Faculty Bibliography

In this study, we investigated whether treatment with L-deprenyl, a selective monoamine oxidase B (MAO B) inhibitor, also inhibits MAO A or the dopamine transporter in the human brain. Six normal volunteers (age 46+/-6 yrs) had two PET sessions, one at baseline and one following L-deprenyl (10 mg/day) for 1 week. Each session included one scan with [11C]clorgyline (to assess MAO A) and one scan 2 hours later with [11C]cocaine (to assess dopamine transporter availability). A 3-compartment model was used to compare the plasma-to-brain transfer constant, K1 (a function of blood flow) and lambdak3 (a kinetic term proportional to brain MAO A) before and after treatment. Dopamine transporter availability was measured as the ratio of distribution volumes of the striatum to cerebellum (DVR) which is equal to Bmax/KD +1. L-Deprenyl treatment for 1 week did not affect either brain MAO A activity or dopamine transporter availability. There was a non-significant trend for an increase in K1 after L-deprenyl. These results confirm that L-deprenyl after one week of treatment at doses typically used clinically is selective for MAO B and that it does not produce a measurable affect on the dopamine transporter, suggesting that MAO A inhibition and dopamine transporter blockade do not contribute to its pharmacological effects

RATIONALE: Previous studies indicate that chronic food restriction augments the rewarding and motor-activating effects of diverse drugs of abuse. The drugs that have so far proved susceptible to the augmenting effect of food restriction all increase synaptic concentrations of dopamine (DA). It is not known whether behavioral effects of selective, direct DA receptor agonists are also subject to the augmenting effect of food restriction. OBJECTIVES: The first objective of this study was to investigate whether the rewarding and locomotor-activating effects of the D1 agonist, A77636, and the D2 agonist, quinpirole are augmented by chronic food restriction. The second purpose was to investigate whether the augmented rewarding and locomotor-activating effects of d-amphetamine in food-restricted rats are reversed by the D1 antagonist, SCH23390. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. Locomotor-activating effects were measured in terms of the number of midline crossings exhibited by rats in a shuttle apparatus. RESULTS: A77636 (1.0 and 2.5 mg/kg, i.p.) produced a greater threshold-lowering effect in food-restricted than ad libitum fed rats but produced variable effects on locomotor activity with no difference between groups. Quinpirole (0.2 and 0.5 mg/kg, i.p.) produced a marginally greater threshold-lowering effect in food-restricted rats and a dramatic locomotor response that was exclusive to food-restricted rats. The D1 antagonist, SCH23390, at a dose of 0.01 mg/kg (i.p.), had no effect on the lowering of LHSS threshold by amphetamine (0.5 mg/kg, i.p.) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. SCH23390, at a dose of 0.025 mg/kg, had no effect on locomotor activity induced by amphetamine (0.5 mg/kg) in ad libitum fed rats but blocked the augmentation otherwise observed in food-restricted rats. CONCLUSIONS: These results indicate that the augmentation of reward by food restriction extends to drugs that bypass the DA terminal and act postsynaptically. When taken together with prior immunohistochemical and behavioral findings, these results suggest that food restriction may increase the 'enabling' effect of the D1 receptor on DA-mediated behaviors

Prepulse inhibition (PPI) of startle is a sensorimotor gating task in which a low-intensity acoustic stimulus presented prior to a high-intensity, startle-eliciting stimulus can attenuate the acoustic startle response (ASR). Previous studies on startle reactivity in cocaine-withdrawn rats have found minimal changes; the present study extends this work to the gating of ASR. In Experiment 1, rats were injected daily with either saline or cocaine (30 mg/kg i.p.) for 2 weeks. ASR and PPI were measured prior to, and at 3- and 14-day withdrawal from, the chronic treatment. No effect of cocaine treatment was found on either measure. In Experiment 2, treatment was extended to 8 weeks, and an earlier withdrawal time point (1 day) was added. Rats treated with cocaine for 8 weeks exhibited lower startle reactivity during withdrawal compared with saline-treated controls. PPI did not differ between treatment groups. Thus, extended chronic treatment with cocaine rendered significant effects on startle responsivity. Further, this finding mirrors the blunted ASR exhibited in chronic cocaine users [Neuropsychopharmacology 22 (2000) 89.]

