Differences in regional cerebral blood flow response to a 5HT3 antagonist in early- and late-onset cocaine-dependent subjects.

5-hydroxytryptamine 3 (5HT3) receptors are important modulators of mesostriatal dopaminergic transmission and have been implicated in the pathophysiology of cocaine reward, withdrawal and self-administration. In addition, the 5HT3 antagonist ondansetron is effective in treating early-onset, but not late-onset, alcohol-dependent subjects. To explore the role of 5HT3 receptor systems in cocaine addiction using functioning imaging, we administered ondansetron to 23 abstinent, treatment-seeking cocaine-addicted and 22 sex-, age- and race-matched healthy control participants. Differences between early- (first use before 20 years, n = 10) and late-onset (first use after 20 years, n = 10) cocaine-addicted subjects were also assessed. On two separate days, subjects were administered ondansetron (0.15 mg/kg intravenously over 15 minutes) or saline. Regional cerebral blood flow (rCBF) was measured following each infusion with single photon emission computed tomography. No significant rCBF differences between the cocaine-addicted and control participants were observed following ondansetron relative to saline. Early-onset subjects, however, showed increased (P < 0.001) right posterior parahippocampal rCBF following ondansetron. In contrast, late-onset subjects showed decreased rCBF following ondansetron in an overlapping region of the right parahippocampal/hippocampal gyrus. Early-onset subjects also displayed increased rCBF in the left anterior insula and subthalamic nucleus following ondansetron; late-onset subjects showed decreased rCBF in the right anterior insula. These findings suggest that the age of drug use onset is associated with serotonergic biosignatures in cocaine-addicted subjects. Further clarification of these alterations may guide targeted treatment with serotonergic medications similar to those successfully used in alcohol-dependent patients.

Altered neural cholinergic receptor systems in cocaine-addicted subjects.

Changes in the brain's cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimer's disease, schizophrenia, and depression. An emerging preclinical literature also reveals that acetylcoholine may have an important function in addictive processes, including reward, learning, and memory. This study was designed to assess alterations in cholinergic receptor systems in limbic regions of abstinent cocaine-addicted subjects compared with healthy controls. On three separate days, 23 1- to 6-week abstinent, cocaine- (and mostly nicotine-) addicted subjects and 22 sex-, age-, and race-matched control subjects were administered the muscarinic and nicotinic cholinergic agonist physostigmine, the muscarinic antagonist scopolamine, and saline. Regional cerebral blood flow (rCBF) after each infusion was determined using single photon emission-computed tomography. Both cholinergic probes induced rCBF changes (p<0.005) in relatively distinct, cholinergic-rich, limbic brain regions. After physostigmine, cocaine-addicted subjects showed altered rCBF, relative to controls, in limbic regions, including the left hippocampus, left amygdala, and right insula. Group differences in the right dorsolateral prefrontal cortex, posterior cingulate, and middle temporal gyrus were also evident. Scopolamine also revealed group differences in the left hippocampus and right insula as well as the posterior cingulate and middle temporal gyrus. Cocaine addicted and controls differ in their subcortical, limbic, and cortical response to cholinergic probes in areas relevant to craving, learning, and memory. Cholinergic systems may offer a pharmacologic target for cocaine addiction treatment.

Adrenocortical and pituitary glucocorticoid feedback in abstinent alcohol-dependent women.

BACKGROUND: The long-term ingestion of alcohol diminishes hypothalamic-pituitary-adrenal (HPA) axis reactivity in alcohol-dependent men, potentially altering future relapse risk. Although sex differences in HPA axis functioning are apparent in healthy controls, disruptions in this system have received little attention in alcohol-dependent women. In this study, we assessed the basal secretory profile of adrenocorticotropic hormone (ACTH) and cortisol, adrenocortical sensitivity in both the presence and absence of endogenous corticotropic pituitary activation, and feedback pituitary glucocorticoid sensitivity to dexamethasone. METHODS: Seven women 4- to 8-week abstinent alcohol-only dependent subjects and 10 age-matched female healthy controls were studied. All subjects were between 30 and 50 years old, not taking oral contraceptives, and were studied during the early follicular phase of their menstrual cycle. Circulating concentrations of ACTH and cortisol were measured in blood samples collected at frequent intervals from 2000 to 0800 hour. A submaximal dose of cosyntropin (0.01 microg/kg), a synthetic ACTH (1-24), was administered at 0800 hour to assess adrenocortical sensitivity. In a separate session, low-dose cosyntropin was also administered following high-dose dexamethasone (8 mg intravenous) to assess adrenocortical sensitivity in the relative absence of endogenous ACTH. In addition, the ACTH response to dexamethasone was measured to determine the pituitary glucocorticoid negative feedback. Sessions were 5 days apart, and blood draws were obtained every 5 to 10 minutes. RESULTS: Mean concentrations and pulsatile characteristics of ACTH and cortisol over 12 hours were not statistically different between the 2 groups. Healthy controls had a somewhat higher (p < 0.08) net peak, but not net integrated, cortisol response to cosyntropin relative to the alcohol-dependent women. There were no significant group differences in either the ACTH or cortisol response to dexamethasone nor in the net cortisol response to cosyntropin following dexamethasone. CONCLUSION: Significant differences in pituitary-adrenal function were not apparent between alcohol-dependent women and matched controls. Despite the small n, it appears that alcohol-dependent women do not show the same disruptions in HPA activity as alcohol-dependent men. These findings may have relevance for gender-specific treatment effectiveness.

