Pretranslational and posttranslational mechanisms for regulating beta-endorphin-adrenocorticotropin of the anterior pituitary lobe.

Stress-induced activation of secretion of ACTH and beta-endorphin (beta-END) from anterior lobe corticotrophs leads to both short term and longer term perturbation of the system. Immediately following an acute stress session, the rate of translation of the ACTH/beta-END precursor proopiomelanocortin appears accelerated by 50% and the rate of conversion of the precursor into products is doubled. These changes appear to take place at the translational and posttranslational level and reflect a better use of the preformed messenger RNA which compensates for the stress-induced peptide depletion. When the animal is subjected daily to the stress session, longer term mechanisms appear to emerge. The ACTH/beta-END stores in the gland are increased, apparently owing to an increase in transcription, as reflected by a small but significant increase in proopiomelanocortin messenger RNA. The posttranslational processing is no longer accelerated after further stress. This longer term mechanism appears to be pretranslational and to supplant the posttranslational mechanisms observed after acute stress. These two levels of control may represent different points in the regulation of this critical peptide system.

Pyrimidine acyclic nucleosides, 1-[(2-Hydroxyethoxy)methyl]pyrimidines as candidate antivirals.

A number of pyrimidine acyclic nucleosides were synthesized and tested for activity against herpes simplex virus type 1. Synthesis of 1-[(2-hydroxyethoxy)methyl]cytosine (8) and 1-[(2-hydroxyethoxy)methyl]uracil (14) was accomplished in two or three steps from 2,4-diethoxypyrimidine and 2-(benzoyloxy)ethoxymethyl chloride. The 5-methyl (20), 5-(trifluoromethyl) (21), and 5-fluoro (22) analogues of 14 were available in two steps form the appropriate bis(trimethylsilyl)ated 5-substituted uracil and 2-(acetoxymethoxy)ethyl acetate or 2-(benzoyloxy)ethoxymethyl chloride. Bromination of 8 and 14 or iodination of 14 gave the 5-halogeno-1-[(2-hydroxyethoxy)methyl]pyrimidines 9, 23, and 24. These pyrimidine acyclic nucleosides exhibited little or no activity against herpes simplex virus type 1 or against a range of other DNA and RNA viruses. This is compatible with their lack of substrate properties toward herpes simplex virus induced thymidine kinase.

Effect of acyclic pyrimidines related to 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine on herpesviruses.

A series of pyrimidines related to the potent antiherpetic agent 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (1, BW B759U), all containing the same acyclic chain, have been synthesized. Some of the compounds were derivatives of the naturally occurring bases, cytosine, uracil, and thymine; others included compounds in which the 5-position of the cytosine and uracil moieties were substituted by bromo, iodo, fluoro, methyl, and amino groups. Other variations of the cytosine derivatives were the 5-aza, 2-mercapto, 4-methylamino, 4-dimethylamino, and isocytosine congeners. A 4-aminopyrimidine adduct was also made. Antiviral testing showed that 1-[(1,3-dihydroxy-2-propoxy)methyl]cytosine (18, BW A1117U) was equivalent to the guanine analogue in potency against human cytomegalovirus and Epstein Barr virus. Other compounds in the series were largely inactive in antiviral screening against the herpesviruses.

Inhibition of arabinose 5-phosphate isomerase. An approach to the inhibition of bacterial lipopolysaccharide biosynthesis.

Arabinose 5-phosphate ( A5P ) isomerase is a key enzyme in the biosynthesis of lipopolysaccharide, an essential component of the outer membrane of Gram-negative bacteria. The mechanism of the isomerase is envisioned to involve an enediol intermediate. A series of compounds, which are analogues of the substrates or intermediate, were tested as inhibitors of A5P isomerase with the belief that a good inhibitor would stop bacterial growth or render the cells more susceptible to other antibiotics or natural defenses. In a series of phosphorylated sugars, the order of isomerase inhibitory activity was as follows: aldonic acids greater than alditols greater than aldoses. Nonphosphorylated sugars were much less inhibitory. The best inhibitor was erythronic acid 4-phosphate (54), which had Km/Ki = 29. None of the compounds displayed antibacterial activity in vitro.

Clinician perspective on achieving and maintaining remission in depression.

