Novel psychoactive substances: What educators need to know.

Novel psychoactive substances (NPS) are synthetic, psychoactive drugs that are generally not under international regulatory control. NPS are frequently sold as alternatives to classic "street drugs" such as ecstasy or LSD. However, little is known about their pharmacology and toxicity and they therefore pose unknown health risks. Further, risk for harms are elevated because users often do not know what they are taking, and therefore cannot predict dose, potency, or other potential properties.

Young brains on cannabis: It's time to clear the smoke.

Cannabis is the most commonly used illicit substance among youth. Recent policy developments and ongoing debate related to this drug underscore the urgent need to "clear the smoke" and better understand what the scientific evidence says about the health and behavioral effects of cannabis use, particularly on youth whose brains are undergoing rapid and extensive development.

Polymorphism of the serotonin-2A receptor gene (HTR2A) associated with childhood attention deficit hyperactivity disorder (ADHD) in adult women with seasonal affective disorder.

INTRODUCTION: Several lines of research point to a possible overlap between seasonal affective disorder (SAD) and attention deficit hyperactivity disorder (ADHD), particularly in females. There is also emerging evidence that variation of the 5-HT2A receptor gene (HTR2A) contributes to both SAD and ADHD. The current study investigated whether variation in HTR2A was associated with symptoms of childhood ADHD in adult women with SAD. METHOD: Sixty-six women with SAD were administered the Wender-Utah Rating Scale (WURS), which retrospectively assesses childhood ADHD, as part of an ongoing genetic study of SAD. WURS scores were compared across the three genotypic groups defined by the T102C polymorphism of HT2RA. RESULTS: Analysis of variance indicated a significant difference in mean 25-item WURS scores across the three genotypic groups (p = 0.035). Post-hoc tests revealed that the C/C genotypic group had a significantly higher mean score than both the T/T group and T/C group. Based on previously established WURS criteria, 38% of subjects with the C/C genotype, and none with the T/T genotype, had scores consistent with childhood ADHD. LIMITATIONS: The current sample size is small, and childhood ADHD diagnoses were based on retrospective recall. CONCLUSION: These preliminary results suggest a possible association between variation in HTR2A, childhood ADHD, and the later development of SAD in women.

Changes in regional brain glucose metabolism measured with positron emission tomography after paroxetine treatment of major depression.

OBJECTIVE: Depression is commonly associated with frontal hypometabolic activity accompanied by hypermetabolism in certain limbic regions. It is unclear whether successful antidepressant treatments reverse these abnormalities or create new resting levels of metabolism. The aim of the present study was to assess the effects of successful paroxetine treatment on regional glucose metabolism in patients with major depression. METHOD: Positron emission tomography with [(18)F]fluorodeoxyglucose was performed on 13 male patients before and after 6 weeks of paroxetine therapy. Resting state scans were also acquired under similar conditions in 24 healthy male subjects for comparison. RESULTS: After successful paroxetine therapy, increased glucose metabolism occurred in dorsolateral, ventrolateral, and medial aspects of the prefrontal cortex (left greater than right), parietal cortex, and dorsal anterior cingulate. Areas of decreased metabolism were noted in both anterior and posterior insular regions (left) as well as right hippocampal and parahippocampal regions. In comparison to metabolism levels in a group of healthy volunteers, the increase in prefrontal metabolic activity represented a normalization of previously reduced metabolic activity, whereas the reduction in pregenual anterior cingulate activity represented a decrease from previously elevated metabolic levels. CONCLUSIONS: These results provide further support for a dysfunction in cortical-limbic circuitry in depression, which is at least partly reversed after successful paroxetine treatment.

Cholecystokinin modulates both the development and the expression of behavioral sensitization to amphetamine in the rat.

