce both acute (1-3 h) and persistent (19-20 h) changes in extracellular levels of dopamine and its metabolites in the nucleus accumbens and striatum. In the present study, local administration of ibogaine to the striatum and nucleus accumbens produced effects that mimicked both the acute and persistent effects of systemic administration: perfusion with high concentrations (200 and 400 microM) of ibogaine mimicked the acute effects (decreased extracellular dopamine levels and increased extracellular metabolite levels) whereas perfusion with a low concentration (10 microM) of ibogaine mimicked the persistent effects (decreased extracellular levels of DOPAC). These results indicate that ibogaine acts directly in brain regions containing dopaminergic nerve terminals and that long-lasting effects of systemically administered ibogaine might be mediated by persisting low levels of ibogaine. Locally administered ibogaine (10 microM) was also found to enhance the effects of systemically administered D-amphetamine (1.25 mg/kg, i.p.) on extracellular dopamine levels, and conversely, systemically administered ibogaine (40 mg/kg, i.p.; 19 h pretreatment) enhanced the effects of locally administered D-amphetamine (1-10 microM). These results indicate that, in addition to a metabolic mechanism implicated previously, a pharmacodynamic mechanism contributes to the interaction between ibogaine and D-amphetamine. The relevance of such mechanisms to claims regarding ibogaine's anti-addictive properties is unclear.

A series of 14 beta-[(nitrocinnamoyl)amino]codeinones and morphinones, some of which contain a 5 beta-methyl group, were prepared from 14 beta-aminocodeinones and 14 beta-[N-(cyclopropylmethyl)-amino]norcodeinones. The affinities of the target compounds for the mu, delta, and kappa opioid receptors were determined by radiolabeled binding experiments using bovine brain membranes. An analogous series of 7,8-dihydrocodeinones and morphinones was prepared and assayed in the same systems. The 3-methoxy derivatives 3 and 4 were more selective than the corresponding morphinones for the mu receptor. The 5 beta-methylcodeinones 25 and 27 had lower affinity at all receptors than the corresponding morphinones, but the 5 beta-methylmorphinones had affinities similar to the morphinones 5 and 6. A similar pattern was observed in the 7,8-dihydro series. Two compounds, 5 beta-methyl-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydromorphinone, 20 (MET-CAMO), and N-(cyclopropylmethyl)-14 beta-[(p-nitrocinnamoyl)amino]-7,8-dihydronormorphinone, 22 (N-CPM-MET- CAMO), acted as nonequilibrium ligands in antinociception and membrane binding studies. In mice after icv administration, neither ligand showed any agonist activity but 8-24 h after administration both compounds acted as potent mu antagonists. A Scatchard plot of the effect of N-CPM-MET-CAMO on [3H]DAMGO ([3H]D-Ala2, (Me)-Phe4, Gly(ol)5] enkephalin) binding to bovine striatal membranes showed that there was a significant decrease in the Bmax value and a marginal effect on the Kd value suggesting that the number of binding sites was reduced. When taken together, these results support the view that 20 and 22 bind covalently to the mu receptor. On the other hand, when N-acetylcysteine and 22 were allowed to react in a buffered solution, 22 was recovered unchanged. Under these conditions no Michael reaction was observed.

Using in vivo microdialysis, ethanol-induced dopamine release in nucleus accumbens and striatum was examined in adult male and female Long-Evans rats exposed prenatally to ethanol and in controls. Following dialysis, ethanol intake was measured in an operant paradigm. Control rats showed increased dopamine release in nucleus accumbens and striatum in response to 0.5 g/kg ethanol, but not to 1.0 g/kg. Fetal ethanol-exposed rats showed no dopamine response at 0.5 g/kg. At 1.0 g/kg, fetal ethanol-exposed males showed increased dopamine release in both structures. Prenatally exposed females showed no change in accumbens, and decreased release in striatum. Fetal ethanol exposure did not significantly influence ethanol intake. The findings suggest that prenatal ethanol exposure influences subsequent neurochemical responses to ethanol; however, how these neurochemical measures are related to ethanol intake could not be determined in the present study. Data are discussed in terms of sex-specific shifts in the dose-response function for ethanol-induced dopamine release resulting from prenatal ethanol exposure.

In vivo microdialysis was used to examine changes in nucleus accumbens and striatal dopamine, dihydrophenylacetic acid (DOPAC), and homovanillic acid (HVA) following acute administration of ethanol (0.0, 0.25, 0.5, 1.0, or 2.0 g/kg) in male and female Long-Evans rats. Following dialysis, rats were trained to bar-press for oral ethanol reinforcement. In nucleus accumbens, females showed significant increases in extracellular dopamine following 0.25 or 0.5 g/kg ethanol, but did not show significant increases over baseline at the higher doses. Males showed slight increases in dopamine at the lower doses and decreased dopamine at 2.0 g/kg. In striatum, both sexes showed increased dopamine at the lower doses and decreased dopamine at 2.0 g/kg. There were slight increases in nucleus accumbens DOPAC and HVA at some doses in both sexes, but no changes in striatal metabolite levels. In addition to showing increased responsiveness to ethanol-induced mesolimbic dopamine stimulation, females consumed more ethanol than males during behavioral testing. The pattern of both greater ethanol-induced nucleus accumbens dopamine release and greater ethanol consumption in females supports the hypothesis that ethanol reward is mediated, at least in part, by the mesolimbic dopamine system.

