Faculty Bibliography

RATIONALE: Previous studies indicate that the D(3) dopamine (DA) receptor is preferentially expressed in limbic forebrain DA terminal areas and may mediate functional effects opposite those of the D(1) and D(2) receptor types. However, the locations of the D(3) receptors that regulate behavior, and the range of behavioral functions regulated, are not clear. OBJECTIVE: The objective of this study was to evaluate behavioral and cellular effects of the preferential D(3) dopamine receptor antagonist, U99194A. METHODS: In experiment 1, the rewarding effect of U99194A (5.0, 10.0 and 20.0 mg/kg, SC) was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) in ad libitum fed rats. To amplify a possibly weak reward signal, testing was also conducted in food-restricted rats. The ability of U99194A to alter the threshold-lowering effect of d-amphetamine was also assessed. In experiment 2, effects of U99194A on horizontal and vertical motor activity were compared in ad libitum fed and food-restricted rats. In experiment 3, effects of a behaviorally active dose of U99194A (5.0 mg/kg) on brain c-fos expression were measured and compared to those produced by d-amphetamine (0.5 mg/kg, IP). In experiment 4, the motor and cellular activating effects of U99194A were challenged with the D(1) dopamine receptor antagonist, SCH-23390 (0.1 mg/kg). RESULTS: U99194A displayed no rewarding efficacy in the LHSS paradigm. U99194A did, however, augment the rewarding effect of d-amphetamine. U99194A also produced a motor activating effect, reversible by SCH-23390, which was greater in food-restricted than ad libitum fed rats. The pattern and intensity of fos-like immunoreactivity (FLI) induced by U99194A was similar to that produced by d-amphetamine and was blocked, in caudate-putamen and nucleus accumbens, by SCH-23390. CONCLUSIONS: These results indicate that U99194A has psychostimulant-like effects on motor activity and striatal c-fos expression that are dependent upon the D(1) DA receptor. However, doses of U99194A that are adequate to stimulate motor activity and c-fos expression in striatal and limbic structures do not possess direct rewarding effects in the LHSS paradigm. Overall, these results seem consistent with the hypothesis that D(3) antagonism enhances D(1)/D(2) mediated signaling with behavioral effects dependent on both the density of D(3) receptors and the prevailing level of DA transmission in particular brain regions

Chronic food restriction and maintenance of low body weight have long been known to increase the self-administration and motor-activating effects of abused drugs. Using a lateral hypothalamic self-stimulation (LHSS) rate-frequency method, it is shown that chronic food restriction augments the rewarding (i.e., threshold lowering) effect of diverse drugs of abuse. Further, the effect is attributed to increased sensitivity of a neural substrate, rather than a change in drug bioavailability or pharmacokinetics, because it is preserved when drugs are injected directly into the lateral cerebral ventricle (intracerebroventricularly). The food restriction regimen that augments drug reward also increases the induction of c-fos, by intracerebroventricular amphetamine, in limbic forebrain dopamine (DA) terminal areas. The possibility of increased DA receptor function is suggested by findings that rewarding and motor-activating effects of direct DA receptor agonists are augmented by food restriction, and the augmented behavioral effects of amphetamine are reversed by an otherwise subthreshold dose of D-1 antagonist. Initial studies of DA receptor-mediated signal transduction, that are focused on the D-2 receptor, suggest increased functional coupling between receptor and G-protein (i.e., quinpirole-stimulated [35S]GTPgammaS binding) in dorsal striatum. Unlike behavioral sensitization induced by intermittent stress or psychostimulant treatment, which persist indefinitely following induction, the augmenting effect of food restriction abates within 1 week of restored ad libitum feeding and weight gain. The possible involvement of endocrine hormones and/or 'feeding-related' neuropeptides, whose levels change dynamically with depletion and repletion of adipose stores, is therefore under investigation. Initial tests have been limited to acute treatments aimed at attenuating the effects of hypoinsulinemia, hypoleptinemia and elevated corticosterone levels in food-restricted rats. None of these treatments has attenuated the behavioral effect of food restriction. While a melanocortin receptor agonist has been found to enhance drug reward, melanocortin receptors do not seem to mediate the augmenting effect of food restriction. Continuing investigations of endocrine adiposity signals, 'feeding-related' neuropeptides and dopaminergic signal transduction may further elucidate the way in which drugs of abuse exploit mechanisms that mediate survival-related behavior, and help explain the high comorbidity of drug abuse and eating disorders