OBJECTIVE: The purpose of this study was to evaluate the extent to which demographic, sexual, and non-injection drug use practices predict adolescent initiation of injection drug use. METHODS: Street recruited injection drug users 15-30 years of age in Baltimore, Maryland, who initiated injection within five years of study enrollment, completed a questionnaire that included a year-by-year history regarding the five years prior to initiation of injection. Factors associated with initiation during adolescence (< or = 21 years of age) versus young adulthood (>21 ) were determined using logistic regression. RESULTS: Of 226 participants, most were female (61%) and African American (64%). Median age of participants was 25; median age at initiation of injection was 23. Factors significantly associated with adolescent initiation in multivariate analysis included race other than African American, and practices prior to initiating injection including condom use, lack of cocaine use, exclusive crack smoking just prior to initiation, and smoking marijuana. Adolescent initiates also had shorter durations of illicit drug use prior to initiating injection. CONCLUSION: Short-term non-injection drug use, particularly exclusive crack smoking, was associated with adolescent initiation of injection drug use. Early prevention efforts targeting this high-risk group of younger drug users are warranted in order to delay or prevent onset of injection drug use.

Electrophysiological studies suggest that drug therapy of anxiety/depression involves regionally-specific changes in 5-HT1A receptor sensitivity. Furthermore, the purported net effect of clinically-relevant repeated drug treatment is enhancement of hippocampal 5-HT neurotransmission. Depending on the drug, decreased sensitivity of inhibitory somatodendritic autoreceptors, increased sensitivity of postsynaptic hippocampal receptors, or both, occurs after 2-3 weeks of treatment. This hypothesis was tested using autoradiographic analysis of agonist-stimulated (35S)GTPgammaS binding. Groups of rats were treated with saline, fluoxetine, 10; imipramine, 10; clorgyline, 1; or ipsapirone, 2X20 mg/kg for 21 days and sacrificed on day 22. Quadruplicate serial sections were incubated under standard conditions as described previously (JPET 292:684, 2000) in the presence or absence of 3 muM N,N-dipropyl-5-carboxamidotryptamine. Three brain regions were examined: dorsal raphe (DR; somatodendritic), and dorsal hippocampus (DH) and lateral septum (LS) (postsynaptic). Only imipramine (+17%) and (unexpectedly) fluoxetine (+54%) significantly increased agonist-stimulated binding in DH. All drugs except imipramine decreased binding in DR (-20 to -40%). While the results support the concept of net enhancement of hippocampal 5-HT neurotransmission, the pattern of changes in receptor sensitivity differed somewhat from the results of electrophysiological studies. The most consistent and striking effect, however, was a decrease in (35S)GTPgammaS binding in the LS by all four drug treatments (-14 to -23%), a finding previously reported also after chronic buspirone treatment

RATIONALE: Chronic food restriction augments the self-administration and locomotor stimulating effects of opiates, psychostimulants and NMDA antagonists. The extent to which these effects can be attributed to changes in drug pharmacokinetics and bioavailability versus sensitivity of the neuronal circuits that mediate the affected behavioral functions, has not been established. Recent studies point to central adaptive changes insofar as rewarding, locomotor and c-fos-inducing effects of amphetamine and MK-801, injected directly into the lateral ventricle, are greater in food-restricted than ad libitum fed rats. The increased expression of c-fos in nucleus accumbens (NAC) shell, in particular, suggests that food restriction may augment drug reward by modulating dopamine (DA) synaptic function in this area. OBJECTIVES: The first purpose of this study was to investigate whether the rewarding effects of cocaine and the delta1 opioid agonist DPDPE, both of which increase DA synaptic transmission, are augmented by food restriction. The second purpose was to determine whether the delta2 opioid agonist, deltorphin-II, which has been reported to exert DA-independent rewarding effects, is subject to the potentiating effect of food restriction. METHODS: Rewarding effects of drugs were measured in terms of their ability to lower the threshold for lateral hypothalamic self-stimulation (LHSS) using a rate-frequency method. RESULTS: In separate experiments, cocaine (50, 100 and 150 microg, ICV) and DPDPE (10 and 25 microg, ICV) produced greater threshold-lowering effects in food-restricted than ad libitum fed rats. Deltorphin-II (5.0, 10 and 25 microg, ICV) had no effect on reward thresholds, regardless of feeding regimen. CONCLUSIONS: While the reported DA-independence of deltorphin-II rewarding effects seemed to offer a means of testing the hypothesis that DA transmission is the critical modulated variable in food-restricted subjects, rewarding effects of this compound could not be demonstrated in the LHSS paradigm. The present results do, however, confirm and extend prior findings indicating that the enhanced self-administration of abused drugs by food-restricted subjects is due to enhanced sensitivity of a final common pathway for drug reward