RATIONALE: Repeated administration of psychostimulants such as amphetamine (AMPH) produces an enduring augmentation of their locomotor effects. Previous research suggests that this phenomenon, termed sensitization, is related to changes within the mesolimbic dopamine (DA) system. OBJECTIVES: The present experiments were designed to investigate the contribution of endogenous cholecystokinin (CCK), a neuropeptide co-localized with DA in the mesolimbic system, to the development (experiment 1) and the expression (experiment 2) of locomotor sensitization to AMPH. METHODS: In experiment 1, rats were injected (IP) with the CCK(A) antagonist devazepide (0, 0.001, 0.01, or 0.1 mg/kg) or the CCK(B) antagonist L-365,260 (0, 0.001, 0.01, 0.1, or 1.0 mg/kg) followed by AMPH (1.5 mg/kg) once daily for seven days. Following 10 days withdrawal, rats were administered AMPH (0.75 mg/kg) and their locomotor activity recorded. In experiment 2, rats were administered AMPH (1.5 mg/kg) once daily for 7 days. Following 10 days withdrawal, rats were injected with devazepide (0, 0.0001, 0.001, 0.01, 0.1, or 1.0 mg/kg) or L-365,260 (0, 0.001, 0.01, or 0.1 mg/kg) followed 30 min later by AMPH (0.75 mg/kg) and their locomotor activity recorded. RESULTS: When administered during the AMPH pretreatment phase of experiment 1, the two highest doses of L-365,260 attenuated, and the lowest dose of L-365,260 potentiated, the sensitized locomotor response to AMPH challenge. When administered prior to the AMPH challenge phase of experiment 2, devazepide attenuated the sensitized locomotor response to AMPH. CONCLUSIONS: These results suggest that CCK(B) and CCK(A) receptors modulate the development and the expression of behavioral sensitization to AMPH, respectively.

Neurohormonal responses to cholecystokinin tetrapeptide: a comparison of younger and older healthy subjects.

We recently found that, compared with younger healthy subjects, older healthy subjects had less symptomatic and cardiovascular response to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). As an exploratory part of that study, we also evaluated the effect of aging on neurohormonal responses to CCK-4. These hormonal data are the focus of this article. Forty healthy volunteers aged 20-35 years and 40 healthy volunteers aged 65-81 years, divided equally between men and women, were compared on their hormonal responses (maximum change from baseline in growth hormone [GH], prolactin, adrenocorticotropic hormone [ACTH], and cortisol) to the intravenous administration of 50 microg of CCK-4 or placebo. Blood samples for serum hormone determination were collected at 2 minutes prior to the intravenous challenge (baseline) and at 2, 5, and 10 minutes after the challenge. In both age groups, maximum increase in prolactin, ACTH and cortisol was significantly greater with CCK-4 than with placebo. Following administration of CCK-4, younger and older groups did not significantly differ in maximum increase in prolactin, ACTH, or cortisol. Older subjects had a statistically significant smaller increase in GH compared with younger subjects but the magnitude of the difference was small and of doubtful clinical relevance. Older subjects who had a panic attack had significantly greater elevations of all hormones compared with those who did not panic and younger panickers had a significantly greater elevation of GH compared with young nonpanickers. For the most part, maximum changes in hormonal levels were not correlated with symptom severity, suggesting that other factors may have contributed to the differential effect of panic on the HPA axis.

Self-administration of intravenous amphetamine is predicted by individual differences in sucrose feeding in rats.

RATIONALE: Previous studies have shown that individual differences in oral sucrose consumption are predictive of the psychomotor and dopamine (DA) stimulant properties of amphetamine in rats. OBJECTIVES: The present experiment was designed to examine the relationship between sucrose feeding and the reinforcing properties of amphetamine using the intravenous (i.v.) drug self-administration paradigm. METHODS: Based on a median split of sucrose intake during a final 1-h feeding test session, male Wistar rats were designated as either low (LSF) or high sucrose feeders (HSF). Acquisition of i. v.-amphetamine self-administration across ten daily 30-min sessions was then assessed. Following acquisition, i.v. self-administration of several doses of amphetamine was similarly tested across daily 30-min sessions. RESULTS: Data from this experiment revealed augmented responding in HSF compared with LSF during acquisition of amphetamine self-administration. Correspondingly, when given access to different doses of amphetamine, responding was greater in HSF than in LSF across several doses (3 microg and 10 microg per infusion). CONCLUSIONS: These data support the notion that individual differences in oral sucrose consumption are predictive of the reinforcing properties of psychostimulant drugs.