BACKGROUND: In vivo magnetic resonance studies have found that cocaine dependence is associated with T2 signal hyperintensities and metabolite abnormalities in cerebral white matter (WM). Functional neuroimaging studies have suggested that chronic cocaine use is primarily associated with frontal lobe deficits in regional cerebral blood flow and brain glucose metabolism levels; however, the effects of cocaine dependence, if any, on frontal WM microstructure are unknown. Thus, we sought to examine the effects of cocaine dependence on frontal WM integrity. METHODS: Diffusion tensor imaging was employed to examine the WM integrity of frontal regions at four levels: 10 mm above, 5 mm above, 0 mm above, and 5 mm below the anterior commissure-posterior commissure (AC-PC) plane. The fractional anisotropy (FA) of 12 cocaine-dependent patients and 13 age-similar control subjects was compared. RESULTS: The cocaine-dependent patients had significantly reduced FA in the frontal WM at the AC-PC plane and a trend toward reduced FA at 5 mm below the AC-PC plane, suggestive of reduced WM integrity in these regions. CONCLUSIONS: These findings were consistent with the hypothesis that cocaine dependence involves alterations in orbitofrontal connectivity, which may be involved in the decision-making deficits seen in this disorder

OBJECTIVE: The goal of our study was to elucidate characteristics of persons likely to transition into injection drug use so that an identifiable group with high-risk for blood-borne infection may be targeted for interventions. METHODS: An age-matched case-control analysis was performed from a cohort study in Baltimore, 1997-1999, of street-recruited non-injection and injection drug users (IDUs), aged 15-30. Cases were IDUs injecting < or = 2 years and controls were age-matched persons who used non-injection heroin, cocaine or crack. At baseline, all were interviewed about prior year-by-year behaviors; analysis using conditional logistic regression was based on information for the year prior to injection onset for the case and the same calendar time for the controls as well as recent behaviors for both groups. RESULTS: Of 270 participants, most were African American (78%), female (61%), and HIV seroprevalence was 7% at baseline. IDUs were significantly more likely than controls to be non-African American (adjusted odds ratio (AOR)=0.09) and report high school dropout (AOR=2.32), early sex-trading (AOR=2.72), and recent violence victimization (AOR=9.28). CONCLUSION: Given that new injectors are at high-risk for HIV and hepatitis yet difficult to reach for prevention efforts, our data suggest some categories to use to target non-injectors who are likely to transition into injection use.

RATIONALE: Numerous forms of evidence support a functional association between drug-seeking and ingestive behavior. One example is the augmentation of rewarding and cellular-activating effects of abused drugs by chronic food restriction. Within the past several years, a variety of orexigenic and anorexigenic neuropeptides that mediate adaptive responses to changes in energy balance and body weight have been identified. The involvement of these neuropeptidergic signaling systems in the modulation of drug reward has received little experimental attention. alpha-Melanocyte-stimulating hormone (alpha-MSH) and agouti-related protein, which act as agonist and antagonist, respectively, at melanocortin receptors (MCRs), are of particular interest because of their neuroanatomical distribution and opponent actions at a common receptor type. OBJECTIVES: The objective of this study was to determine whether lateral ventricular (i.c.v.) injections of the MCR agonist MTII and MCR antagonist SHU9119 at doses that decrease and increase food intake, respectively, modify the rewarding effect of amphetamine. METHODS: The rewarding effect of amphetamine was measured in terms of its ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. The modulatory effects of MTII and SHU9119 were evaluated by preceding i.c.v. amphetamine injection with i.c.v. injection of one of these MCR ligands or vehicle. Tests were conducted in both ad-libitum-fed and food-restricted subjects. RESULTS: SHU9119, the agouti-related protein-like antagonist, markedly increased overnight food intake of ad-libitum-fm-fed rats following i.c.v. injection of 1.0 microg and 0.5 microg. However, these injections had no effect on thresholds for LHSS tested 25 min or 60 min post-injection, nor did they alter the threshold-lowering effect of amphetamine (50 microg) tested 25 min, 100 min, or 24 h post-injection. MTII, the alpha-MSH-like agonist, suppressed overnight food intake of ad-libitum-fed rats following i.c.v. injection of 1.0 microg. MTII had no effect on thresholds for LHSS tested 60 min post-injection. However, this MCR agonist potentiated the threshold-lowering effect of amphetamine tested 100 min but not 24 h post-injection. This effect was evident in both ad-libitum-fed and food-restricted rats. CONCLUSIONS: These results indicate that agonist activity at MCRs potentiates amphetamine reward and that the anorexigenic neuropeptide alpha-MSH may exert this effect physiologically

