Effects of SR141716A on ethanol and sucrose self-administration.

BACKGROUND: Previous studies have demonstrated that administration of central cannabinoid receptor (CB1) ligands can produce marked effects on ingestive behaviors. However, the possible relationship to ethanol self-administration has not been fully examined. The present series of experiments was designed to characterize further the role of CB1 receptors in appetitive and consummatory behaviors related to sucrose and ethanol. METHODS: To determine the relative contribution of CB1 receptors to ethanol seeking and consumption, a series of experiments was designed using the sipper-tube model. In this paradigm, the appetitive and consummatory phases of ethanol and sucrose self-administration are separated. In the appetitive phase, animals are required to complete a response requirement (16 lever presses) within 20 min. If the requirement is successfully completed, access to a sipper tube containing either sucrose or ethanol (consummatory phase) is made available for 20 min. RESULTS: In the ethanol condition, the CB1 receptor antagonist SR141716A (0.3-3.0 mg/kg, ip) produced dose-related decreases in the probability of response requirement completion without significantly affecting latency to first lever press or overall lever press rate. In the sucrose condition, SR141716A (0.3-3.0 mg/kg, ip) increased first lever press latency without affecting lever press rate. In the consummatory phase, SR141716A (0.3-3.0 mg/kg, ip) administration markedly decreased total intake and the total number of licks for both ethanol and sucrose. CONCLUSIONS: These data indicate that CB1 receptors are involved in mediating both appetitive and consummatory aspects of ingestive behaviors related to sucrose and ethanol.

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.

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

In the present study the effects of the repeated administration of the novel tropane analog PTT (2beta-propanoyl-3beta(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.

Self-administration of two long-acting monoamine transport blockers in rhesus monkeys.

RATIONALE: 2beta-propanoyl-3beta-(4-tolyl)-tropane (PTT) is a cocaine analog with high affinity at and selectivity for the dopamine transporter (DAT). 2beta-propanoyl-3beta-(2-naphthyl)-tropane (HD-23), like cocaine, binds with approximately equal affinity to the DAT, the serotonin transporter, and the norepinephrine transporter but has over a 100-fold higher affinity for these monoamine transporters than cocaine. The reinforcing effects of these drugs have not been evaluated in cocaine-na nonhuman primates. OBJECTIVE: The primary goal of the present study was to examine the reinforcing effects of PTT and HD-23 in rhesus monkeys before and after a history of intravenous cocaine self-administration. METHODS: Monkeys (n=4) were initially trained to respond under a fixed-ratio 30 schedule of food presentation. When responding was stable, saline, PTT (0.001-0.03 mg/kg per injection), and HD-23 (0.0003-0.0056 mg/kg per injection) were made available for self-administration for least five sessions per dose. Next, a cocaine dose-effect function (0.0003-0.3 mg/kg per injection) was determined and then

Behavioral profile of constituents in ayahuasca, an Amazonian psychoactive plant mixture.

Ayahuasca is a psychoactive plant mixture typically composed of the beta-carboline-rich Banisteriopsis caapi vine and the hallucinogenic plant Psychotria viridis. Ayahuasca has long been used by aboriginal populations for its putative spiritual and medicinal benefits. Although the presumed primary chemical constituents of ayahuasca have been identified, little is known about the basic in vivo pharmacology of the extract. Two principal constituents of ayahuasca, the beta-carboline harmine and N,N-dimethyltryptamine (DMT) were selected for detailed study in mice using the Functional Observational Battery (FOB). The B. caapi extract was then examined alone and in combination with DMT. Harmine and the B. caapi extract produced similar effects in the FOB, particularly in the open field. Clonic and tonic motor movements were augmented by DMT administration. Harmine and B. caapi decreased acoustic startle amplitude without significantly affecting prepulse inhibition. DMT appeared to attenuate startle-decreasing effects of harmine and B. caapi, although these effects fell just short of significance. These results suggest that the behavioral effects of B. caapi in mice may be attributed in large part to its principal alkaloid species, harmine, and related beta-carbolines in the extract. Hence, the presence of the banisteriopsis vine in the admixture may directly contribute to the unique subjective effects of ayahuasca.

The role of monoamine neurotransmitter systems in the nicotine discriminative stimulus.

Nicotine serves as a reinforcer and induces a robust discriminative stimulus which is primarily mediated by neuronal nicotinic receptors. As a secondary effect of nicotinic stimulation, nicotine elicits an enhanced release of the biogenic amine neurotransmitters dopamine, norepinephrine and serotonin. In particular, compounds with dopaminergic activity have been reported to modify both the reinforcing and discriminative stimulus properties of nicotine. The present study examined a number of dopaminergic, noradrenergic and serotonergic compounds for their effectiveness in reproducing or modifying the stimulus properties of nicotine in rats. The non-selective dopamine agonists amphetamine, cocaine and apomorphine produced partial substitution for nicotine, while the selective D2/D3 agonists bromocriptine and 7-OH-DPAT and the dopamine autoreceptor antagonist (+)-AJ-76 had little effect. The substitution of amphetamine for nicotine was not blocked by haloperidol, suggesting a minimal role for D2 receptors in the nicotine-like discriminative effects of stimulants. The selective D1 agonist SKF 81,297 produced partial substitution for nicotine (45% maximum), but further experiments with the D1 antagonist SCH 23,390 and with rats trained in a three-way discrimination procedure failed to support a primary role for this receptor in the substitution of dopaminergic drugs for nicotine. Finally, tests of compounds with effects on noradrenergic or serotonergic neurotransmission did not yield strong evidence for the involvement of these systems. Taken together, these data support earlier suggestions that activation of dopamine receptor subtypes plays a role in the nicotine-like stimulus properties of abused stimulants, but do not clearly identify a single subtype that is uniquely responsible.