The majority of large-scale clinical trials of depression focus on response, typically defined as a 50% reduction in symptoms, as the endpoint. Response in the absence of remission places patients at greater risk for relapse, decreases their level of functioning, and erodes quality of life. Most importantly, both research and our clinical experience suggest that remission, or "getting well," is an attainable goal for patients with major depressive disorders. Pharmacotherapy, psychotherapy, and combination regimens are all treatment options. Recent studies across a range of patient populations have demonstrated the benefit of affecting multiple transmitter systems over a single antidepressant mechanism. Pooled data from more than 2000 patients comparing venlafaxine, a serotonin-norepinephrine reuptake inhibitor, and selective serotonin reuptake inhibitors suggest that the dual mechanism of action of venlafaxine provides significantly greater efficacy in achieving remission. Ultimately, achieving a good clinical outcome is desirable, but sustaining the mood state is, perhaps, more important. Studies of venlafaxine show it is possible to prevent more relapses and recurrences of depression with dual-mechanism treatment than with placebo. These data highlight the need for setting appropriately aggressive goals and working closely with our patients to achieve them. By doing so, we create the best opportunity for restoring patients to "wellness" and, ultimately, a normal and fulfilling life.

Medial septal lesions disrupt spatial, but not nonspatial, working memory in rats.

In Experiment 1, rats with small medial septal lesions were less able than were control rats to remember the location of the arm of a Y maze they had been forced to enter on the preceding sample run. Moreover, as the retention interval between the sample and choice runs on this spatial delayed nonmatching-to-sample (DNMTS) task was increased to 1 and 2 min, the magnitude of the deficit increased. In contrast, these same lesioned rats were not deficient in Experiment 2 in their ability to remember the object they had encountered in the straight alley on the sample run. In fact, when the retention interval was increased to 1 min on this nonspatial DNMTS task, the rats with medial septal lesions were more accurate than were the controls. This pattern of results did not appear to be due to task difficulty, recovery of function, or sequence of training. Rather, these results indicate that damage to the septohippocampal system disrupts spatial working memory more than it disrupts nonspatial working memory.

Lesions of the dorsomedial amygdala, but not the nucleus accumbens, reduce the aversiveness of morphine withdrawal in rats.

Small lesions of the dorsomedial amygdala reduced the magnitude of the conditioned place aversion produced by naltrexone-precipitated morphine withdrawal, whereas large lesions of the ventral nucleus accumbens had no effect. This finding that the dorsomedial amygdala, which has not been implicated in opiate reward, is involved in mediating the aversiveness of opiate withdrawal is consistent with data indicating that amygdala lesions reduce the aversiveness of a variety of aversive events. In contrast, the nucleus accumbens, which is involved in mediating the rewarding effects of opiates, does not appear to be critically involved in mediating the aversive effects of opiate withdrawal. Together, these findings suggest that the neural structures that mediate the rewarding effects of opiates may be at least partially distinct from the structures that mediate the aversive effects of opiate withdrawal.

Ventromedial septal lesions in rats reduce the effects of inescapable shock on escape performance and analgesia.

Lesions of the ventromedial septum reduced or eliminated several effects of exposure to inescapable shock in rats, whereas lesions of the dorsolateral septum did not. Experiment 1 demonstrated that ventromedial septal lesions reduced the loss in body weight produced by inescapable shock and eliminated the subsequent (24 hr later) interference with escape performance (learned helplessness). Experiment 2 demonstrated that ventromedial septal lesions reduced the analgesia that occurs immediately following inescapable shock and the analgesia reinstated by exposure to escapable shocks 24 hr later. These findings, in conjunction with the findings that ventromedial septal lesions also reduce the secretion of corticosterone (Kelsey, 1975) and stomach erosions (Kelsey, Note 1) produced by inescapable shocks, indicate that ventromedial septal lesions reduce several responses to inescapable shock and suggest that possibility that all of these effects may reflect a unitary deficit. It is hypothesized that ventromedial septal lesions reduce these effects of exposure to inescapable shock either by reducing the ability of the rats to learn that their responses and shocks were uncorrelated or by reducing the emotional impact of this lack of correlation.

Procedures that produce context-specific tolerance to morphine in rats also produce context-specific withdrawal.

Rats previously injected with morphine in the presence of a distinct environment (paired animals) were more tolerant to the analgesic effects of morphine in that environment than were rats previously injected with morphine in another environment (unpaired animals). When injected with saline instead of morphine in the distinct environment, paired animals were more reactive to pain (hyperalgesic) than unpaired animals, but no more reactive to pain than animals never given morphine. More important, the paired animals also exhibited more withdrawal symptoms (wet dog shakes, genital licking, circling, rearing, and defecation) during abstinence and naltrexone-precipitated withdrawal in the distinct environment than did the unpaired and saline animals. Thus, procedures that are capable of producing context-specific opiate tolerance are also capable of producing context-specific opiate withdrawal.

Medial septal lesions disrupt spatial mapping ability in rats.