Neuroanatomic correlates of CCK-4-induced panic attacks in healthy humans: a comparison of two time points.

BACKGROUND: Several functional imaging studies have demonstrated increases of brain activity in the temporofrontal, cingulate, and claustrum regions during a pharmacologically induced panic attack when scanning was done at a single point in time. However, no study has evaluated changes in brain activity at two time points during a panic attack. We hypothesized that in response to a single bolus injection of the panicogen cholecystokinin-4 (CCK-4) in healthy volunteers, changes in regional cerebral blood flow (rCBF) might be different if scanning were done at two different time points. METHODS: To test this hypothesis, we conducted a single-blind study, using positron emission tomography (PET). To determine the time effect of panic attack on brain activity, we performed either early scan or late scan covering the first or the second minute after CCK-4 bolus injection, respectively. The PET images were analyzed by statistical parametric mapping (SPM) followed by region of interest (ROI) analysis. RESULTS: The results showed significant differences between the early and the late scan. The early effects of CCK-4 are accompanied by increases in rCBF in the hypothalamic region, whereas the late scan showed an increase in rCBF in the claustrum-insular region. Reductions in rCBF were observed for both time groups in the medial frontal region. A separate scan for anticipatory anxiety demonstrated rCBF increases in the anterior cingulate region and decreases in the occipital regions. CONCLUSIONS: These results may support the hypothesis that changes in rCBF as a function of time during CCK-4-induced panic might correspond to a neurocircuitry involved in panic attacks.

The expression of behavioral sensitization to amphetamine: role of CCK(A) receptors.

These studies investigated whether endogenous activation of CCK(A) receptors mediates the expression of amphetamine (AMP)-induced locomotor activity. In Experiment 1, locomotor activity was assessed in rats pretreated with the CCK(A) antagonist devazepide (0.001, 0.01, and 0.1 mg/kg) and subsequently injected with AMP (1.5 mg/kg). In Experiment 2, rats were administered AMP (1.5 mg/kg) once daily for 7 days. Following a 10-day withdrawal, locomotor activity was assessed following treatment with devazepide (0.001, 0.01, and 0.1 mg/kg) and AMP (0.75 mg/kg). In both studies, rats were classified as low (LR) or high (HR) responders based upon a median split of their locomotor response to a novel environment. Results from Experiment 1 showed that AMP potentiated the expression of locomotor activity, and this effect was most pronounced in HR rats. However, devazepide did not affect AMP-induced locomotion. Results from Experiment 2 demonstrated that chronic AMP pretreatment augmented the locomotor response to subsequent AMP challenge, and this effect was most pronounced in the HR group. Further, this augmented response was blocked by devazepide in HR rats. These findings constitute the first demonstration that endogenous CCK(A) receptor activation is an important substrate mediating AMP-induced locomotor activity in animals with a previous history of AMP treatment.

CCK-A receptor antagonists have selective effects on nutrient-induced food intake suppression in rats.

To provide additional support to the hypothesis that only dietary protein (Pro; chicken egg albumin) and not amino acids (AA; patterned after albumin), carbohydrates (CHO; cornstarch), or fats (Fat; corn oil) produces a satiating effect via CCK receptors, two CCK-A receptor antagonists (PD-140,548 and devazepide) were coadministered with each nutrient. Given alone [4 ml intragastrically (ig)] Pro (1.0 g), AA (1.0 g), CHO (1.4 g), and Fat (2.4 g) suppressed (P < 0.05) food intake on average during the first 2 h of feeding by 1.4 (36%), 1.5 (48%), 1.0 (33%), and 1.2 g (41%), respectively. Devazepide (0.5 mg/kg) and PD-140,548 (1.0 mg/kg) given alone increased food intake during 0-2 h by 0.7 g (18%) and during 0-1 h by 0.5 g (15%), respectively. When coadministered with PD-140,548 (1.0 mg/kg ip), the suppression of food intake caused by Pro was modulated during 0-2 h by 57% (Pro x drug interaction, P < 0.05), but AA-, CHO-, and Fat-induced suppression of feeding was not affected (nutrient x drug interaction, P > 0.05). Devazepide (0.5 mg/kg ip) did not modulate AA-, CHO-, and Fat-induced food intake suppression during any time period (nutrient x drug interaction, P > 0.05). These studies provide additional evidence that CCK-A receptors play a role in Pro (albumin) but not AA-, CHO (cornstarch)-, or Fat (corn oil)-induced food intake suppression in rats.