Morphine administered at high doses produces a biphasic locomotor effect, characterized by an initial locomotor depression, followed a short time later by hyperlocomotion. Prior exposure to morphine produces tolerance to the motor-depressive effects and sensitization to the motor-activating effects of morphine. Little is known of the neurochemical changes that occur to produce tolerance and sensitization to morphine. In the present study, we developed a morphine pretreatment regimen in rats that produced both tolerance and sensitization to a high (30 mg/kg) dose of morphine. Using in vivo microdialysis, we then measured dopamine (DA), dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) release in the nucleus accumbens (NAC) and striatum (STR) in morphine- and saline-pretreated rats after acute morphine administration. In morphine-tolerant/sensitized rats, basal DA concentrations in the NAC were higher and levels of DOPAC and HVA in the NAC after acute morphine injection were greater compared to controls. These results suggest that the NAC, but not the STR, may be important in mediating tolerance and sensitization to opiates.

The chakragati (ckr) mouse is a transgenic insertional mutant that displays lateralized circling behavior, locomotor hyperactivity, hyperexcitability as well as body weight deficits. The mutation is autosomal and recessive. We have previously found that ckr mice have bilateral asymmetric elevations in striatal dopamine (DA) D2-like (D2, D3 and/or D4), but not D1-like (D1 and/or D5) receptors. Predictably, these mice increase turning in response to the D2-like agonist quinpirole and spontaneously rotate contralateral to the striatal side with the higher D2-like receptors. The overall objective of the present study was to assess the neurochemical specificity of the mutation in ckr mouse, particularly since motor behaviors can be elicited by a multitude of brain regions and neurotransmitter systems within the basal ganglia. Using quantitative receptor autoradiography, we examined the regional distribution of DA uptake sites and 5-HT1A, 5-HT1B/1D, GABAA and mu opioid receptors. Also, we wanted to determine whether increased behavioral laterality as seen in rotation is evident with another test of laterality, such as lateral paw preference. The ckr mice showed greater paw preferences than normal mice; however, neither the degree nor direction of these preferences correlated with rotational behavior. The ckr mice showed moderate decreases in the density of DA uptake sites in all subregions of the striatum, but not in the nucleus accumbens or olfactory tubercle. Interestingly, these decreases in ckr mice were not accompanied by a reduction in striatal tissue DA content. 5-HT1 and mu opiate receptor populations were normal in ckr mice. However, GABAA sites in the mediodorsal thalamus and superior colliculus were bilaterally and asymmetrically elevated in ckr mice. These data are consistent with the idea that the motor phenotypes of the ckr mouse result from specific disturbances within nigro-striatal, striato-pallido-thalamic and striato-nigro-collicular circuitry. The implications of these and past findings are discussed in relation to current thinking about hyperkinetic motor syndromes in humans involving reduced basal ganglia outflow.

Our initial report of a preferential expression of experimental alcoholic embryopathy affecting the male offspring contiguous in utero to male siblings of Long-Evans rats was based on gavage administration of alcohol to pregnant rats without regard to isocaloric, pair-fed exposure paradigms. In this study, pregnant Long-Evans rats were given 35% ethanol-derived calories (EDC) in one of two different liquid diets: 1) a liquid alcohol diet based on Sustacal, a flavored liquid food formulated for human nutritional standards; and 2) a high-protein liquid rodent diet devised by Lieber and DeCarli (L&D). The diets were administered from day 6 to 15 of gestation. Pregnant rats were pair-fed liquid diets containing 0% EDC, but isocalorically balanced to 35% EDC with either sucrose (Sustacal) or maltose-dextrin (L&D). A fifth group of pregnant rats was given access ad libitum to standard certified laboratory rodent diet and served as free-fed controls. On day 20 of gestation, all pregnant rats were euthanized and the products of conception examined by standard teratologic techniques. Pregnant animals fed Sustacal-based diets consistently consumed fewer calories per kilogram body weight per day from day 6 to 15 of gestation (i.e., they were significantly calorie-deprived during pregnancy) as compared with the standard laboratory-diet-fed controls or those consuming L&D diets. Body weights of rats consuming Sustacal diets (both 0 and 35% EDC) were significantly lower throughout gestation when compared with all other groups. Higher (> 150 mg/dl) blood alcohol levels were attained by rats consuming 35% EDC in Sustacal diet as compared with L&D (100 mg/dl) diets.(ABSTRACT TRUNCATED AT 250 WORDS)

'Premature' rats that were delivered by cesarean section on day 21 of gestation and 'normal' rats that were delivered spontaneously on day 22 of gestation were tested for basal locomotor activity and locomotor stimulation in response to D-amphetamine at 19-21 days of age. Compared to normal rats, premature rats had increased basal levels of locomotor activity and showed enhanced sensitivity to the locomotor stimulant effects of D-amphetamine. Cesarean-delivered premature rats may be a useful animal model for investigating mechanisms of neurobehavioral deficits associated with premature birth in humans.