Neural response to lidocaine in healthy subjects.

Recent studies suggest that some of cocaine's central nervous system (CNS) effects may be mediated through its sodium channel inhibiting local anesthetic properties. Local anesthetics that lack cocaine's strong affinity for the dopamine transporter (DAT) also produce sensory and mood effects, further suggesting a role for this neural pathway. Due to an absence of affinity at the DAT, the local anesthetic lidocaine may offer the potential to assess sodium channel activity in vivo in humans. To assess the utility of lidocaine as a CNS probe, we determined regional cerebral blood flow (rCBF) with single photon emission computed tomography (SPECT) following the intravenous administration of lidocaine (0.5 mg/kg) and compared this response to procaine (0.5 mg/kg and 1.0 mg/kg), a local anesthetic with partial affinity for the DAT, and saline. Infusions were administered in nine healthy female controls over a 10-day period with at least 2 days between each scan. Increased rCBF was observed following lidocaine, relative to saline, in the insula, caudate, thalamus, and posterior cingulate. Decreased rCBF was detected in a different region of the posterior cingulate. In general, increases in rCBF were more marked following lidocaine relative to procaine. Mood and sensory changes following lidocaine were limited and significantly less than those induced by either dose of procaine. There were no significant changes in blood pressure or heart rate following either medication. These findings suggest that lidocaine can be safely used to assess sodium channel function in persons with addictive and other psychiatric disorders.

Sex differences in medial and lateral orbitofrontal cortex hypoperfusion in cocaine-dependent men and women.

BACKGROUND: The different clinical trajectories of cocaine-dependent men and women may be a consequence of distinct neurobiological substrates. Hypoperfusion of the orbitofrontal cortex (OFC) has previously been reported in individuals addicted to cocaine and has been posited as a biological mediator of relapse due to impulsivity or impaired decision making. OBJECTIVE: This study assessed regional cerebral blood flow (rCBF) between abstinent cocaine-dependent men and women and sex-matched healthy controls. METHODS: Cocaine-dependent subjects were abstinent from cocaine for 11 to 28 days and had no other major mental health or substance use disorders. rCBF was assessed with single photon emission computed tomography after administration of a placebo saline infusion. A resting scan was also obtained in a subset of cocaine-dependent and control men. RESULTS: In the 35 cocaine-dependent and 37 healthy control subjects examined, a sex-by-group effect was observed for the left lateral (P=0.001), right lateral (P=0.002), and medial (P<0.02) OFC. Cocaine-dependent men demonstrated significantly lower right and left lateral, but not medial, OFC rCBF compared with sex-matched healthy controls after placebo infusion (P

Striatal dopamine transporter availability with [123I]beta-CIT SPECT is unrelated to gender or menstrual cycle.

OBJECTIVES: The effect of gender and female menstrual cycle on human striatal dopamine transporters (DATs) was investigated with single-photon emission computed tomography (SPECT) using the ligand 2beta-carbomethoxy-3beta-(4-[(123)I]iodophenyl)tropane. METHODS: Ten female subjects aged 18-40 years (25.3+/-7.3 years) were scanned twice during the early follicular and the mid-luteal phases to detect any hormone-mediated changes in DAT availability in the striatum or serotonin transporter (SERT) availability in brainstem-diencephalon. Plasma estradiol and progesterone levels were obtained at the time of SPECT and confirmed the expected increases from the follicular to the luteal phases. Finally, in a post hoc analysis of a previously published healthy-subject sample, striatal DAT availability was compared between 70 male and 52 female subjects who ranged in age from 18 to 88 years. RESULTS: In the ten menstrual cycle subjects, DAT availability (V(3)'') in striatum and SERT availability in brainstem-diencephalon did not differ between follicular and luteal phases. Moreover, change in V(3)'' for striatum or brainstem-diencephalon was uncorrelated with change in plasma estradiol or progesterone from the follicular to the luteal phase. In the larger healthy-subject sample, there was no significant effect of gender or the interaction of age and gender on striatal V(3)''. CONCLUSIONS: These findings suggest that in using DAT or SERT ligands in the study of neuropsychiatric disorders, matching of female subjects according to a menstrual cycle phase is unnecessary. Although the present investigation did not confirm previous reports of gender differences in striatal DAT availability, controlling for gender in such studies still seems advisable.