Self-administration of intravenous amphetamine: effect of nucleus accumbens CCKB receptor activation on fixed-ratio responding.

RATIONALE: The mesolimbic dopamine (DA) system is implicated in psychostimulant drug self-administration. The neuropeptide cholecystokinin (CCK) is co-localised with DA and inhibits nucleus accumbens (NAcc) DAergic neurotransmission via CCKB receptors. OBJECTIVES: The present experiment was designed to examine the effects of intra-NAcc CCKB receptor stimulation on fixed-ratio (FR) amphetamine self-administration. METHODS: Wistar rats with intravenous catheters and NAcc cannulae were trained to self-administer amphetamine under a FR3 schedule of reinforcement. Animals performing stable self-administration were microinjected with pentagastrin and assessed during 3-h sessions. RESULTS: Intra-NAcc pentagastrin dose dependently increased amphetamine intake. CONCLUSIONS: These results are consistent with the notion that NAcc CCKB receptor activation attenuates amphetamine reward.

Effects of CCK-4 infusion on the acoustic eye-blink startle and psychophysiological measures in healthy volunteers.

The acoustic startle response (ASR) and a range of psychophysiological parameters were evaluated during a continuous intravenous administration of cholecystokinin-tetrapeptide (CCK-4) in healthy volunteers. Subjects (n=28) were randomly assigned to double-blind infusion of either CCK-4 (0.5 mg/60 min) or placebo. The ASR sessions were performed prior to infusion and at 20 min and 50 min after the onset of infusion by recording eye-blink response to a series of acoustic stimuli (110 dB, 40 ms). An effect of CCK-4 on the eye-blink startle was observed in the first half of infusion. CCK-4 produced an increase of eye-blink startle amplitude from baseline values in contrast to the decrease observed at this time point with placebo. A mild increase in anxiety and heart rate followed by fatigue was reported with CCK-4. Administration of CCK-4 produced increases in plasma concentrations of adrenocorticotropic hormone, cortisol, prolactin and growth hormone. The results of this study show that a prolonged intravenous administration of CCK-4 may be a useful challenge method for further studies on the role of CCK system in the modulation of human anxiety and stress response.

Individual differences in sucrose intake predict behavioral reactivity in rodent models of anxiety.

We have previously shown that individual differences in oral sucrose consumption are predictive of behavioral reactivity of rats in the elevated plus-maze (EPM). The present experiments were designed to replicate the EPM results and to extend them to another animal model of anxiety, the acoustic startle reflex (ASR) paradigm. In two experiments, sucrose consumption was assessed in separate groups of rats across eight daily 1-h feeding sessions. Animals were designated as either low (LSF) or high sucrose feeders (HSF) based on a median split of their sucrose intake on the final test day. Following this assay, animals were tested in the EPM in Experiment 1, and in the ASR paradigm in Experiment 2. Results from Experiment 1 replicated our previous findings and showed that the percentage of time spent on, and entries into, open arms was significantly lower in LSF than HSF. Further, results from Experiment 2 revealed a significantly augmented startle response to acoustic stimuli (94-108 dB SPL) in LSF compared to HSF. These data provide converging evidence to support the notion that individual differences in baseline levels of oral sucrose consumption are predictive of anxious behaviors in rats.

Cholecystokinergic innervation of nucleus accumbens subregions.