Previous studies in rats have shown that ibogaine inhibits neurochemical and behavioral effects of morphine yet potentiates similar effects of (+)-amphetamine. To assess whether these different functional interactions have a metabolic basis, brain levels of morphine and (+)-amphetamine were measured by gas chromatography-mass spectrometry after ibogaine pretreatment (19 h before injection of morphine or (+)-amphetamine). Ibogaine pretreatment had no effect on brain morphine levels, either at 30 min or 2 h after morphine injection; however, ibogaine significantly increased brain amphetamine levels at 30 min and, to a greater extent, at 2 h after (+)-amphetamine injection. These and other data suggest that ibogaine irreversibly inhibits an amphetamine-metabolizing enzyme. The functional interactions between ibogaine and (+)-amphetamine, but not those between ibogaine and morphine, may result from a hepatic drug-drug interaction.

We have previously reported the discovery of a transgenic insertional mutant, recently named the chakragati (ckr) mouse, which displays lateralized circling, locomotor hyperactivity, hyperreactivity, as well as body weight deficits. Since lateralized dopamine function is associated with circling behavior we sought to determine whether dopamine (DA) D1 and D2 receptors were asymmetrically distributed in the striata of adolescent and adult ckr mice using receptor autoradiography. Stereotypic and rotational responses to quinpirole served as behavioral indices of D2 receptor function. The ckr mice showed hemispherically asymmetric elevations in DA D2 receptors in the lateral subregions of the striatum whereas medial regions of the striatum were symmetrically and bilaterally elevated (overall elevation = 30%). As a group, ckr mice had higher D2 receptor levels on the side which was contralateral to the preferred direction of spontaneous nocturnal rotation. Striatal D1 receptors and mesolimbic D2 and D1 receptors of ckr mice were neither elevated nor differentially asymmetric. Young adult ckr mice showed dose-dependent increases in net rotations in response to quinpirole whereas normal mice showed no change from baseline levels. Both groups showed similar stereotypic responses. Older adult ckr mice, however, showed dose-dependent reductions in rotation after quinpirole whereas normal mice turned at baseline levels. Older ckr mice also displayed significantly greater stereotyped sniffing behavior. This unique mutant provides a novel genetic model of basal ganglia dysfunction, and may be useful in studying aspects of neuropsychiatric disorders associated with dopaminergic abnormalities.

Because of the claim that ibogaine suppresses the symptoms of "narcotic withdrawal" in humans, the effect of ibogaine on naltrexone-precipitated withdrawal signs in morphine-dependent rats was assessed. Morphine was administered subcutaneously through implanted silicone reservoirs for 5 days. Ibogaine (20, 40 or 80 mg/kg, i.p.) or saline was administered 30 min prior to challenge with naltrexone (1 mg/kg, i.p.) and withdrawal signs were counted for the following 2 hr. Ibogaine (40 and 80 mg/kg) significantly reduced the occurrence of four signs (wet-dog shakes, grooming, teeth chattering and diarrhea) during naltrexone-precipitated withdrawal; three other signs (weight loss, burying and flinching) were unaffected. Ibogaine induces head and body tremors lasting for 2-3 hr and the tremors might have interfered with the expression of opioid withdrawal. To examine this issue, another experiment was conducted in which ibogaine (40 mg/kg) or saline was administered 4 hr prior to challenge with naltrexone. Although there was a complete absence of tremors, ibogaine still significantly reduced the occurrence of the same four signs of withdrawal.