Regional cerebral blood flow in female cocaine-addicted subjects following limbic activation.

BACKGROUND: Cocaine dependence follows a different disease course in men and women, possibly as a consequence of sex-specific neurobiologic responses to chronic cocaine use. We have previously reported that male cocaine-dependent subjects demonstrate a significantly different limbic response to the limbic-stimulus procaine, as measured by regional cerebral blood flow (rCBF), compared with male controls. In this study, we assessed the limbic rCBF response to procaine in female cocaine-addicted subjects (n=10) and female controls (n=10). METHODS: Subjects were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Single photon emission computed tomography (SPECT) was used to compare the rCBF response to procaine. RESULTS: Female cocaine-dependent subjects demonstrate a markedly muted, and distinctly different, limbic response to procaine compared with matched healthy controls. CONCLUSIONS: The rCBF response to procaine in female cocaine-dependent subjects suggests significant CNS differences compared with non-addicted female controls. Coupled with findings previously observed in male cocaine-dependent subjects, these biologic differences suggest that both male and female subjects experience alterations in limbic responsiveness following the chronic use of cocaine.

Resting regional cerebral blood flow and gambling task performance in cocaine-dependent subjects and healthy comparison subjects.

OBJECTIVE: Orbitofrontal cortex regional cerebral blood flow (rCBF) is lower in cocaine-dependent subjects than in non-cocaine-dependent subjects. Performance on the Gambling Task, a test of decision making, is a putative correlate of orbitofrontal cortex activity and is reportedly impaired in drug-dependent subjects. The authors tested the hypothesis that lower Gambling Task scores would be associated with lower resting orbitofrontal cortex rCBF in cocaine-dependent subjects. METHOD: Fifteen healthy comparison subjects and 13 abstinent cocaine-dependent subjects underwent resting single photon emission computed tomography to measure rCBF, after which they completed the Gambling Task. RESULTS: Resting anterior cingulate and left dorsolateral prefrontal cortex rCBF significantly correlated with performance on the Gambling Task, but orbitofrontal cortex rCBF did not. Left dorsolateral prefrontal cortex rCBF was lower in the cocaine-dependent subjects than in the comparison subjects. CONCLUSIONS: Resting anterior cingulate and dorsolateral prefrontal cortex rCBF is significantly related to decision making, as assessed by the Gambling Task.

Gender differences in limbic responsiveness, by SPECT, following a pharmacologic challenge in healthy subjects.

Limbic system functioning is integral to the control and modulation of affect, motivation, reward, and memory. Neuropsychiatric disturbances involving disruptions in these cognitive and emotional dimensions exhibit different prevalence rates for men and women. Gender-specific differences in this integrated brain area may therefore be important in understanding both normal behavioral functioning and the etiologic underpinnings of neuropsychiatric disorders. To further explore such differences in limbic system function, we assessed regional cerebral blood flow, by SPECT, in men and women following the administration of procaine. Procaine is a local anesthetic that preferentially stimulates limbic structures. Psychiatrically and medically healthy, age-matched women (n = 15, 33.2 +/- 6.9 years) and men (n = 15, 32.8 +/- 6.9 years) were administered 1.38 mg/kg procaine or saline intravenously in two separate sessions. Using voxel-based analyses (P < 0.001), males significantly activated the bilateral insular cortex following procaine, whereas females more strongly activated the bilateral anterior and mesial temporal cortex. Both groups demonstrated significant anterior cingulate activation. Subjective responses to procaine did not significantly differ between the men and women. To our knowledge, this is the first report demonstrating gender-specific responses in limbic activation following a pharmacologic challenge. These findings suggest that men and women can activate different limbic structures following the same provocative pharmacologic stimulus, despite sharing a similar subjective experience. Studies assessing pharmacologic challenges of limbic system structures should consider gender as a critical variable in assessing biologic responsiveness.

Dose-response measures of rCBF and subjective changes following procaine in healthy female volunteers.

The intravenous administration of procaine shows relatively specific activation of limbic structures. Several investigators have utilized this property of procaine to probe limbic system dysfunction in neuropsychiatric disorders. The dose of procaine utilized in human studies varies significantly, however, and the optimal dose of procaine as a limbic probe has not been demonstrated. In two 10-individual groups of healthy female volunteers, we assessed the regional cerebral blood flow (rCBF) response, by single-photon emission computed tomography (SPECT), to saline and 1.38 mg/kg procaine (Group I), and saline, 0.5 mg/kg and 1.0 mg/kg procaine (Group II). Compared to saline, 0.5 mg/kg procaine produced minimal rCBF changes, 1.0 mg/kg procaine induced both limbic and non-limbic activation, and 1.38 mg/kg procaine showed relatively specific rCBF limbic activation. Subjective responses increased in a dose-response manner. We conclude that a dose of 1.38 mg/kg procaine provides a more limited and specific activation of limbic structures than 1.00 mg/kg procaine and thus may be more useful as a specific probe of limbic function.