Behavioral and pharmacological evidence has shown a different and opposite role of the neuropeptide cholecystokinin (CCK) on the dopamine (DA) function in the caudal versus rostral part of the nucleus accumbens. Previous reports have speculated that the caudal region of the nucleus accumbens would receive CCKergic innervation from dopaminergic neurons of the mesencephalic ventral tegmental area, whereas the CCKergic input to the rostral accumbens would originate in non-dopaminergic neurons from extra-mesencephalic areas of the brain. In the present study, this issue was addressed using retrograde tracing techniques in conjunction with immunocytochemistry. Retrograde tracers were injected in the three compartments of the accumbens (i.e., rostral pole, core and septal shell). In summary, our results demonstrate that 1) the main CCKergic input of the accumbens originates in the ventral mesencephalon; 2) the rostral pole is equally innervated by CCK neurons projecting from both substantia nigra pars compacta and ventral tegmental area; 3) the primary source of CCK innervation of the accumbal core is the substantia nigra pars compacta; and 4) whereas the CCKergic input to the septal shell originates primarily in the ventral tegmental area. Additionally, our results also showed that most of the CCKergic neurons projecting to any of the accumbal compartments also produce dopamine. These data constitute the first neuroanatomical evidence for the differential effects of CCK on dopamine actions in the different regions of the nucleus accumbens.

Individual differences in the feeding and locomotor stimulatory effects of acute and repeated morphine treatments.

Rats with high propensity to ingest sugar (HIGH) show increased responsiveness to amphetamine treatments than rats with low propensity to ingest sugar (LOW). Intrinsic variation in the functioning of the mesolimbic dopamine system has been suggested to account for these individual differences. Morphine has stimulatory effects on feeding and locomotion that are in part mediated by the mesolimbic dopamine system. The present study therefore examined whether LOW and HIGH rats would exhibit differences in the feeding and locomotor stimulating effects of morphine. Morphine (1, 2, and 4 mg/kg) significantly stimulated the intake of chow and sugar in LOW rats without affecting food consumption in HIGH rats. Further, it was found that both groups of rats did most of their feeding in the first 20 min following injection, and that the stimulatory effect of morphine in LOW rats was restricted to the first hour of the 3-h test session. Repeated morphine (2 mg/kg) stimulated sugar intake in LOW but not HIGH rats, and there was no evidence of increased intake across injections. Acute administration of 5.0 mg/kg, but not 2.0 mg/kg, of morphine produced higher levels of locomotor activity in LOW rats compared to HIGH rats; repeated treatment with 5.0 mg/kg morphine produced a sensitized locomotor response in both LOW and HIGH rats. These results indicate that LOW rats exhibit increased responsiveness to the locomotor and feeding stimulatory effects of morphine compared to HIGH rats. One implication arising from these findings is that LOW and HIGH rats may be distinguished by differences in opiatergic function, as well as by differences in dopaminergic function.

Hormonal and subjective responses to intravenous m-chlorophenylpiperazine in women with seasonal affective disorder.

BACKGROUND: There is emerging evidence of serotonergic dysfunction in patients with seasonal affective disorder (SAD). We examined central serotonergic function in female patients with SAD (fall-winter pattern) by means of neuroendocrine and subjective responses to the postsynaptic serotonin receptor agonist m-chlorophenylpiperazine. METHODS: Using a double-blind, randomized, placebo-controlled design, we assessed neuroendocrine and subjective responses to m-chlorophenylpiperazine (0.1 mg/kg intravenously) and placebo in 14 unmedicated female patients with SAD in the depressed state and 15 female normal controls. All testing was done in the fall-winter months and during the follicular phase of the menstrual cycle. Plasma prolactin and cortisol levels were used as neuroendocrine measures, while subjective responses were assessed by means of visual analog scales of 10 mood states. RESULTS: On the basis of net responses to m-chlorophenylpiperazine (placebo effects subtracted from drug effects), patients with SAD exhibited blunted prolactin responses and less sadness than normal controls in response to the drug. When order of presentation of drug and placebo was taken into consideration, altered "calm" and "high" responses were also found in the patient group. CONCLUSION: Evidence of dysfunction at or downstream to central serotonergic receptors in female patients with SAD confirms and extends findings from previous research.

Effect of aging on cholecystokinin-induced panic.

