Joseph M. Moerschbaecher

Δ9-Tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1 receptors

We investigated involvement of the autonomic nervous system in gastric motor and cardiovascular responses to delta9-tetrahydrocannabinol (delta9-THC) in anesthetized rats. Intravenously administered delta9-THC evoked long-lasting decreases in intragastric pressure and pyloric contractility, bradycardia, and hypotension. The changes in gastric motor function and bradycardia were abolished by vagotomy and ganglionic blockade, whereas spinal cord transection prevented the hypotensive response. Administered intravenously alone, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide, a putative cannabinoid CB1 receptor antagonist, evoked transient decrease in intragastric pressure, and hypertension that was associated with bradycardia. However, this agent completely blocked the gastric motor and cardiovascular responses to intravenous delta9-THC. Application of delta9-THC to the dorsal surface of the medulla resulted in small and short-lasting decreases in gastric motor and cardiovascular function. We conclude that the decrease in gastric motor function and bradycardia are partially due to an action of delta9-THC in the dorsal medulla and that intact vagal nerves are required. The hypotension was mediated through sympathetic pathways. Both gastric motor and cardiovascular effects of peripherally administered delta9-THC seem to be mediated through cannabinoid CB1 receptors.

Comparison of the effects of full and partial allosteric modulators of GABA(A) receptors on complex behavioral processes in monkeys.

Two baselines involving a repeated acquisition task were used to assess the effects of bretazenil, imidazenil, and triazolam. The first baseline was a multiple schedule of repeated acquisition and performance of conditional discriminations. In the first component, the subject acquired a four-response chain by responding sequentially on three keys in the presence of different combinations of colors and geometric forms displayed on a center key. Acquisition of the discrimination was defined by a decrease in errors as the session progressed. In the performance component, the four-response chain was the same each session. Incorrect responses in either component produced a 5 s time out during which responding had no programmed consequence. The second procedure, which has been used to evaluate the effects of drugs on memory, involved the acquisition of a discrimination, followed by a 1 h delay and a retest of the same discrimination to assess retention. Triazolam (0.32 and 0.56 mg/kg) administered alone, produced dose-related decreases in response rate in each component In addition, triazolam also produced a dose-related increase in percentage errors in acquisition with no effect in performance. Triazolam (0.32 mg/kg) eliminated retention (0 percent savings) in the memory task. Bretazenil (0.1–5.6 mg/kg) or imidazenil (0.1–1.8 mg/kg) administered alone had little or no effect on either rate of responding or accuracy in either component. Furthermore, bretazenil but not imidazenil disrupted retention at the higher doses tested. The combination of imidazenil or bretazenil with triazolam produced dose-related attenuation of the disruptive effects of triazolam on both behavioral baselines. These data suggest that the disruptive effects of benzodiazepines on learning and memory may be a function of the intrinsic efficacy of these compounds at different GABAA receptor subtypes.

Tolerance to chronic delta-9-tetrahydrocannabinol (Δ⁹-THC) in rhesus macaques infected with simian immunodeficiency virus.

Although Δ⁹-THC has been approved to treat anorexia and weight loss associated with AIDS, it may also reduce well-being by disrupting complex behavioral processes or enhancing HIV replication. To investigate these possibilities, four groups of male rhesus macaques were trained to respond under an operant acquisition and performance procedure, and administered vehicle or Δ⁹-THC before and after inoculation with simian immunodeficiency virus (SIV(mac251), 100 TCID₅₀/ml, i.v.). Prior to chronic Δ⁹-THC and SIV inoculation, 0.032-0.32 mg/kg of Δ⁹-THC produced dose-dependent rate-decreasing effects and small, sporadic error-increasing effects in the acquisition and performance components in each subject. Following 28 days of chronic Δ⁹-THC (0.32 mg/kg, i.m.) or vehicle twice daily, delta-9-THC-treated subjects developed tolerance to the rate-decreasing effects, and this tolerance was maintained during the initial 7-12 months irrespective of SIV infection (i.e., +THC/-SIV, +THC/+SIV). Full necropsy was performed on all SIV subjects an average of 329 days post-SIV inoculation, with postmortem histopathology suggestive of a reduced frequency of CNS pathology as well as opportunistic infections in delta-9-THC-treated subjects. Chronic Δ⁹-THC also significantly reduced CB-1 and CB-2 receptor levels in the hippocampus, attenuated the expression of a proinflammatory cytokine (MCP-1), and did not increase viral load in plasma, cerebrospinal fluid, or brain tissue compared to vehicle-treated subjects with SIV. Together, these data indicate that chronic Δ⁹-THC produces tolerance to its behaviorally disruptive effects on complex tasks while not adversely affecting viral load or other markers of disease progression during the early stages of infection.