Repeated microdialysis measurements, conducted 1 week apart at the same tissue site, were used to investigate the changes in basal and cocaine-stimulated extracellular dopamine (DA) levels after a single prior exposure to either saline or cocaine. Dialysis probes were placed into rats previously implanted with guide cannulas and basal levels of dopamine (DA), and its metabolites (DOPAC and HVA) were estimated in 20-min fractions of the dialysate. Basal levels in the extracellular fluid (ECF), estimated from pre-implantation calibration of the probes, were 7.9 +/- 0.7 nM DA, 4.9 +/- 0.8 microM DOPAC, and 3.6 +/- 0.6 microM HVA. After a stable baseline was obtained saline (1 ml/kg, i.p.) or cocaine (20 mg/kg, i.p.) was injected. Saline produced no significant changes in any of the neurochemical markers. A cocaine injection produced a sixfold increase in DA, while DOPAC and HVA were unchanged. One week later the same procedure was repeated except this time both groups received cocaine. In rats that had received cocaine 1 week earlier, basal DA levels in the ECF were doubled, whereas they were unchanged in rats that received saline a week earlier. Furthermore, the dopamine release in response to acute cocaine during the second week was elevated in animals which had been previously exposed to cocaine. Rotation was also measured during both weeks and, while a tendency toward behavioral sensitization was observed, it did not reach significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Ibogaine, an indolalkylamine, has been proposed for use in treating stimulant addiction. In the present study we sought to determine if ibogaine had any effects on the neurochemical and motor changes induced by D-amphetamine that would substantiate the anti-addictive claim. Ibogaine (40 mg/kg, i.p.) injected 19 h prior to a D-amphetamine challenge (1.25 mg/kg, i.p.) potentiated the expected rise in extracellular dopamine levels in the striatum and in the nucleus accumbens, as measured by microdialysis in freely moving rats. Using photocell activity cages, the same ibogaine pretreatment enhanced the stimulatory motor effects induced by a wide range of D-amphetamine doses (0.625, 1.25, 2.5 or 5 mg/kg, i.p.). These findings suggest that ibogaine might increase the reinforcing efficacy of D-amphetamine. However, since high doses of D-amphetamine can be aversive, the potentiation of D-amphetamine's effects by ibogaine might also lead to a decrease in the reinforcing efficacy of D-amphetamine.

Using in vivo microdialysis, this study attempted to determine whether a neurochemical predisposition to self-administer morphine could be identified. Extracellular levels of dopamine and its metabolites were measured bilaterally in the mesocorticolimbic and nigrostriatal systems of naive rats that were subsequently trained to self-administer morphine intravenously. There were several significant relationships between dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels and rates of morphine self-administration during both acquisition and asymptotic phases of testing. DOPAC and HVA levels in the striatum were inversely correlated with self-administration rates during the asymptotic phase whereas hemispheric asymmetries in striatal metabolite levels were inversely correlated with self-administration during the acquisition phase. DOPAC and HVA levels in in the right but not in the left side of the medial prefrontal cortex were positively correlated with self-administration rates during the acquisition phase; right/left asymmetries in cortical metabolite levels were also correlated with acquisition rates. There were no significant relationships between neurochemical indices and rates of bar-pressing for water. These results suggest that the normal variability in drug seeking behavior is at least in part attributable to individual differences in the organization and activity of brain dopamine systems. Furthermore, different mechanisms appear to be responsible for the initiation and maintenance of morphine intake: DA release in the nucleus accumbens appears to be a critical component of both mechanisms; DA release in the striatum appears to modulate maintenance and, in relationship to striatal lateralization, modulate initiation; DA release in the right but not in the left medial prefrontal cortex appears to be an important predictor of initiation.

Ibogaine, an indolalkylamine, proposed for use in treating opiate and stimulant addiction, has been shown to modulate the dopaminergic system acutely and one day later. In the present study we sought to systematically determine the effects of ibogaine on the levels of dopamine (DA) and the dopamine metabolites 3,4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in tissue at several time points, between 1 h and 1 month post-injection. One hour after ibogaine-administration (40 mg/kg i.p.) a 50% decrease in DA along with a 37-100% increase in HVA were observed in all 3 brain regions studied: striatum, nucleus accumbens and prefrontal cortex. Nineteen hours after ibogaine-administration a decrease in DOPAC was seen in the nucleus accumbens and in the striatum. A week after administration of ibogaine striatal DOPAC levels were still reduced. A month after ibogaine injection there were no significant neurochemical changes in any region. We also investigated the effects of ibogaine pretreatment on morphine-induced locomotor activity, which is thought to depend on DA release. Using photocell activity cages we found that ibogaine pretreatment decreased the stimulatory motor effects induced by a wide range of morphine doses (0.5-20 mg/kg, i.p.) administered 19 h later; a similar effect was observed when morphine (5 mg/kg) was administered a week after ibogaine pretreatment. No significant changes in morphine-induced locomotion were seen a month after ibogaine pretreatment. The present findings indicate that ibogaine produces both acute and delayed effects on the tissue content of DA and its metabolites, and these changes coincide with a sustained depression of morphine-induced locomotor activity.

To investigate a possible basis for the proposed anti-addictive property of ibogaine, the effects of an ibogaine (40 mg/kg i.p.) pretreatment on in vivo neurochemical and motor effects induced by cocaine (20 mg/kg i.p.) were studied. Ibogaine, administered 19 h earlier, potentiated the increase in extracellular dopamine levels in striatum and nucleus accumbens as well as the stimulated motor activity induced by cocaine. Although high doses of cocaine can become aversive by producing an anxiogenic reaction, it is unknown whether the potentiation of cocaine's effects by ibogaine would also cause aversion and lead to a decrease in cocaine addiction.