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Evidence for CCK(A) receptor involvement in the acquisition of conditioned activity produced by cocaine in rats.

Cholecystokinin (CCK) is co-localized with dopamine (DA) in the nucleus accumbens (NAC) where evidence suggests that CCK(B) receptor-mediated mechanisms inhibit, while CCK(A) receptor-mediated mechanisms facilitate, DA function. As DA has been implicated in the acquisition of conditioned activity, the present experiments investigated the effects of CCK(A) and CCK(B) receptor selective antagonists on the acquisition and expression of conditioned activity produced by cocaine. Paired rats received four cocaine-environment pairings whereas Unpaired rats received the two stimuli explicitly unpaired, in that they received cocaine in the home cage. Using this procedure, cocaine (10 mg/kg, i.p.) reliably produced conditioned activity such that the Paired group showed a higher level of locomotion than the Unpaired group on a subsequent drug-free test day. Systemic administration of devazepide, a CCK(A) receptor antagonist, but not L-365,260, a CCK(B) receptor antagonist, blocked the acquisition of conditioned activity. Microinjection of the CCK(A) antagonist PD-140548 into the NAC similarly impaired the acquisition of conditioned activity. However, systemic administration of neither the CCK(A) nor CCK(B) receptor antagonist modified the expression of cocaine-induced conditioned activity once established. These studies suggest that CCK(A), but not CCK(B), receptor mediated mechanisms in the NAC play a key role in the acquisition of conditioned activity.

A review of functional neuroimaging in mood disorders: positron emission tomography and depression.

OBJECTIVE: To examine the progress of positron emission tomography (PET) as a tool for understanding the psychobiology of mood disorders, particularly major depression and bipolar disorder. METHOD: Review of the literature on functional imaging of mood disorders. RESULTS: Functional imaging techniques have been used in psychiatric research as a noninvasive method to study the behaviour and function of the brain. Techniques used so far have involved the manipulation of emotion in healthy volunteers, the evaluation of depressed (unipolar and bipolar as well as secondary depression), manic, and normal subjects under resting and various activation conditions, such as cognitive activation, acute pharmacological challenge, and chronic thymoleptic treatments. As a result, functional imaging studies tend to support abnormalities in specific frontal and limbic regions. CONCLUSION: Different PET methods demonstrate consistent abnormalities in the prefrontal, cingulate, and amygdala regions. These findings are in agreement with past animal and clinical anatomical correlates of mood and emotions.

Activation of amygdala cholecystokininB receptors potentiates the acoustic startle response in the rat.

The acoustic startle reflex is a sensitive index of "anxiety" and "fear." Potentiation of startle by conditioned and unconditioned fear stimuli appears to be mediated by the amygdala. CholecystokininB (CCKB) agonists increase "anxiety" in laboratory animals and induce "panic" in humans. Here, we investigate the role CCKB receptor-mediated mechanisms in the amygdala in the potentiation of startle. First, intra-amygdala infusions of the CCKB receptor agonist pentagastrin (0, 0.01, 0.1, 1, and 10 nM) produced a dose-related potentiation of acoustic startle responses. At the highest dose, startle amplitudes were increased up to 90% above preinfusion baseline levels. Second, similar infusions of pentagastrin had no effect on locomotor activity over the same time course, showing that increases in startle responsivity after infusions of pentagastrin are not attributable to nonspecific changes in motor activity. Third, infusions of similar doses of pentagastrin into the striatum or nucleus accumbens did not potentiate startle responses. Fourth, pretreatment with the CCKB receptor antagonist L-365,260 (0.1 mg/kg, i.p.) attenuated the potentiation of startle produced by intra-amygdala infusions of pentagastrin. Finally, intra-amygdala infusion of the CCKB receptor-selective antagonist PD-135158 (10 micro;g) blocked the potentiation of startle produced by i.c.v. infusions of pentagastrin, suggesting that i.c.v. infusions of pentagastrin potentiate startle responses via activation of amygdala CCKB receptors. These results show that amygdala CCKB receptor-mediated mechanisms are involved in the potentiation of acoustic startle responses.