Cory S. Freedland

Effects of SR141716A, a central cannabinoid receptor antagonist, on food-maintained responding

Previous reports have indicated that administration of the central cannabinoid receptor (CB(1)) antagonist SR141716A decreases intake of highly palatable food and drink. Disruption of normal food intake has been reported only at high doses known to disrupt spontaneous behaviors. The present study was designed to determine if rates of responding for normal food were sensitive to the effects of cannabinoid receptor blockade. Adult, male Sprague-Dawley rats were trained to lever press for normal food pellets under a fixed-ratio 15 (FR 15) schedule of reinforcement. SR141716A (0.3-3.0 mg/kg) produced dose-dependent reductions in response rate. WIN 55,212-2 (0. 3 mg/kg), a high efficacy cannabinoid agonist, given as a pre-treatment to SR141716A, significantly attenuated the rate-suppressing effects of SR141716A, suggesting a principal role of CB(1) receptors in mediating these behavioral effects. These data indicate that high palatability is not necessary to observe an anorectic effect of SR141716A.

Functional consequences of the repeated administration of Δ9-tetrahydrocannabinol in the rat

The repeated administration of Delta(9)-tetrahydrocannabinol (THC) results in tolerance to many of its behavioral and physiological effects. It also produces changes in the functionality of cannabinoid receptors. What is not completely understood is how these cellular events translate into the behavioral and physiological changes that are associated with repeated cannabinoid agonist treatment. The purpose of these studies was to determine the development of changes in the patterns of functional activity, as measured by the 2-[14C]deoxyglucose method (2DG), associated with repeated THC exposure. Male Sprague-Dawley rats (n=4-5) were administered THC (vehicle or 10 mg/kg, intraperitoneally), daily for 7 or 21 days. Fifteen minutes following the final THC treatment the 2DG procedure was initiated. In separate sets of rats similarly treated with THC, locomotor activity and core body temperature were measured at corresponding time points in order to establish the behavioral profile of repeated THC administration. The acute administration of THC following 7 or 21 days of drug exposure resulted in a significant attenuation of changes in rates of glucose utilization throughout the majority of brain regions analyzed when compared to the large global decreases observed following a single administration of THC. After 7 and 21 days of treatment, cerebral metabolic rates were no longer different from vehicle-treated controls in most cortical, thalamic and basal ganglia regions. This attenuation closely paralleled the development of tolerance to the effects of THC on locomotor activity and core body temperature. However, glucose utilization remained altered in the nucleus accumbens, mediodorsal thalamus, basolateral amygdala, portions of the hippocampus and median raphe. These data suggest that the development of tolerance to the cerebral metabolic effects of THC is regionally specific and temporally distinct. The persistence of effects in limbic areas as well as portions of the hippocampal complex, however, suggests that processes such as stress, reward, and aspects of memory mediated by these brain regions may continue to be affected by THC even after prolonged THC exposure.

Functional consequences of the acute administration of the cannabinoid receptor antagonist, SR141716A, in cannabinoid-naive and -tolerant animals: a quantitative 2-[14C]deoxyglucose study

Cannabinoid systems have been shown to be involved in the regulation of ingestive behaviors. Administration of the cannabinoid antagonist, SR141716A, markedly reduces intake of sucrose solutions, food pellets, and ethanol. The purpose of the present studies was to identify the neural substrates that mediate these actions in rats using the quantitative autoradiographic 2-[14C]deoxyglucose (2-DG) method. In the first study, rats were trained to lever press in daily 15-min sessions for food pellets under a fixed-ratio schedule of food presentation. On the day of the experiment, rats received SR141716A (0, 1 or 3 mg/kg, i.p.) 15 min prior to behavioral testing, and the 2-DG procedure was initiated immediately after the operant test session. The acute administration of SR141716A dose-dependently decreased rates of responding and was accompanied by decreases in glucose utilization concentrated in the limbic system, particularly those areas mediating motivated behavior. Because the effects of SR141716A on behavior are intensified in animals tolerant to the effects of Delta(9)-THC, the purpose of the second study was to assess the effects of the SR141716A administration on food-maintained responding and rates of glucose utilization in tolerant animals. The suppression of responding was greater in tolerant than in drug-naive animals. Furthermore, decreases in cerebral metabolism were more intense and widespread. Although still concentrated in limbic regions, functional changes now included areas subserving the regulation of ingestive behavior including the hypothalamus. These data suggest that the effects of SR141716A administration shift in the tolerant animal and may involve different aspects of feeding behavior than in cannabinoid-naive animals.

Structural and Functional Neuroimaging of the Effects of Cocaine in Human and Nonhuman Primates

Cocaine abuse throughout the world continues to be a major public-health concern. Drug abuse has enormous psychological, medical, economic, and social costs. Dependence on cocaine has been associated with increased rates of incarceration, high rates of infection with HIV, impaired job performance, and significant family dysfunction. Intense research efforts over the past few decades have resulted in a greatly increased understanding of the neurobiological basis of cocaine’s effects and the adaptations that occur as a result of its chronic use and abuse.

A comparison of the behavioral effects of the repeated administration of PTT, 2β-propanoyl-3β-(4-tolyl)tropane and cocaine

Abstract In the present study the effects of the repeated administration of the novel tropane analog PTT (2β-propanoyl-3β(4-tolyl)tropane) on spontaneous locomotor activity were compared to those of cocaine. Previous reports describing the in vivo effects of PTT have focused solely on its acute effects following a single administration. In Experiment 1, PTT (1.0, 3.0 mg/kg), cocaine (30 mg/kg), or vehicle were administered intraperitoneally to male Sprague–Dawley rats daily for 10 consecutive days and locomotor activity was assessed. In Experiment 2, the locomotor effects of PTT (1.0 mg/kg) and cocaine (15 mg/kg) were assessed following 5 days of drug exposure to either PTT (1.0, 3.0 mg/kg) or cocaine (30 mg/kg) and 18 days of withdrawal. In both paradigms, PTT (1.0, 3.0 mg/kg) and cocaine (30 mg/kg) produced marked increases in locomotor activity acutely and an augmented response to drug challenge following repeated exposure, indicative of behavioral sensitization. These data indicate that, despite differences in the pharmacological profiles of PTT and cocaine, both drugs produce behavioral sensitization. These data are consistent with previous reports in the literature describing the effects of the repeated administration of other dopamine reuptake inhibitors and suggest that the development of behavioral sensitization is a uniform characteristic of this class of drugs.

Impact of Intoxication

During the past three decades, methods have been developed that provide accurate measures of brain structure and function in vivo. These methods are powerful tools for studying the effects of a wide variety of pharmacological, physiological, and psychological stimuli, and they have given us new insights into the way the brain works.