Assays using radioligands were used to assess the actions of ibogaine and harmaline on various receptor types. Ibogaine congeners showed affinity for opiate receptors whereas harmaline and harmine did not. The Ki for coronaridine was 2.0 microM at mu-opiate receptors. The Kis for coronaridine and tabernanthine at the delta-opiate receptors were 8.1 and 3.1 microM, respectively. Ibogaine, ibogamine, coronaridine and tabernanthine had Ki values of 2.08, 2.6, 4.3 and 0.15 microM, respectively, for kappa-opiate receptors. Long-lasting, dose-dependent behavioral effects of ibogaine have been reported. The possibility that these effects were due to irreversible binding properties of ibogaine at kappa-receptors was considered; however, radioligand wash experiments showed a rapid recovery of radioligand binding after one wash. A voltage-dependent sodium channel radioligand demonstrated Ki values in the microM range for all drugs tested. Using radioligand binding assays and/or 36Cl- uptake studies, no interaction of ibogaine or harmaline with the GABA receptor-ionophore was found. The kappa-activity of ibogaine (or an active metabolite) may be responsible for its putative anti-addictive properties whereas the tremorigenic properties of ibogaine and harmaline may be due to their effects on sodium channels.

The anticonflict activity of gepirone, a putative anxiolytic and antidepressant, was examined on three schedules which conditioned the suppression of licking. The novel schedules differed in the degree to which they predicted (signalled) the presentation of a conflict-inducing electric shock. Three doses of gepirone (1.25, 2.5, and 5 mg/kg SC) were evaluated on a predictable, a moderately predictable, and an unpredictable schedule of shock presentation. Gepirone induced a nondose-dependent increase from baseline in punished licking on the predictable schedule on the last two days of a five-day test period. The lowest dose (1.25 mg/kg) of gepirone induced a significant increase in punished licking on the moderately predictable schedule on the last two days of testing. The highest dose (5 mg/kg) induced initial decreases in overall responding on this schedule. However, responding returned to baseline over the course of the four days of testing. When administered to rats trained on an unpredictable schedule of shock presentation, all doses of gepirone induced an initial decrease from baseline. The lowest dose group returned to baseline control response levels over the next four days, whereas the suppressive effects of the higher doses persisted. The initial decrease in responding observed on all schedules may be due to the effects of gepirone on motor functioning. However, the 2.5-mg/kg dose induced a proconflict or anxiogenic effect on the last test day (decreased punished responding alone) on the unpredictable schedule, while inducing an anticonflict effect on the predictable one. The unpredictable schedule is sensitive to detecting decreases as well as increases in punished responding and as such may be a unique conflict model for evaluating novel anxiolytics.(ABSTRACT TRUNCATED AT 250 WORDS)

The anti-conflict activities of diazepam and buspirone were examined on three schedules designed to condition the suppression of licking. The schedules differed in the degree to which they predicted (signalled) the presentation of a conflict inducing electric shock. The first study investigated the effects of three doses of diazepam (0.5, 2, and 5 mg/kg IP) on a predictable, a moderately predictable, and an unpredictable schedule of shock presentation. Diazepam induced a significant increase from baseline in licking during the shock component on all three schedules. These anticonflict effects were the most consistent on the predictable schedule, and least consistent on the unpredictable schedule. A second experiment investigated the anticonflict activity of three doses of buspirone (0.125, 0.25, and 0.625 mg/kg SC) on each of these three schedules. The predictable and moderately predictable schedules failed to detect anticonflict activity at any dose of buspirone. However, the lowest dose (0.125 mg/kg) of buspirone increased shocked licking and the highest dose (0.625 mg/kg) decreased shock component licking on the unpredictable schedule. Thus the unpredictable schedule was sensitive to both anticonflict (anxiolytic) and proconflict (anxiogenic) effects of buspirone.

In a previous study (Ratty et al., 1990), the discovery of a transgenic mutant mouse that displayed abnormal circling behavior was reported. Mice homozygous for the transgene display this phenotype, whereas heterozygotes are phenotypically normal. In this study, circling mutants displayed excessive lateralized circling behavior and locomotor hyperactivity by Postnatal Days (PND) 14 and 16, respectively. These abnormalities persisted unattenuated through adolescence and adulthood. Disturbances in rearing and grooming were also observed in circling mutants. Surface-righting ability in the mutants was normal, and the age of eye opening was only marginally delayed. However, body weights of the mutants were reduced compared with normal mice from PND 15 to adulthood. Possible relationships between the behaviors that are exhibited by circling mutants and previous neurochemical findings are discussed.