Rats with lesions of the medial septum were more likely to begin swimming in the wrong direction, swim farther, and, therefore, require more time to find a platform hidden in a Morris water tank than were control rats. Although the performance of the rats with medial septal lesions did improve over trials, their asymptotic performance also failed to equal that of the controls. Movement of the platform to a new position in the tank disrupted the performance of both groups, and, again, the rats with medial septal lesions were slower to locate the moved platform. However, this deficit was completely eliminated when a visual cue indicating the location of the moved platform was introduced. We suggest that these data indicate that damage to the septo-hippocampal cholinergic projection system produces a deficit in the formation or utilization of a spatial map (reference memory) that represents the location of a place with respect to the surrounding distal cues.

Acute corticosterone replacement reinstates performance on spatial and nonspatial memory tasks 3 months after adrenalectomy despite degeneration in the dentate gyrus.

Long-term adrenalectomy (ADX) causes loss of spatial memory and of dentate gyrus cells. These effects are prevented by chronic replacement of corticosterone (CORT). The effects of acute replacement 3 months after ADX in rats classified as ADX or incomplete ADX (INC) on the basis of saline intake, weight, and plasma CORT levels were investigated. ADX rats swam longer and farther to find a platform in a spatial water-maze task (Exp. 1) and were impaired on a nonspatial object-recognition task (Exp. 2) compared with INC and SHAM rats. In both experiments, ADX decreased the size of the dentate gyrus, and replacement with CORT either 5 or 10 days prior to and during testing restored the performance of ADX rats without affecting the size of the dentate. CORT did not affect INC and SHAM rats. Thus, the adverse effects of ADX on memory may not be due to damage in the dentate, and the effects of CORT replacement may operate outside the hippocampus.

Context-specific morphine withdrawal in rats: duration and effects of clonidine.

Rats previously injected with morphine in a particular environment (paired rats) emitted more withdrawal symptoms in that environment than did rats previously injected with morphine in another environment (unpaired rats) after both 1 day and 5 days of morphine abstinence. Thus, reexposure to an environment previously associated with morphine can elicit context-specific withdrawal even after several days of morphine abstinence. Clonidine (0.06 mg/kg) reduced most of the withdrawal symptoms seen 5 days after morphine abstinence in both the paired and unpaired rats. However, clonidine enhanced many of the withdrawal symptoms in both groups of rats during naltrexone-precipitated withdrawal 1 day after morphine abstinence.

Lesions of the nucleus accumbens in rats reduce opiate reward but do not alter context-specific opiate tolerance.

Bilateral electrolytic lesions of the nucleus accumbens in rats eliminated the capacity of 10 mg/kg morphine to produce a conditioned place preference (Experiment 1). However, these lesions did not alter the capacity to establish context-specific tolerance to the analgesic effects of 5 mg/kg of morphine (Experiment 2). This latter finding indicates that rats with nucleus accumbens lesions are not impaired in associating the effects of morphine with a particular location. Thus, the failure of morphine to produce a conditioned place preference in these lesioned rats probably cannot be attributed to an inability to associate the effects of morphine with a particular chamber, i.e., the initially nonpreferred chamber. Rather, morphine may fail to establish a conditioned place preference in these rats because nucleus accumbens lesions disrupt a pathway that is critical in mediating the rewarding effects of opiates.

Medial septal lesions in rats enhance locomotor sensitization to amphetamine.

RATIONALE: The mesolimbic dopamine (DA) system appears to play a major role in the locomotor activating and sensitizing effects of several addictive drugs. However, less is known about the neural structures that may modulate this system. OBJECTIVE: We examined the effects of medial septal lesions on the locomotor activating and sensitizing effects of amphetamine in between-subjects (experiment 1) and within-subjects (experiment 2) experiments. RESULTS: Repeated injections of 0.6 mg/kg (experiment 1) or 1.0 mg/kg (experiment 2) amphetamine over six sessions produced more locomotion in the lesioned rats than in the sham-operated controls. This repeated exposure to amphetamine subsequently increased the locomotor response to 0.2 mg/kg (experiment 2) and 0.4 mg/kg (both experiments) amphetamine in the lesioned rats, such that these sensitized, lesioned rats moved more in response to these doses than unsensitized, lesioned rats and sensitized controls did. Both experiments also indicated that this prior sensitization enhanced the locomotor response to 0.4 mg/kg amphetamine more in the lesioned rats than in the control rats when compared with the response produced by saline following sensitization or by the same dose of amphetamine prior to sensitization. In contrast, prior exposure to amphetamine decreased the locomotor response to 4.0 mg/kg amphetamine in the lesioned rats (experiment 1). CONCLUSIONS: Although medial septal lesions occasionally enhance locomotor responses to moderate doses of amphetamine prior to sensitization, a main effect of these lesions is to further enhance the effects of locomotor sensitization to amphetamine. Implications for drug addiction are discussed.