Tolerance to the disruptive effects of Δ9-THC on learning in rats

Abstract Tolerance to the effects of the cannabinoid agonist Δ9-tetrahydrocannabinol (Δ9-THC) was characterized in rats responding under a multiple schedule of repeated acquisition and performance. During the acquisition component, subjects acquired a different three-response sequence each session, whereas in the performance component the sequence was the same each session. Responding was maintained under a second-order fixed-ratio 2 (FR2) schedule of food reinforcement. Acute doses of Δ9-THC (1–10 mg/kg) decreased rate and accuracy in both components, whereas doses of the cannabinoid (CB1) receptor antagonist N-(piperidin-1-yn-)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A; 0.32 and 1 mg/kg) were ineffective. While 5.6 mg/kg of Δ9-THC disrupted responding when administered acutely, tolerance to the rate-decreasing and error-increasing effects of this dose developed in both components after daily administration. When 1 mg/kg of SR141716A was substituted for Δ9-THC during chronic administration, this previously ineffective dose selectively increased within-session errors in the acquisition component of the multiple schedule. During the postchronic phase, subjects were generally less sensitive to the disruptive effects of Δ9-THC. In summary, these data demonstrated that tolerance to Δ9-THC developed across two different behavioral tasks and that learning was generally more sensitive than performance to the effects of SR141716A during chronic treatment with Δ9-THC.

Testosterone potentiates scopolamine-induced disruptions of nonspatial learning in gonadectomized male rats.

Whereas research into the effects of the gonadal hormones on learning and memory has primarily focused on estrogen in females, recent evidence suggests that testosterone can also modulate learning in males through an interaction with the cholinergic system. In the present study, the interactive effects of testosterone and scopolamine (0.1- 0.32 mg/kg), a muscarinic receptor antagonist, on complex behavioral processes were investigated in male rats trained to respond under a multiple schedule of repeated acquisition and performance. In the acquisition component, subjects acquired a different 3-response sequence each session, whereas in the performance component, they responded on the same 3-response sequence each session. Although gonadectomy did not disrupt responding in either component, gonadectomized rats were less sensitive to the disruptive effects of scopolamine on both response rate and accuracy. In contrast, after receiving exogenous testosterone replacement, these gonadectomized males were more sensitive to the behavioral disruptions produced by scopolamine (i.e., the effects of scopolamine were similar to those obtained in gonadally intact males). These results suggest that testosterone replacement can enhance scopolamine-induced behavioral effects in gonadectomized male rats responding under a multiple schedule of repeated acquisition and performance, a finding that is in contrast to those previously found for certain spatial tasks. Furthermore, the present findings suggest that testosterone may decrease the activity of the cholinergic system during nonspatial tasks and thereby work in concert with the antagonism produced by scopolamine.

Effects of pregnanolone in rats discriminating cocaine

The discriminative stimulus effects of cocaine are typically attributed to its ability to increase dopaminergic transmission, although drugs that have different mechanisms of action can substitute for cocaine and modulation of the GABA(A) receptor system has been reported to alter its discriminative effects. Therefore, a discrimination procedure was used to extend the characterization of cocaines discriminative effects and to examine the interaction between cocaine and pregnanolone, a drug that can modulate the GABA(A) receptor complex. Rats (n=15) were trained to discriminate saline from 5.6 or 10 mg/kg of cocaine under a fixed-ratio (FR) 20 schedule of food presentation. The dopamine releaser d-amphetamine and two monoamine uptake inhibitors bupropion and desipramine substituted for cocaine. In contrast, the positive GABA(A) modulators pregnanolone and lorazepam and the opioid agonist morphine did not substitute for cocaine. When administered prior to cocaine, the D(2) receptor antagonist haloperidol and pregnanolone, but not lorazepam, produced a small rightward shift of the cocaine dose-effect curve. The results of the present studies suggest that the discriminative stimulus effects of cocaine are not solely mediated by increases in dopaminergic transmission and that positive modulation of GABA(A) receptors by pregnanolone can alter these effects, albeit at doses that also decrease overall response rate.

Relative potency and effectiveness of flunitrazepam, ethanol, and beta-CCE for disrupting the acquisition and retention of response sequences in rats.

Despite the knowledge that gamma-aminobutyric acidA modulators can affect learning and memory, their capacity for disrupting each of these complex processes is rarely compared, and often mistakenly assumed to occur with identical potency. For these reasons, the effects of flunitrazepam (0.056–3.2 mg/kg), ethanol (0.25–1.5 g/kg), and ethyl-&bgr;-carboline-3-carboxylate (&bgr;-CCE; 1–17.8 mg/kg) were compared in groups of rats responding under baselines that assessed learning and memory separately. The first baseline was a multiple schedule of repeated acquisition and performance of tandem response sequences, whereas the second baseline was a retention or memory procedure where a tandem response sequence was acquired and then retested after a 30-min delay. Under both procedures, responding was maintained under a second-order fixed-ratio-2 schedule of food reinforcement, and incorrect responding (errors) produced a 5-s timeout. With regard to the effects of the three drugs on sequence acquisition (learning), all three drugs dose dependently decreased the overall response rate and increased the percentage of errors. Both flunitrazepam and &bgr;-CCE affected accuracy more potently than response rate, whereas ethanol was equipotent in affecting these two dependent measures. With regard to the effects of these drugs on sequence retention (memory), both flunitrazepam and ethanol dose dependently decreased retention at doses that had little or no effect on sequence acquisition under the multiple schedule, whereas &bgr;-CCE decreased retention and sequence acquisition similarly at the doses tested. Together, these data show that drugs with differing capacities for altering the function of gamma-aminobutyric acidA receptors differ in their capacity for disrupting the acquisition and retention of response sequences and that positive modulation of this receptor complex may be more predictive of disruptions in memory than disruptions in learning.

