Susan E. Best

Altered Neural Cholinergic Receptor Systems in Cocaine-Addicted Subjects

Changes in the brains cholinergic receptor systems underlie several neuropsychiatric disorders, including Alzheimers 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.

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<or=0.001). Similar bilateral OFC decreases were observed in male cocaine-dependent subjects at rest. In contrast, cocaine-dependent women showed lower rCBF in the medial, but not lateral, OFC relative to sex-matched healthy controls after placebo infusion (P<0.01). Male cocaine-dependent subjects also showed decreased rCBF (P<0.01) in the bilateral anterolateral temporal cortex and anterior cingulate, whereas decreased rCBF was observed in female cocaine-dependent subjects in the bilateral superior frontal gyri. Large and diffuse areas of increased rCBF were observed after placebo infusion in cocaine-dependent men, but not in women, relative to sex-matched healthy controls. CONCLUSIONS rCBF appears to be reduced in the bilateral OFC in cocaine-dependent men and in the medial OFC in cocaine-dependent women. Sex differences in the medial and lateral OFC rCBF may be relevant to understanding relapse characteristics differentiating men and women addicted to cocaine.

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.

Opioid Addiction: Recent Advances in Detoxification and Maintenance Therapy

SummaryNew pharmacological treatments for opioid dependence include detoxification agents such as clonidine and lofexidine, and maintenance agents such as levacetylmethadol (levo-α-acetylmethadol; LA AM) and buprenorphine. Detoxification from opioids has been facilitated by the development of clonidine, particularly in combination with naltrexone. New experimental approaches have also been tried to reduce the time that it takes to complete the process of detoxification or to further reduce residual withdrawal symptoms not completely relieved by clonidine. Maintenance on levacetylmethadol or buprenorphine has become a viable alternative to methadone maintenance and holds promise for the future.

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.

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.

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.

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.

Neural response to lidocaine in healthy subjects

Recent studies suggest that some of cocaines central nervous system (CNS) effects may be mediated through its sodium channel inhibiting local anesthetic properties. Local anesthetics that lack cocaines 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.

SPECT following Intravenous Procaine in Cocaine Addiction

Cocaine has been shown to stimulate the limbic system in both preclinical and clinical studies, and the euphorigenic effects of cocaine have been correlated with limbic system activation. Previous investigators have suggested that a state of permanent limbic neuronal hyperexcitability may be present in cocaine addicts, such that spontaneous or cue-related episodes of limbic neuronal discharge may occur.1 Limbic discharge may subsequently induce craving in cocaine-dependent patients, precipitating relapse. Procaine has previously been shown to stimulate limbic regions in humans.2 In order to explore the phenomena of sensitization in cocaine addicts, we administered procaine to cocaine-addicted patients and healthy controls. Subjective responses and regional cerebral blood flow (rCBF), by SPECT, were assessed following both placebo and procaine infusion. We hypothesized that, as a result of cocaine-induced limbic sensitization, patients with a history of cocaine dependence would demonstrate greater procaine-induced limbic activation compared to healthy controls.