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Diphenhydramine (DPH) is an over-the-counter medication used in the treatment of allergic symptoms. While DPH abuse is infrequent, recent preclinical evidence suggests that DPH and cocaine combinations may have enhanced reinforcing properties.The aims were to assess the reinforcing effectiveness of cocaine and DPH alone or in combination under a second-order schedule of reinforcement and to examine the neurochemical basis of this interaction using in vivo microdialysis in awake rhesus monkeys.Cocaine (0.03-0.3 mg/kg per injection), DPH (0.3-3.0 mg/kg per injection), or a combination was available under a second-order schedule of intravenous drug reinforcement (n = 3). In microdialysis studies, noncontingent cocaine (0.1-1.0 mg/kg, iv), DPH (1.7 and 3.0 mg/kg, iv), or a combination was administered and changes in extracellular dopamine levels in the caudate nucleus were examined (n = 3-5).Cocaine and DPH dose-dependently maintained operant responding. Dose combinations of 1.0 or 1.7 mg/kg per injection DPH and 0.03 mg/kg per injection cocaine maintained greater rates of operant responding than 0.03 mg/kg per injection cocaine alone in the second component of the behavioral session. In microdialysis studies, cocaine dose-dependently increased extracellular dopamine levels, but no dose of DPH tested significantly increased dopamine levels above baseline. Moreover, combining DPH with cocaine did not enhance cocaine-induced dopamine increases.The results support previous evidence of enhanced reinforcement with cocaine and DPH combinations and extend this finding to operant behavior maintained under a second-order schedule. However, the reinforcing effects of DPH alone or in combination with cocaine do not appear to be mediated via changes in dopamine overflow.

Background Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo. Methods Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety. Results None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures. Discussion The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants. Conclusion Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs.

The abuse of over-the-counter (OTC) medications has been widely reported. However, there are few preclinical studies examining the behavioral effects of OTC medications at higher, abused doses.The objectives of the current study were to determine whether the anti-histamine diphenhydramine (DIP) and the antitussive dextromethorphan (DEX), either alone or in combination, would have stimulant properties and be self-administered in animals.For drug self-administration, naive rats with no history of exposure to other drugs were trained to self-administer i.v. DEX+DIP (0.5+0.5, 1+1 or 2+2 mg/kg per injection), DEX alone (1 mg/kg) or DIP (1 mg/kg) alone under five-response fixed-ratio (FR) schedule with a 30-s time-out after each injection in 2-h sessions 3-5 days a week. Separate groups of rats were tested on locomotor activity. After 8 consecutive days of habituation, naive rats were injected with 3, 10, or 30 mg/kg DEX or DIP alone i.p., or in combination of 3+3 mg/kg, 10+10 mg/kg, or 30+30 mg/kg DEX+DIP i.p. Saline was injected i.p. during the intervening days. Locomotor activity was measured for each session.DEX+DIP combinations were self-administered, but the drugs alone were not. The acquisition of DEX+DIP self-administration was rapid with a majority of rats reaching the final FR5 schedule in 22-23 sessions. The total i.v. combination dose for each final scheduled session ranged from 40 mg/kg to 160 mg/kg DEX+DIP. Significant increases in locomotor activity were observed for DIP, an effect that was significantly enhanced when DIP was given in combination with DEX. Significant mortality was also observed for the drug combination at each dose tested when given i.v., with the highest mortality following the highest dose (2+2 mg/kg). When given i.p., no mortality was observed.These results show that combinations of DEX and DIP have stimulant properties and are self-administered by animals. Abuse of this combination in humans would be expected.

Sedation following antihistamine use poses a danger to ambulant patients involved in daily activities such as driving. To investigate effects of levocetirizine (5 mg), diphenhydramine (50 mg), and placebo on driving ability during normal traffic. Forty-eight healthy volunteers participated in a double-blind, placebo-controlled, randomized clinical trial. Treatments were administrated on days 1, 2, 3 and 4, exactly 1.5 h before the start of the standardized driving test (performed on day 1 and day 4). In the standardized driving test, subjects were instructed to drive with a steady lateral position, while maintaining a constant speed (95 km/h). Primary parameter was the standard deviation of lateral position (SDLP; cm). Statistical analyses were performed separately for day 1 and day 4, using analysis of variance and an equivalence test. Equivalence to placebo was evidenced if the 95% confidence interval lay between −2.6 cm and +2.6 cm. SDLP after levocetirizine was equivalent to placebo on both day 1 (−0.66 cm; +1.12 cm) and day 4 (−0.37 cm; +1.28 cm). In contrast, SDLP after diphenhydramine differed significantly from placebo on both day 1 (P

