N,N-dipropyltryptamine (DPT) is a synthetic tryptamine hallucinogen which has been used psychotherapeutically in humans, but has been studied preclinically only rarely. In the present studies, DPT was tested in a drug-elicited head twitch assay in mice, and in rats trained to discriminate lysergic acid diethylamide (LSD), N,N-dimethyl-4-phosphoryloxytryptamine (psilocybin), or 3,4-methylenedioxymethamphetamine (MDMA). A separate group of rats was also trained to recognize DPT itself as a discriminative stimulus, and in all cases, the behavioral effects of DPT were challenged with the selective serotonin (5-HT) 2A antagonist M100907, the 5-HT 1A selective antagonist WAY-100635, or their combination. In the head twitch assay, DPT elicited dosedependent effects, producing a biphasic dose-effect curve. WAY-100635 produced a parallel rightward shift in the dose-effect curve for head twitches, indicative of surmountable antagonism, but the antagonist effects of M100907 were functionally insurmountable. DPT produced partial to full substitution when tested in rats trained to discriminate LSD, psilocybin or MDMA, and served as a discriminative stimulus. In all cases, the antagonist effects of M100907 were more profound than were those of WAY-100635. DPT is thus active in two rodent models relevant to 5-HT 2 agonist activity. The effectiveness with which M100907 antagonizes the behavioral actions of this compound strongly suggests that the 5-HT 2A receptor is an important site of action for DPT, but the modulatory actions of WAY-100635 also imply a 5-HT 1A -mediated component to the actions of this compound.

Few studies have characterized the subjective effects of N-substituted piperazines, but these drugs show potential for abuse in humans, and have often been associated with MDMA ("ecstasy") in this regard. The aim of the present study was to test the capacity of N-substituted piperazines to induce a head twitch response, alter locomotor activity, and induce MDMA-like discriminative stimulus effects in mice. Various doses of l-benzylpiperazine (BZP), 1-(3-trifluoromethylphenyl) piperazine (TFMPP), 1-(3-methoxybenzyl) piperazine (m-MeO-BZP) or meta-chlorophenyl piperazine (m-CPP) were administered to mice to determine the effects on these behavioral endpoints. BZP, but not its meta-methoxyl analogue, increased locomotor activity in a dose-dependent manner; the phenylpiperazines and m-MeO-BZP only decreased locomotor activity. TFMPP was the only compound active in the head twitch assay, eliciting a moderate head twitch response which was comparable to that previously observed with the MDMA enantiomers. BZP, TFMPP and m-CPP fully substituted in S(+)-MDMA-trained animals, but did not elicit significant drug lever responding in mice trained to discriminate R(-)-MDMA. m-MeO-BZP partially substituted for both training drugs. The present results suggest that BZP has stimulant-like effects, and that TFMPP has hallucinogen-like effects. Their structural analogues, however, do not share these behavioral profiles. Further studies into the relationships between the N-substituted piperazines and MDMA are warranted.

BackgroundIndividuals with a positive family history for alcoholism (FHP) have shown differences from family-history-negative (FHN) individuals in the neural correlates of reward processing. FHP, compared to FHN individuals, demonstrate relatively diminished ventral striatal activation during anticipation of monetary rewards, and the degree of ventral striatal activation shows an inverse correlation with specific impulsivity measures in alcohol-dependent individuals. Rewards in socially interactive contexts relate importantly to addictive propensities, yet have not been examined with respect to how their neural underpinnings relate to impulsivity-related measures. Here we describe impulsivity measures in FHN and FHP individuals as they relate to a socially interactive functional magnetic resonance imaging (fMRI) task.MethodsForty FHP and 29 FHN subjects without histories of Axis-I disorders completed a socially interactive Domino task during functional magnetic resonance imaging and completed self-report and behavioral impulsivity-related assessments.ResultsFHP compared to FHN individuals showed higher scores (p = .004) on one impulsivity-related factor relating to both compulsivity (Padua Inventory) and reward/punishment sensitivity (Sensitivity to Punishment/Sensitivity to Reward Questionnaire). Multiple regression analysis within a reward-related network revealed a correlation between risk-taking (involving another impulsivity-related factor, the Balloon Analog Risk Task (BART)) and right ventral striatum activation under reward >punishment contrast (p<0.05 FWE corrected) in the social task.ConclusionsBehavioral risk-taking scores may be more closely associated with neural correlates of reward responsiveness in socially interactive contexts than are FH status or impulsivity-related self-report measures. These findings suggest that risk-taking assessments be examined further in socially interactive settings relevant to addictive behaviors.

Methamphetamine (METH) is a potent stimulant that induces both acute and long-lasting neurochemical changes in the brain including neuronal cell loss. Our laboratory demonstrated that the neuropeptide substance P enhances the striatal METH-induced production of nitric oxide (NO). In order to better understand the role of the striatal neuropeptides on the METH-induced production of NO, we used agonists and antagonists of the NPY (Y1R and Y2R) receptors infused via intrastriatal microinjection followed by a bolus of METH (30 mg/kg, ip) and measured 3-NT immunofluorescence, an indirect index of NO production. One striatum received pharmacological agent while the contralateral striatum received aCSF and served as control. NPY receptor agonists dose dependently attenuated the METH-induced production of striatal 3-NT. Conversely, NPY receptor antagonists had the opposite effect. Moreover, METH induced the accumulation of cyclic GMP and activated caspase-3 in approximately 18% of striatal neurons, a phenomenon that was attenuated by pre-treatment with NPY2 receptor agonist. Lastly, METH increased the levels of striatal preproneuropeptide Y mRNA nearly five-fold 16 hours after injection as determined by RT-PCR, suggesting increased utilization of the neuropeptide. In conclusion, NPY inhibits the METH-induced production of NO is striatal tissue. Consequently, production of this second messenger induces the accumulation of cyclic GMP and activated caspase-3 in some striatal neurons, an event that may precede the apoptosis of some striatal neurons.