Predictors for the development of tardive dyskinesia (TD) have been studied extensively over the years, yet there are few studies of predictors of the course of TD after it has developed. Moreover, few studies have examined predictors of the course of other extrapyramidal side effects (EPS) in patients maintained on neuroleptics. The purpose of this study was to determine which modifiable variables are important in the prediction of EPS in patients with persistent TD over a period of as long as 2 years. One hundred fifty-eight patients enrolled in the Veterans Affairs Cooperative Study 394 were included in this study. A linear mixed-effects (LME) analysis to estimate the Abnormal Involuntary Movement Scale score (for TD severity), Simpson-Angus Scale (for parkinsonism severity), and Barnes Akathisia Scale at any given time after intake assessment was performed. The severity of each of the TD and EPS outcomes at any given visit was predicted by their respective baseline severity scores. Additional predictors of a favorable course of TD included lower doses of antipsychotic medications and use of anticholinergic medications. Other predictors of a favorable course of EPS included younger age and the use of atypical antipsychotic medication (for rigidity) and the use of anticholinergic medication (for tremor). These findings indicate that clinician-modifiable factors related to medication usage can influence the outcome of TD and EPS in patients with persistent TD

Chronic food restriction augments the rewarding, motor-and cellular-activating effects of direct and indirect dopamine (DA) agonists injected directly into the brain ventricular system. Neuroadaptations within the brain DA system that may be involved in these effects have yet to be demonstrated. In the present study, rats had ad libitum access to food or were restricted to a single 10 g meal per day until body weight decreased by 20% (approximately 2 weeks). Rats were then maintained for an additional week with body weight of the food-restricted group clamped at this value. Caudate-putamen (CPU) and nucleus accumbens (NAC) were micropunched from frozen coronal brain sections. Stimulation of (35S)GTPgammaS binding in membranes, by the D2/3 DA agonist, quinpirole, was measured using quinpirole concentrations ranging from 30nM to 100muM. The maximal stimulation observed in CPU membranes of ad libitum fed rats was 33.9% over the basal level. In CPU membranes of food-restricted rats, the concentration-response curve was shifted to the left and maximal stimulation increased to 43.9% over the basal level (p<.05). Although quinpirole also produced a concentration-related stimulation of (35S)GTPgammaS binding in NAC membranes, there was no difference between groups. These results suggest that an amplification of D2-mediated signal transduction in CPU may be involved in the augmented behavioral effects of quinpirole and various indirect DA agonists in chronically food-restricted rats

Numerous forms of evidence support a functional association between drug-seeking and ingestive behavior. We recently demonstrated that lateral ventricular injections of the melanocortin receptor agonist, MTII, potentiate the rewarding effect of amphetamine in rats (Cabeza de Vaca, et al., Psychopharm, 2002, 161:77-85). The objective of the present study was to explore the effect of MTII on the rewarding effect of cocaine (3.0 mg/kg, i.p.). Rewarding effects were measured in terms of the lowering of threshold for lateral hypothalamic self-stimulation (LHSS) using a psychophysical rate-frequency method. Results: MTII at 0.5 mg and 1.0 mg doses decreased overnight food intake by 61% and 80%, respectively. These same doses had no effect on LHSS thresholds when administered alone but potentiated the threshold-lowering effect of cocaine by approximately 53% and 67%, respectively. Initial experiments in a microinjection mapping study cast doubt on nucleus accumbens (NAC) as the site of MTII action on cocaine reward. The present results parallel the findings previously reported for another psychostimulant, d-amphetamine

Neuronal substrates that mediate the conditioned effects of cocaine have not been well characterized. To examine dopaminergic mechanisms, three antagonists were tested for their capacity to inhibit the expression of conditioned locomotor activity and conditioned place preference in rats. Antagonists were also assessed against acute cocaine-stimulated locomotor activity for comparison. For locomotor activity conditioning, six conditioning sessions were conducted over a 10-day period. Paired rats received 10 mg/kg cocaine prior to activity sessions and saline after; unpaired controls received saline prior and cocaine after. For place preference conditioning, eight conditioning sessions were conducted over a 13-day period; rats received 10 mg/kg cocaine while restricted to one of two distinct chambers and, on alternate days, they received saline in the other. Antagonists (haloperidol, raclopride and SCH23390; 0.03-0.1 mg/kg) were given only on test days for conditioned effects. All three antagonists significantly and dose-dependently attenuated the direct stimulatory effect of cocaine. SCH23390 showed a tendency to reduce the expression of conditioned locomotor activity, and only haloperidol blocked the expression of conditioned place preference. Thus, direct and conditioned stimulant effects of cocaine were shown to be differentially sensitive to dopamine receptor blockade. Further, conditioned stimulant effects differed from conditioned reinforcing effects in this regard