Determining brain regions in which neuroleptic drugs of different types produce similar effects, especially where these effects are not shared with drugs lacking antipsychotic efficacy, provides evidence as to how and where the clinical effects of neuroleptic drugs are mediated.For this study, the pattern of expression of the protein Fos, a marker of cellular activation, was compared after administration of the typical neuroleptic haloperidol, the antipsychotic drug clozapine, and the atypical neuroleptic olanzapine, as well as the sedative drug diphenhydramine and the anxiolytic lorazepam.Animals (Sprague-Dawley rats, three per cohort) received intraperitoneal injections of haloperidol (1 mg/kg), clozapine (20 mg/kg), olanzapine (5 mg/kg), diphenhydramine hydrochloride (1 mg/kg), lorazepam (5 mg/kg) or vehicle (2% lactic acid, 1 ml/kg). Two hours after drug administration, animals were killed. Patterns of activated cells were observed by immunohistochemistry for Fos-like antibodies in regions previously suggested as responding to all antipsychotic drugs, including nucleus accumbens, central amygdala, and central medial thalamus. Cells staining for Fos were counted by semi-automated methods. RESULTS. A very similar pattern and number of Fos positive cells in nucleus accumbens, central amygdala, and central medial thalamus followed administration of each antipsychotic drug. The numbers of apparently activated cells were much greater following antipsychotic drug administration than after vehicle, with differences between each drug and vehicle being highly statistically significant in each region. Lorazepam produced apparent activation of cells of the central amygdala similar in degree and location but not identical in distribution to that of antipsychotic drugs. Diphenhydramine produced no apparent activation of cells in any of the sites tested.Typical and atypical antipsychotic drugs shared a distinctive pattern of robust activation of cells in nucleus accumbens, central medial thalamus, and central amygdala. Antipsychotic drug-induced activation of amygdala was shared by lorazepam, but activation of thalamus and nucleus accumbens was much greater following antipsychotic drugs than following lorazepam. The pattern of activated cells may be relevant to the therapeutic actions of antipsychotic drugs.

Twenty volunteers were trained to discriminate between 75 mg tripelennamine (TP) and placebo. During the first four sessions, the drugs were identified prior to ingestion by letter code. During the next six sessions, the procedure was the same except the capsules were not identified. At the end of the 3-h session, participants indicated which capsule they believed they received using the letter codes. When correct, they received a monetary bonus. If they were correct on five sessions, they entered the third phase which had ten additional training and 12 test sessions. During tests, participants received capsules that contained other drugs, including diphenhydramine (50 and 75 mg), chlorpheniramine (4 and 6 mg), diazepam (5 and 10 mg), d-amphetamine (5 and 10 mg), as well as tripelennamine (25, 50 and 75 mg) and placebo. Thirteen participants learned the discrimination and nine entered the third phase. Except for placebo, most participants identified the test compounds as TP and labeled them as sedatives. TP produced significant changes on several subjective and physiological measures. The test compounds produced varied effects which were neither clearly dose-related nor related to the identification as TP or placebo. These results indicate that tripelennamine can function as a discriminative stimulus, but with little evidence of pharmacological specificity.

Peak saccadic eye movement velocity (SEV) and average smooth pursuit gain (SP) are reduced in a dose-dependent manner by diazepam and provide reliable, quantitative measures of benzodiazepine agonist effects. To evaluate the specificity of these eye movement effects for agents acting at the central GABA-benzodiazepine receptor complex and the role of sedation in benzodiazepine effects, we studied eye movement effects of diphenhydramine, a sedating drug which does not act at the GABA-benzodiazepine receptor complex. Ten healthy males, aged 19-28 years, with no history of axis I psychiatric disorders or substance abuse, received 50 mg/70 kg intravenous diphenhydramine or a similar volume of saline on separate days 1 week apart. SEV, saccade latency and accuracy, SP, self-rated sedation, and short-term memory were assessed at baseline and at 5, 15, 30, 45, 60, 90 and 120 min after drug administration. Compared with placebo, diphenhydramine produced significant SEV slowing, and increases in saccade latency and self-rated sedation. There was no significant effect of diphenhydramine on smooth pursuit gain, saccade accuracy, or short-term memory. These results suggest that, like diazepam, diphenhydramine causes sedation, SEV slowing, and an increase in saccade latency. Since the degree of diphenhydramine-induced sedation was not correlated with changes in SEV or saccade latency, slowing of saccadic eye movements is unlikely to be attributable to sedation alone. Unlike diazepam, diphenhydramine does not impair smooth pursuit gain, saccadic accuracy, or memory. Different neurotransmitter systems may influence the neural pathways involved in SEV and smooth pursuit again.

