Alan S. Bloom

Neural correlates of high and craving during cocaine self-administration using BOLD fMRI.

Modern theories of drug dependence hold the hedonic effects of drug-taking central to understanding the motivation for compulsive drug use. Previous neuroimaging studies have begun to identify brain regions associated with acute drug effects after passive delivery. In this study, a more naturalistic model of cocaine self-administration (SA) was employed in order to identify those sites associated with drug-induced high and craving as measures of reward and motivation. Non-treatment seeking cocaine-dependent subjects chose both when and how often i.v. cocaine administration occurred within a medically supervised SA procedure. Both functional magnetic resonance imaging (fMRI) data and real-time behavioral ratings were acquired during the 1-h SA period. Drug-induced HIGH was found to correlate negatively with activity in limbic, paralimbic, and mesocortical regions including the nucleus accumbens (NAc), inferior frontal/orbitofrontal gyrus (OFC), and anterior cingulate (AC), while CRAVING correlated positively with activity in these regions. This study provides the first evidence in humans that changes in subjective state surrounding cocaine self-administration reflect neural activity of the endogenous reward system.

Neural responses to acute cocaine administration in the human brain detected by fMRI

An improved functional MRI (fMRI) method for the reduction of susceptibility artifacts has been utilized to measure blood oxygen level-dependent (BOLD) responses to acute cocaine administration in the human brain of cocaine users. Intravenous administration of cocaine (20 mg/70 kg) activated mesolimbic and mesocortical dopaminergic projection regions and showed temporal positive or negative BOLD responses. These results obtained from human cocaine users supported the involvement of the dopaminergic pathway in cocaine addiction from animal models. In addition, the cocaine administration also induced activations in the hierarchical brain networks in the anterior prefrontal cortex (aPFC) of the Brodmann area 10 (BA10) and orbitofrontal cortex (OFC). It is suggested that the dopaminergic pathways and the hierarchical brain networks may participate in mediating cocaine reward processes, associative learning, motivation, and memory in cocaine addiction in the human brain.

A comparison of some pharmacological actions of morphine and Δ9-tetrahydrocannabinol in the mouse

The effects of morphine and Δ9-tetrahydrocannabinol (THC) on the tail-flick reflex, body temperature, and catecholamine synthesis were examined in the mouse in order to compare their effects in a single species and strain under uniform conditions. Naloxone antagonism of THC and cross-tolerance between morphine and THC were also studied. Both morphine and THC produced antinociception, hypothermia, and increased catecholamine synthesis at 30 min after s.c. injection. Morphine produced greater increases in dopamine synthesis and was a more potent antinociceptive agent, while THC produced greater increases in norepinephrine synthesis and was a more potent hypothermic agent. Naloxone pretreatment (1 mg/kg) partially antagonized the hypothermia and increase in catecholamine synthesis produced by THC. There was also crosstolerance between morphine and THC, but it was asymmetric in that THC-tolerant animals were crosstolerant to only the hypothermic action of morphine and morphine-tolerant animals cross-tolerant to only the antinociceptive action of THC.

Determination of Drug-Induced Changes in Functional MRI Signal Using a Pharmacokinetic Model

As the applications of functional magnetic resonance imaging (fMRI) expand, there is a need for the development of new strategies for data extraction and analysis that do not require the presentation of stimuli in a repeated on/off pattern. A description and evaluation of a method and computer algorithm for the detection and analysis of brain activation patterns following acute drug administration using fMRI are presented. A waveform analysis protocol (WAP) input function has been developed that is based upon the single‐dose pharmacokinetics of a drug of interest. As a result of this analysis, regional brain activation can be characterized by its localization and intensity of activation, onset of action, time to peak effect, and duration of action. A global statistical test for significant drug effects based upon the probability of a voxel being activated by a saline vehicle injection is applied to grouped data on a voxel by voxel basis. Representative data are presented using nicotine as a prototypical agent. Using this method, statistically significant drug‐induced brain activation has been identified in several key cortical and subcortical brain regions. Hum Brain Mapping 8:235–244, 1999.

Effect of Intraventricular β-Endorphin and Morphine on Hypothalamic-Pituitary-Adrenal Activity and the Release of Pituitary β-Endorphin

The effects of intraventricular (i.v.t.) morphine sulfate (MS) and beta-endorphin (beta-EP) on pituitary-adrenal activity and the release of pituitary beta-EP were studied in rats. Pituitary-adrenal activity was monitored by measuring plasma corticosterone (CS) levels. 45 min after i.v.t. injection, both MS and beta-EP caused dose-related increases in plasma CS, with beta-EP being approximately ten times more potent on a molar basis. MS injected i.v.t. at 0.3, 1.0, 3.0 and 10.0 microgram did not cause a significant reduction in pituitary immunoreactive (i.r.) beta-EP, but did cause an increase in plasma i.r. beta-EP at 3 microgram of MS. beta-EP injected i.v.t. at 1.5 microgram caused a reduction of pituitary i.r. beta-EP. Since i.v.t.-injected beta-EP may have contributed to the measured plasma i.r. beta-EP, a nonimmunoreactive analog (Des-Asn20-beta c-EP) was used to assess the change in plasma i.r. beta-EP. 5 microgram of DES-Asn20-beta c-EP injected i.v.t. caused increases in plasma i.r. beta-EP and CS, as well as a 40% reduction in pituitary i.r. beta-EP. The concomitant intraperitoneal (i.p.) injection of naloxone HCl (10 mg/kg) significantly blocked the increase in plasma CS induced by 5 microgram of beta-EP. When naloxone HCl, 10 mg/kg was injected alone, a significant increase in plasma CS was found. The results indicate that i.v.t. beta-EP is more potent than MS in causing the release of pituitary ACTH and beta-EP. These findings are consistent with a role for brain endorphins in the regulation of CRF release.