Ibogaine, an indolalkylamine, has been claimed to be effective in abolishing drug craving in heroin and cocaine addicts. The present study used in vivo microdialysis to determine the effects of ibogaine on extracellular levels of dopamine (DA) and its metabolites and the effects of ibogaine pretreatment on morphine stimulation of brain DA systems. Acutely, ibogaine (40 mg/kg i.p.) decreased extracellular DA levels in the striatum, increased them in the prefrontal cortex and had no significant effects in the nucleus accumbens. Nineteen hours after ibogaine injection. DA levels were still decreased in the striatum and the metabolite levels were lower in all three regions. When injected 19 h prior to a morphine challenge (5 mg/kg i.p.), ibogaine (40 mg/kg, i.p.) prevented the rise in DA levels in all three regions normally observed after a morphine injection. A high dose of morphine (30 mg/kg i.p.), administered alone, produced no increase in extracellular DA levels; it is therefore unclear whether ibogaine antagonized or potentiated the effects of the lower dose of morphine. Regardless of the nature of this interaction, it appears that ibogaine affects brain DA systems for a period of time that exceeds its elimination from the body and, during this time, alters the responses of these systems to morphine.

Rats exposed to stressors that cannot be controlled may develop a deficit in their ability to subsequently learn to control a new stressor. This phenomenon is known as 'learned helplessness' and is a well-accepted animal model of depression. Evidence is presented showing that rats having different directional biases of brain laterality, as indicated in tests of rotational behavior, differ greatly in their response to stressors and to the lack of stressor control. Differences in brain laterality appear to be an important source of variability within the animal model of depression. As with humans, only some rats are vulnerable to depression-like symptoms. These findings are relevant to biological theories of depression that are based upon lateralized specialization of the human brain for affect.

Exposure to various mild stressors has been shown to result in the activation of dopamine containing neuronal systems projecting to the medial prefrontal cortex (PFC), to a lesser extent the nucleus accumbens septi/olfactory tubercle (NAS) and, in a few studies, the striatum. It has also been shown that dopamine (DA) systems on different sides of the PFC are successively activated as stressors are prolonged. We have therefore examined the effects of variation in the duration of a restraint stressor (15, 30 and 60 min) on region and side dependent alterations in DA utilization in the PFC, NAS and striatum. Increases in the concentrations of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and/or homovanillic acid (HVA) or in their ratios with DA were seen in all regions examined with the largest effects occurring in the PFC and lesser effects in the NAS and striatum. In each region, the magnitude of these effects varied with time of restraint exposure. In the PFC, lateralized alterations in HVA and DA were seen over time with effects progressing from a left greater than right involvement at 15 min to a right greater than left involvement at 60 min. These results are discussed with reference to side and region dependent effects on brain DA systems as stressors are prolonged and the implications they may have for lateralized regional brain activity associated with stressor precipitated psychiatric disease.

Ibogaine, a naturally occurring alkaloid, has been claimed to be effective in treating addition to opiate and stimulant drugs. As a preclinical test of this claim, the present study sought to determine if ibogaine would reduce the intravenous self-administration of morphine in rats. Ibogaine dose dependently (2.5-80 mg/kg) decreased morphine intake in the hour after ibogaine treatment (acute effect) and, to a lesser extent, a day later (aftereffect); while the acute effect could be attributed to abnormal motor behavior (whole body tremors), the aftereffect occurred at a time when ibogaine should have been entirely eliminated from the body and when there was no obvious indication of ibogaine exposure. In some rats, there was a persistent decrease in morphine intake for several days or weeks after a single injection of ibogaine; other rats began to show such persistent changes only after two or three weekly injections whereas a few rats were apparently resistant to prolonged aftereffects. Aftereffects could not be attributed to a conditioned aversion. Although ibogaine also depressed responding acutely in rats trained to bar-press for water, there was no evidence of any aftereffect a day or more later; the interaction between ibogaine and morphine reinforcement was therefore somewhat specific. Further studies are needed to characterize the nature of the ibogaine-morphine interaction as well as to determine if ibogaine also affects the self-administration of other drugs.

Alcohol preference and hepatic alcohol dehydrogenase activity in adult rats are known to be sexually dimorphic. Intrauterine sibling contiguity (the intrauterine position of a fetus relative to adjacent siblings of the same or opposite sex) alters selected reproductive, behavioral and enzymatic sexual dimorphisms via intersibling sex hormone transfer. We postulated that sibling contiguity would affect alcohol preference and hepatic alcohol metabolism in adult rats. The results of our study demonstrate that adult mMm male Long-Evans rats (genetic male rat developing in utero between two male siblings) had significantly lower ethanol preference, attained higher blood alcohol levels after standard ethanol "challenge" doses and had significantly lower hepatic alcohol dehydrogenase activity than either male siblings developing in utero between two females (fMf) or genetic females developing between two males or between two females (mFm or fFf). Hepatic cytosolic aldehyde dehydrogenase activity was higher in adult female than male rats regardless of nearest neighbor siblings. It is suggested that the differences in ethanol preference and hepatic alcohol dehydrogenase activity between the adult mMm and fMf male rats is due to differences in prenatal hormonal environment which can modulate sexual dimorphisms in alcohol intake and metabolism in the adult.