The inhibitory effects of some newly developed H1-blockers on the step-through active avoidance response in rats were studied in comparison with those of classical H1-blockers. Single administration of diphenhydramine, pyrilamine, promethazine and chlorpheniramine caused dose-related depressant effects on the active avoidance response. Ketotifen and azelastine caused less potent inhibition than the classical H1-blockers, while the effects of astemizole and oxatomide were almost negligible in suppressing the response. Following chronic administration of pyrilamine and promethazine, the acquisition of active avoidance response was significantly retarded compared with the control group, where-as new H1-blockers caused a somewhat but not significantly slower acquisition than the control group. Chronic administration of astemizole and oxatomide caused only transient suppression of the response. However, classical H1-blockers such as pyrilamine and promethazine caused sustained inhibition for as long as drug administration was continued.

Some histamine H1 (tripelennamine, diphenhydramine and cyclizine) and H2 (ranitidine and cimetidine) antagonists (1 and 10 mg/kg) were administered to morphine-dependent mice to evaluate the changes on naloxone-induced abstinence syndrome. When antihistaminics were administered 30 min before naloxone (1 mg/kg) on day 4 of morphine addiction, the two doses of three H1 antagonists and the higher dose of ranitidine inhibited shaking behavior. Furthermore, the two doses of tripelennamine and the higher dose of diphenhydramine, cyclizine and cimetidine enhanced jumping behavior. When antihistaminics were administered chronically (during the 4 days of morphine addiction), tripelennamine, cyclizine and ranitidine (all at 10 mg/kg) inhibited shaking behavior. The three H1 antihistaminics used enhanced the number of jumps per mouse whereas ranitidine decreased this response. No significant changes were found in the rest of the withdrawal symptoms after the antihistaminics were administered. The participation of serotonergic and catecholaminergic mechanisms is discussed.

The degree to which apparent amnesic effects of various centrally acting drugs are secondary to their effects on arousal remains a contentious issue. The present study uses two methods to dissociate memory and arousal effects of the cholinergic antagonist, scopolamine (SP), and the GABA-A/benzodiazepine receptor agonist, lorazepam (LZ). First, it compared their effects to those of an antihistamine, diphenhydramine (DPh), to provide an active control for arousal reduction. Second, it used the same measure – event-related potentials (ERPs) – as as a parallel index of both the arousal and cognitive effects of the drugs. Fifty participants were allocated to one of five parallel treatment groups (0.6 mg SP; 2 mg LZ; 25, 50 mg DPh; placebo). ERPs were recorded during a continuous word recognition task as well as during an “oddball” task. SP, LZ and 50 mg DPh produced a similar profile of effects on certain indices of arousal and on early components of ERPs. However, SP and LZ (but not DPh) produced marked impairments of episodic memory, and this pattern was similar to that on later components of ERPs. Memory impairments by SP and LZ were highly significant on retention in the continuous recognition task and further, no drug effects were found on response bias. Subsequent free recall was similarly very impaired by SP and LOR but not by the antihistamine. We conclude that benzodiazepines and anticholinergic drugs both reduce arousal and induce amnesia, but these effects are not interdependent. Our findings provide strong evidence for a dissociation between the effects on episodic memory and on arousal of these centrally acting compounds.

The effects of two drugs having opposite effects on the central nervous system were investigated using a newly developed visual vigilance task. Twenty-four male volunteers (median age = 20) performed the task on three separate occasions; after consuming placebo, caffeine (200 mg), or diphenhydramine (25 mg), in a double-blind, Latin Square design. At least 2 days intervened between drug administrations. Caffeine use was restricted for 10 h and smoking for 3 h before drug administration. When compared with placebo, caffeine significantly increased the number of correct responses and decreased response times, whereas diphenhydramine decreased the number of correct responses and increased response times. Low habitual consumers of caffeine (100 mg/day) and non-smokers had more correct responses than did high habitual caffeine consumers (100 mg/day) and smokers, but only in the placebo condition. Non-smokers had faster response times than smokers only in the placebo condition. Both caffeine and diphenhydramine altered certain aspects of mood.