Expectation Modulates Human Brain Responses to Acute Cocaine: A Functional Magnetic Resonance Imaging Study

BACKGROUND Human expectation of psychoactive drugs significantly alters drug effects and behavioral responses. However, their neurophysiological mechanisms are not clear. This study investigates how cocaine expectation modulates human brain responses to acute cocaine administration. METHODS Twenty-six right-handed non-treatment-seeking regular cocaine abusers participated in this study. Changes in blood oxygenation level-dependent (BOLD) signals were measured, and online behavioral ratings during cocaine expectation and acute cocaine administration were recorded. RESULTS Distinct regional characteristics in BOLD responses to expected and unexpected cocaine infusions were observed in the medial orbitofrontal gyrus (Brodmann area [BA] 11), frontal pole (BA 10), and anterior cingulate gyrus regions. Active engagement in the amygdala and the lateral orbitofrontal cortex (OFC; BA 47) by unexpected but not expected cocaine infusion was discovered. Cocaine expectation did not change BOLD responses to acute cocaine administration in a set of subcortical substrates, the nucleus accumbens, ventral putamen, ventral tegmental area, and thalamus. CONCLUSIONS These results suggest that cocaine expectation modulates neural-sensitivity adaptation between the expected events and the actual outcomes but did not modulate the pharmacological characteristics of cocaine. In addition, the amygdala-lateral OFC circuitry plays an important role in mediating stimulus-outcome relations and contextual factors of drug abuse.

A pharmacological study of pyrethroid neurotoxicity in mice

Abstract Permethrin ( cis-, trans- , and technical grade [tech.]) and deltamethrin, representatives of the non-cyano- and cyano-containing classes of synthetic pyrethroids, produced neurotoxic symptoms when administered to mice. ED 50 values for this effect were compared following intracerebroventricular (icv) or peripheral (iv) injection. Both permethrin and deltamethrin showed large increases in potency following icv administration, suggesting a mainly central site of action for both classes of pyrethroid. Pretreatment of mice with drugs affecting central noradrenergic, cholinergic, or serotonergic transmission was demonstrated to potentiate the toxic response to iv injections of tech.-permethrin, while some symptoms of toxicity could be partially alleviated by ip pretreatment with diazepam, aminooxyacetic acid, or cycloheximide.

Cannabinoid-Induced Alterations in Regional Cerebral Blood Flow in the Rat

A specific receptor for cannabinoids has been characterized at the pharmacological, molecular, and neuroanatomical level. However, less is known of the functional localization in the brain for the behavioral and physiological actions of these drugs. We have examined the effects of delta 9-tetrahydrocannabinol (THC) and its active metabolite 11-OH-THC on regional cerebral blood flow in the rat in order to determine functional CNS sites of action for the cannabinoids. Conscious rats were injected i.v. with one of four doses of THC (0.5, 1, 4, 16 mg/kg). 11-OH-THC (4 mg/kg), or vehicle 30 min prior to sacrifice. Regional cerebral blood flow was determined autoradiographically using the freely diffusible tracer method of Sakaruda et al. Changes in regional cerebral blood flow were observed in 16 of the 37 areas measured. Decreases in regional cerebral blood flow following THC were seen in such areas as the CA1 region of the hippocampus, frontal and medial prefrontal cortex, the nucleus accumbens, and the claustrum. Thresholds for these effects ranged from 0.5 to 16 mg/kg. Areas unaffected by THC include the medial septum, ventral tegmental area, caudate, temporal, parietal and occipital cortex, and cerebellum. These data indicate that THC and its active metabolite, 11-OH-THC, cause a heterogeneous alteration in the activity of specific CNS sites, many of which are involved in the characteristic behavioral actions of THC.

Nonclassical and Endogenous Cannabinoids: Effects on the Ordering of Brain Membranes

The effects of several nonclassical cannabinoids and the endogenous cannabinoid ligand, anandam-ide on the lipid ordering of rat brain synaptic plasma membranes (SPM) were examined and compared to Δ9-tetrahydrocannabinol (Δ9-THC). SPM order was determined using fluorescence polarization. All compounds tested affected membrane ordering. Δ9-THC, CP-55,940, CP-55,244 and WIN-55212 decreased lipid ordering in SPM. Some stereospecificity was observed with Δ9-THC and WIN-55212, but not other compounds. Anandamide also decreased lipid order as did its putative precursor, arachidonic acid. In contrast to these compounds, levonantradol increased SPM lipid order. Although all pharmacologically active cannabinoids affect SPM lipid order, potency on this measure does not correlate well with their pharmacological potency. The results of this study suggest that membrane perturbation (either increases or decreases in lipid order) may be a necessary characteristic for cannabinoid pharmacological activity, but it is not a primary or sufficient determinate of action for this class of drugs.

Effects of ß-Endorphin on body temperature in mice at different ambient temperatures

The effect of intracerebroventricular injection of beta-endorphin (beta-END) on body temperature of mice was studied at ambient temperatures (Ta) of 10 degrees, 20 degrees and 31 degrees C. Doses between 0.1 and 10.0 microgram/mouse were studied. The lower (less than 1 microgram) doses of beta-END produced a hyperthermia at all Tas studied. The higher doses of beta-END produced hyper- or hypothermia depending on the Ta. The subcutaneous injection of naloxone (1 mg/kg) antagonized the high dose hypothermic effects, but not the hyperthermic effect of beta-END. These data suggest that there may be different receptors and/or sites of action for high and low doses of beta-END.