Overlapping but not identical discriminative stimulus effects of the neuroactive steroid pregnanolone and ethanol

Many behavioral effects of neuroactive steroids are mediated by GABA(A) receptors; however, other receptors might be involved. Ethanol has a complex mechanism of action, and many of the same receptors have been implicated in the effects of neuroactive steroids and ethanol. The goal of this study was to determine whether actions of neuroactive steroids and ethanol at multiple receptors result in similar discriminative stimulus effects. Rats discriminated 5.6 mg/kg of pregnanolone while responding under a fixed-ratio 20 schedule of food presentation. Pregnanolone, flunitrazepam and pentobarbital produced >80% pregnanolone-lever responding. In contrast, neither morphine nor the negative GABA(A) modulator beta-CCE substituted for pregnanolone up to doses that markedly decreased response rates. Ethanol substituted only in some rats; in other rats, ethanol produced <20% pregnanolone-lever responding up to rate-decreasing doses. Thus, substitution of positive GABA(A) modulators, and not morphine or beta-CCE, for pregnanolone in all rats suggests that positive modulation of GABA(A) receptors is important in the discriminative stimulus effects of pregnanolone. Although pregnanolone might have actions at other receptors, in addition to actions at GABA(A) receptors, substitution of ethanol for pregnanolone only in some rats suggests that the mechanisms of action of pregnanolone and ethanol overlap, but are not identical.

Contingent and noncontingent cocaine administration in rhesus monkeys: a comparison of the effects on the acquisition and performance of response sequences

&NA; Previous studies have suggested that the effects of contingent (response dependent) and noncontingent (response independent) cocaine administration may differ, which could limit the generality and validity of laboratory studies that use only noncontingent administration. Therefore, two separate three‐component multiple schedules of operant responding were used to examine the effects of both types of cocaine administration on the acquisition and performance of response sequences, in four rhesus monkeys. In one multiple schedule, responding under a fixed‐ratio (FR) 60 schedule was followed by intravenous (i.v.) saline or cocaine (0.0032‐0.32 mg/kg per infusion), whereas responding in the other two components (i.e. acquisition and performance) was followed by food presentation. In the second multiple schedule, the cocaine administration component consisted of a variable‐time (VT) schedule that mimicked each subjects pattern of self‐administration. When compared to saline administration, increasing infusion doses of cocaine decreased overall response rates comparably in both food‐maintained components, irrespective of the cocaine contingency. The 0.1‐0.32 mg/kg infusion doses also increased the percentage of errors in 2 of 4 subjects; however, these disruptions in accuracy were not differentially associated with the type of cocaine administration and generally occurred at doses that produced large rate‐decreasing effects. Taken together, these data suggest that the effects of cocaine on complex operant behavior in monkeys may not differ substantially as a function of contingent or noncontingent administration. Behavioural Pharmacology

Comparison of the effects of scopolamine and methylscopolamine on the performance of a fixed-ratio discrimination in squirrel monkeys.

In the presence of a stimulus behind the center key, squirrel monkeys were required to complete one of two fixed ratios (FRs) on the center key (FR 30 or FR 25). Completion of the ratio turned off the center-key stimulus and produced a stimulus behind each of the two side keys. If the completed ratio was high (e.g., FR 30), a response on the left key produced a food pellet. If the ratio was low (e.g., FR 25) a response on the right key produced food. Errors produced a brief timeout. Dose-effect curves for scopolamine (0.001-0.18 mg/kg) and methscopolamine (0.0032-5.6 mg/kg) were determined under a FR 30 vs. FR 25 discrimination, which controlled both moderate levels of accuracy and high rates of responding. Scopolamine produced a dose-related decrease in overall response rates and increase in percent errors. Methscopolamine decreased response rates and increased percent errors in a dose-related manner much like scopolamine. However, scopolamine was found to be about 10 times more potent on a mg/kg basis than methscopolamine. Scopolamine is in general considered to be centrally acting due in part to its lipid solubility. The results from these studies suggest that methscopolamine, in general considered to be peripherally acting, may also cross the squirrel monkey blood-brain barrier at high doses and produce behavioral effects comparable to those of scopolamine.