Acute stressing procedures cause a shortlasting increase in the levels of guanosie 3',5'-monophosphate (cGMP) in mouse brain without significantly influencing the concentrations of adenosine 3'-5'-monophosphate (cAMP). Animals were pretreated with various centrally acting drugs before being stressed in order to study the involvement of specific neurotransmitters in the stress-induced rise of cGMP levels. Centrally depressant drugs affecting different synaptic mechanisms, such as chlorpromazine, reserpine, haloperidol, diazepam, and pentobarbital, inhibited the cCMP increase elicited by stress. Pretreatment with atropine, diphenhydramine, antazoline, cyproheptadine, phentolamine, bunitrolol, and indomethacin had no significant effect. Clonidine and both the (-)- and (+)-isomers of propranolol inhibited the stress-induced cGMP increase in a dose-related manner. Our results suggest that norepinephrine, serotonin, acetylcholine, or prostaglandins are not involved in the elevation of cGMP levels elicited by acute stress. Participation of other neurotransmitter(s), such as dopamine or GABA, cannot be excluded.

In the present study the drugs (Methaqualone + diphenhydramine or Methaqualone alone) were administered daily in a liquid diet to different groups of rats for 3 weeks. Each week the doses of the drugs were increased and daily records of body weight, mean rectal temperature and spontaneous motor activity (SPM) were maintained. During the first week, tolerance to both the drugs was observed when the animals received 152.4 mg/kg-1/day of methaqualone (MQ) and 140.0+14.0 mg/kg-1/day of methaqualone + diphenhydramine (MQ+D) respectively. In the second week the doses were further increased to 302.0 mg/kg-1/day of MQ and 277.8+27.7 mg/kg-1/day of MQ+D respectively.

Studies were performed in healthy subjects to ascertain the neurotransmitter systems involved in the growth hormone (GH)-releasing effect of the potent enkephalin analog FK 33-824. Concomitant evaluation of prolactin (PRL) secretion was also performed in the same subjects. FK 33-824 at a dose of 0.5 mg IV elicited a clear-cut rise in plasma GH and PRL concentrations with peak levels at 45 min. Blockade of muscarinic cholinergic receptors by atropine (0.5 mg SC) or histaminergic H1 receptors by diphenhydramine (50 mg IV bolus plus 50 mg infusion) completely suppressed the GH release induced by FK 33-824, without significantly altering the PRL rise induced by the peptide. Pretreatment with the alpha-adrenergic antagonist phentolamine (0.5 mg IV/min for 120 min) or the dopamine receptor blocker metoclopramide (10 mg IV) did not alter the GH-releasing effect of FK 33-824. Phentolamine failed to alter the PRL rise induced by FK 33-824, while combined FK 33-824-metoclopramide administration induced a greater PRL increase than FK 33-824 alone. These results indicate that cholinergic and histaminergic H1 receptors play an important role in the GH-release induced by FK 33-824 in man, whereas this action seems to occur independently of catecholaminergic mediation. The same receptors are not involved in the PRL-releasing effect of the peptide.

Squirrel monkeys were trained to press a key under a two-component schedule of food presentation. In the presence of either green or red stimulus lights, the 30th response produced a food pellet (fixed-ratio schedule). During the red stimulus lights (punishment component), the first response of each fixed ratio produced either an IV injection of histamine (100.0 micrograms/kg/inj) or a brief electric shock (3.0 mA). Responding was selectively suppressed in either punishment component. Presession IM administration of chlorpheniramine (0.1 and 0.3 mg/kg), diphenhydramine (1.0 and 3.0 mg/kg), or pyrilamine (0.1 and 0.3 mg/kg) increased rates of responding punished by histamine but not those punished by electric shock. Presession administration of promethazine (0.1-3.0 mg/kg) or tripelennamine (0.1 and 0.3 mg/kg) also increased rates of responding punished by histamine in all subjects and response rates punished by electric shock in one of three subjects. Chlordiazepoxide (3.0-56.0 mg/kg) increased rates of responding punished by either histamine or electric shock. These results suggest that the punishing effects of histamine injection are mediated by H1 receptors and that H1-receptor antagonists increase rates of responding suppressed by punishment only under limited conditions including those in which histamine is the punishing stimulus.