The effects of behaviorally equivalent doses of D-amphetamine and cocaine on extracellular dopamine (DA) levels in the left and right medial prefrontal cortex (PFC) were investigated using microdialysis in anesthetized rats. The two drugs increased extracellular DA levels to a similar extent and, in each case, there was a tendency for the effects to be greater in the left than in the right side of the brain. For both drugs, there was a strong negative correlation between basal levels and the magnitude of the drug response; this relationship, while important to consider when comparing one drug to another, could not account for the left-right differences in drug effects. Contrary to some previous reports, the present data indicate that D-amphetamine and cocaine do not differ substantially with regard to their effects on dopamine neurotransmission in the PFC.

We report here of an abnormal circling behavior expressed in the TgX15 transgenic mouse line as a result of insertional mutagenesis. Homozygous transgenic mice expressed the phenotype while heterozygous transgenics were normal. We also found that the dopamine D2 receptor binding sites in the striata of the circling mice were significantly elevated by about 31% compared to normal heterozygous transgenic mice. Other transgenic lines constructed with the same transgene appeared normal suggesting that, in the TgX15 line, a genetic locus significant in mammalian motor behavior has been disrupted.

Recent studies have shown that rats develop a pronounced right-sided population bias when tested repeatedly over several days in a shock-escape T-maze paradigm. In the present study we sought to determine if this bias was the result of learning or of the repeated exposure to a stressor (footshock). Rats were tested in the T-maze for 5 trials on each of 6 consecutive days. One group of rats (HS-C) was allowed a free left or right choice on each trial whereas another group of rats (HS-A) was forced to alternate left and right turns on each trial for the first 5 days of testing and then allowed a free choice on Day 6. The population and individual laterality of the HS-A group did not differ from that of the HS-C group, indicating that learning does not account for the biases. A third group of rats (LS-C) was tested using a lower shock level; this decrease in stressor intensity delayed the development of a right-sided population bias without affecting the development of individual laterality. These results indicate that repeated exposure to a stressor, rather than learning, is primarily responsible for the marked right-sided population bias observed in the T-maze.

An asymmetry of basal ganglia dopaminergic function has been demonstrated in rats and related to both spontaneous and drug-induced rotation. An electronic device that measures the same kind of rotational movements in humans has been developed, and we have utilized this "rotometer" to study spontaneous rotational movement in prepubertal children. There was no significant difference between boys and girls in their average rate of rotation; however, left hemisphere-dominant boys were stronger rotators than left hemisphere-dominant girls. Both boys and girls made significantly more full turns to the left than to the right. These findings did not vary with age. Our observations are strikingly different from those obtained in previous studies of normal adults, in which women were stronger rotators than men, left hemisphere-dominant women turned to the left, and left hemisphere-dominant men rotated to the right. This study suggests that maturational changes in rotational behavior must occur, perhaps progressing to the adult pattern during puberty. The rotometer used in this study may provide useful information regarding the status of the basal ganglia in children with specific neurobehavioral conditions such as attention deficit disorder and Tourette's syndrome.

Circling behavior was measured in female rats treated with amphetamine (1.25 mg/kg d-amphetamine sulfate, IP) on 3 consecutive days. On days 4 and 5 saline was substituted for amphetamine. While the amphetamine-induced response was attenuated by both a D-1 (SCH 23390) and a D-2 (metoclopramide) antagonist. sensitization to amphetamine was attenuated by the D-1 antagonist only. In addition, expression of a placebo-like response observed on day 4 (characterized previously as a Pavlovian conditioned response) was attenuated by both the D-1 and D-2 antagonists without disrupting extinction of the response.

Knowledge of opiate action in laboratory animals can be of great value in developing a rational clinical approach to the treatment of narcotic dependence. Physiological alterations experimentally produced by narcotics have been confirmed in human subjects, and classical laboratory effects of conditioning and operant behavior also have clinical counterparts. Realization of animal-human correlates of narcotic dependence allows a better understanding of the strengths and weaknesses of existing therapeutic modalities.

Male and female rats, selected on the basis of their rotational behavior in response to d-amphetamine, were exposed to either escapable footshock stress, inescapable footshock stress or no stress and were then given a shuttlebox escape task on the subsequent day. Following testing, the magnitude and direction of the animals' rotational responses to d-amphetamine were determined again. Inescapable footshock stress induced a selective change in the direction and intensity of rotational behavior that was dependent upon the subjects' sex and preexisting rotational bias. Right-rotating males and left-rotating females shifted their directional bias toward the opposite side, while left-rotating males and right-rotating females displayed increased rotation in their pre-stress direction. Significant correlations were also noted between the intensity of pre-stress rotational behavior and performance on the shuttlebox shock escape task. The results are discussed with respect to stress' actions on the mesocortical dopamine system and how this system's sex-dependent asymmetrical organization may subserve part of the organism's general reaction to uncontrollable stress.