Temporal factors in the effect of restraint stress on morphine-induced behavioral sensitization in the rat.

The role of associative factors in the effect of 15 min/day of restraint stress on morphine-induced behavioral sensitization was examined. Male rats were initially given seven systemic (10 mg/kg, IP) or intraventral tegmental area (VTA, 5 micrograms/side) [corrected] injections of morphine, and were exposed to restraint, either just prior to drug injection (Paired-Stress) or 24 h after injection (Unpaired-Stress), or to no restraint (Control). In subsequent tests for behavioral sensitization to low doses of morphine (0.75 or 3.0 mg/kg, IP), animals in the Paired-Stress condition were more active than animals in the Unpaired-Stress or Control conditions. These results indicate that temporal and possibly associative factors may contribute to stress-induced changes in sensitization to the behavioral activating effects of opioids.

Perforant path stimulation in rats produces seizures, loss of hippocampal neurons, and a deficit in spatial mapping which are reduced by prior MK-801.

Severe temporal lobe epilepsy in humans is often associated with loss of neurons in the hippocampus and memory deficits. In Experiment 1, 60 min of continuous electrical stimulation of the perforant path sufficient to produce seizures resembling status epilepticus and loss of hilar and pyramidal cells in the hippocampus, produced a deficit in spatial mapping in the Morris water tank. In particular, the previously stimulated rats took longer and swam farther to find a hidden, but not a visually cued, platform, and, in contrast to the unstimulated control rats, were not disrupted by movement of the platform to a new location. In Experiment 2, a single injection of the non-competitive NMDA receptor antagonist, MK-801 (1.0 mg/kg), just prior to the perforant path stimulation reduced the seizures, hippocampal neuronal loss, and deficit in spatial mapping. These data suggest that temporal lobe seizures can induce deficits in spatial memory by selectively destroying neurons within the hippocampus, and that the mechanism by which this occurs involves the activation of NMDA receptors, and, perhaps, consequent excitotoxicity.

Endorphin mediation of post-ictal effects of kindled seizures in rats.

Brief electrical stimulation of the enkephalin-rich globus pallidus at 1-h intervals produced kindled, clonic seizures in rats as rapidly as similar stimulation of the amygdala. Massing the kindling trials at 10-min intervals inhibited the occurrence of subsequent seizures, especially following globus pallidus stimulation. Naloxone (20 mg/kg), an opiate receptor antagonist, reversed this post-ictal inhibition of seizures following massed trials, but had no effect on seizures kindled at 1-h intervals. Thus, endorphin-released during seizures do not appear to mediate the production of kindled seizures, but do appear to mediate the transient posts ictal inhibition of seizures.

Does naloxone suppress self-stimulation by decreasing reward or by increasing aversion?

Fifty-eight rats were implanted with electrodes in the ventrolateral midbrain central gray from which both self-stimulation reward and/or stimulation-produced analgesia can be obtained. Thirty-nine cases were positive for self-stimulation; of these, 24 also displayed significant stimulation-produced analgesia and 15 did not. Injections of the opiate receptor blocker, naloxone, suppressed self-stimulation by approximately 40% at both analgesic and non-analgesic reward sites. Since naloxone failed to act preferentially at analgesic reward sites, the hypothesis that naloxone suppresses self-stimulation primarily by antagonizing endorphin-mediated analgesia, and thereby increasing the aversive properties of the brain stimulation, was not supported. Rather, the data are consistent with the hypothesis that naloxone suppresses self-stimulation by antagonizing endorphin-mediated reward.

Arcuate nucleus lesions reduce opioid stress-induced analgesia (SIA) and enhance non-opioid SIA in rats.

When rats were tested more than two weeks following surgery, lesions of the medial basal hypothalamus centered on the arcuate nucleus enhanced a form of foot-shock stress-induced analgesia (SIA) that was not blocked by injections of the opiate receptor blocker, naltrexone (6 mg/kg;). These arcuate nucleus lesions reduced the SIA produced by the same stressor when similar rats were tested 3-4 days following surgery. Finally, when similar rats were tested more than 2 weeks following surgery these lesions reduced a different form of SIA that was blocked by naltrexone. There were no effects of the lesions or naltrexone on baseline pain reactivity in any of the experiments. We suggest that arcuate nucleus lesions disrupt a system important for the elaboration of opiate-mediated SIA (Expt. 4), perhaps by damaging the brain's beta-endorphin system. In response to damage to this opioid analgesic system, we hypothesize that the damaged brain initiates time-dependent compensatory changes in an undamaged non-opioid analgesic system, resulting in enhanced non-opiate-mediated SIA.

Social phobia: diagnosis and epidemiology, neurobiology and pharmacology, comorbidity and treatment.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.