Three histamine H1-receptor antagonists, chlorpheniramine, diphenhydramine and tripelennamine, were tested alone or in combination with morphine, amphetamine and scopolamine on locomotor activity in mice. All three antihistaminics, at some dosage levels, enhanced morphine-induced hyperactivity, but did not change or even reduce locomotor stimulation induced by amphetamine and scopolamine. The results suggest that H1-blocking agents may specifically interact, though not necessarily directly, with opiate mechanisms in producing behavioural effects.

Rats were kept on a 12-h light-dark cycle. One hour after the light was switched on, physiological saline, (+)-amphetamine 1 mg/kg, and H 77/77 5 mg/kg were injected s.c.; the number of groomings was counted 1-2 h after the treatments. (+)-Amphetamine and H 77/77 produced increased grooming which was antagonized by the tyrosine hydroxylase inhibitor H 44/68 (250 mg/kg), the dopamine-beta-hydroxylase inhibitor FLA 63 (40), the neuroleptics haloperidol (0.1 and 0.5), and clozapine (1 and 5). The (+)-amphetamine-induced grooming was also antagonized by the NA-receptor blocker aceperone (10) but not by the sedative phenothiazines mepazine (10) and diphenhydramine (20) nor diazepam (1). These results indicate that NA-release is involved in the mediation of (+)-amphetamine- and H 77/77-induced grooming. The inhibition of haloperidol and clozapine is presumably due to NA-receptor blockade.

Squirrel monkeys were studied under fixed-interval schedules of reinforcement in which the first response (lever press) after a fixed period of time resulted either in the delivery of a food pellet or in the termination of stimuli associated with impending electric shock delivery. Benztropine mesylate (0.03–1.7 mg/kg), promethazine HCl (0.3–10 mg/kg), and diphenhydramine HCl (0.3–17 mg/kg) all produced marked increases in responding at intermediate doses. The increases in responding were at least as great as those observed with psychomotor stimulants, such as amphetamine, in this species under similar behavioral conditions. Benztropine was most potent and diphenhydramine was least potent in most monkeys and, in some, promethazine and diphenhydramine were about equipotent. The order of potency and the magnitude of potency differences among the drugs suggest that the behavioral effects were due to antagonist actions at histamine H1 receptors, rather than to effects on dopamine uptake or on muscarinic receptors.

Pigeons trained under a two-key drug discrimination procedure eventually learned to discriminate the antihistaminic tripelennamine (5 mg/kg) from saline. When 0.63–7.5 mg/kg doses of tripelennamine were administered in generalization test sessions, the percentage of responses directed to the tripelennamine-appropriate key varied directly with dose. At certain doses, the discriminative stimulus properties of the antihistaminics, diphenhydramine and pyrilamine, clearly generalized to tripelennamine, whereas intermediate generalization was evident with the antihistaminics, chlorpheniramine and promethazine. Chlorpromazine, cimetidine, d-amphetamine, diazepam, morphine, pentazocine, phenobarbital, and sodium valproate failed to produce tripelennamine-like patterns of responding.

Three cognitive tasks in which performance depends primarily on the rate of cognitive processing were given to 24 male subjects before and after oral doses of methamphetamine (10 mg), diphenhydramine hydrochloride (100 mg), and placebo. Each subject was tested on Monday, Wednesday, and Friday of one week with drug orders balanced across subjects. Compared with placebo and diphenhydramine, methamphetamine increased the rate at which a visual display was scanned for a target stimulus. Methamphetamine affected neither a time-production task nor a divided attention task that required the subject to perform two cognitive tasks in a limited amount of time. This suggests that methamphetamine can increase cognitive processing speed on tasks involving familiar cognitive operations but that an increase is not likely in tasks involving more complicated decision processes. Compared with placebo and methamphetamine, diphenhydramine caused subjects no experience geophysical time as passing more slowly, but the drug had no significant effects on the visual search or divided-attention tasks. This suggests that time perception is more likely to be altered by diphenhydramine than is performance on tasks requiring short periods of rapid cognitive processing.