Amphetamine-induced circling behavior increases over the course of repeated administration of the drug; likewise, after repeated administration of amphetamine, an injection of saline prior to placement of the rat in the test apparatus previously associated with the pharmacologic effects of amphetamine will increase circling behavior. Experiments were designed to determine if either of these effects would respond to manipulation of the temporal contiguity between the test environment and the peak effects of amphetamine. The placebo-like response, in accordance with a Pavlovian conditioned response, was reduced by prior non-reinforced exposure to the test environment and subject to extinction. In contrast, the increase in the amphetamine-induced response was entirely dependent on the test environment but not affected by latent inhibition or extinction. These and previous findings indicate that the development and expression of the placebo-like response is the result of a Pavlovian associative process. Although amphetamine sensitization is environment dependent, it does not resemble a conditioned response in other respects.

Ethanol exposure alters sex steroidogenesis and sexually dimorphic behaviors in rodent offspring. Contiguity to siblings of the same or opposite sex in utero also affects steroidogenesis and sexual dimorphism in rodents. The present study with Long-Evans rats shows that maternal exposure to ethanol during the critical period of rodent organogenesis preferentially affects body weights and increases malformations in offspring dependent on their in utero contiguity to siblings of the opposite sex.

The discriminant effects of several behaviorally active and inactive analogs of phencyclidine [PCP; 1-(phenylcyclohexyl) piperidine] and the actions of PCP and three Ca-channel antagonists were examined on electrical excitability in frog and crayfish skeletal muscles. In frog sartorius muscle, 1-[1-(2-thienylcyclohexyl)piperidine (TCP; 100 microM), a behaviorally active analog of PCP, increased action potential duration nearly 9-fold, blocked delayed rectification and at 0.5 to 1 microM also increased the quantal release of transmitter. A partial blockade of delayed rectification and slight prolongation of the action potential occurred with 1-(p-fluorophenylcyclohexyl)piperidine (p-F-PCP; 100 microM), which possesses about 25% of the behavioral activity of PCP. Of the remaining p-phenyl- substituted analogs which never exhibited more than 10% of the behavioral potency of PCP, only 1-(1-p-nitrophenylcyclohexyl)piperidine (p-NO2-PCP; 100 microM) produced a frequency-dependent prolongation of the action potential but, like the p-methoxy-, p-chloro- and p-methyl- analog, it did not block delayed rectification. The order of potencies of these analogs in blocking delayed rectification, prolonging the muscle action potential and in affecting alternation impairment and response rate depression is therefore: PCP much greater than TCP greater than p-F-PCP much greater than p-CH3-PCP = p-CH3O-PCP = p-Cl-PCP = p-NO2-PCP. Like PCP and its behaviorally active analogs, verapamil (50 microM) and bepridil (50 microM), two Ca-channel blockers, also blocked delayed rectification in frog sartorius muscles whereas nifedipine (50 microM), another Ca-channel blocker, did not.(ABSTRACT TRUNCATED AT 250 WORDS)

Scrambled DC current applied to the hind paws of rats caused an analgesic response that was inhibited by the histamine H2-receptor antagonists cimetidine, ranitidine and oxmetidine, but not by high doses of naloxone (the opiate antagonist), or other transmitter receptor antagonists. In contrast, AC current applied to all paws produced analgesia that was blocked by naloxone, but not cimetidine, showing the independence of these systems. These findings indicate a specific role for histamine and H2-receptors as mediators of endogenous non-opiate analgesia. In addition, a combination of cimetidine and naloxone did not abolish either form of footshock analgesia, implying the existence of a non-opiate, non-H2, endogenous pain-relieving system. These results also suggest that drugs capable of penetrating the brain and stimulating H2-receptors might have analgesic properties.

Amphetamine-induced lateralized activity (rotation) and nonlateralized activity (extra quarter turns) was classically conditioned in female rats using the test environment as the conditioned stimulus (CS) and 1.25 mg/kg d-amphetamine as the unconditioned stimulus. Conditioned lateralized activity extinguished more rapidly than nonlateralized activity. Also, d-amphetamine-induced nonlateralized activity was selectively decreased by a schedule of 50% partial reinforcement. These results indicate that the two d-amphetamine responses can be distinguished, that they are differentially affected by learning, and that a schedule of partial reinforcement can selectively attenuate one effect of a drug while leaving the other intact. In addition, haloperidol blocked conditioned lateralized activity; this suggests that the conditioned response may be, like the drug-induced response, mediated by dopamine.