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Scholarly Works (9 results)

  • Thesis
  • Peer Reviewed
UC Santa Barbara Electronic Theses and Dissertations (2018)

Self-administration of cocaine produces an initially euphoric or “high” state, following shortly after by an aversive, anxiogenic “crash”. Although there has been extensive research into the neurobiology of cocaine’s rewarding effects, less attention has focused on understanding the mechanisms of the drug’s aversive component. Recent research has identified regions like the Bed Nucleus of the Stria Terminalis (BNST) and Lateral Habenula (LHb) as key structures that contribute to aversive effects in humans and animals. The specific intent of this dissertation is to investigate the role of serotonin (5-HT) signaling in these two regions as it contributes to the negative effects of cocaine. Three main studies were designed and executed to address this question. First, to assess the role of 5-HT perturbations within the BNST on the development of approach-avoidance retreat behavior in animals trained to run an alley for cocaine. Next, the same methods were used to investigate the role of 5-HT signaling within the LHb, as animals learned about cocaine’s negative effects. Finally, the third study used selective lesions of serotonin fibers in both the LHb and BNST to determine a more precise mechanism of the observed serotonergic effects. Altogether, the experiments described in this thesis support a role for 5-HT signaling, in both regions, in mediating the behavioral consequences of cocaine’s aversive properties.

    Cover page: Serotonergic contributions to the anxiogenic effects of cocaine
    • Thesis
    • Peer Reviewed
    UC Santa Barbara Electronic Theses and Dissertations (2015)

    Consistent with the Opponent Process Theory of motivated behavior, cocaine administration produces dual and opposing affective states: an initial rewarding “high” followed by a dysphoric/anxiogenic “crash”. It therefore seems likely that the motivation to seek cocaine is dependent upon the organism’s assessment of the positive relative to the negative consequences of its use. While the neurobiology of the reinforcing aspects of cocaine has been well established, less is known about the systems responsible for the drug’s negative actions. In this context, the current study involved an assessment of serotonergic (5-HT) function, which is enhanced by cocaine administration and has been linked to the presence of anxiogenic and depressive states in human and animal studies. In particular, we investigated the role of 5-HT within the bed nucleus of the stria terminalis (BNST) – a structure within the extended amygdala that is activated during periods of stress and during the negative affective state associated with the withdrawal from drugs of abuse. The present study tested the hypothesis that increased 5-HT release in the BNST contributes to the anxiogenic effects of cocaine. A runway self-administration paradigm was employed in which animals were trained to traverse a straight alley in order to earn an infusion of IV cocaine (1.0mg/kg) delivered upon goal box entry. Testing consisted of 16 single daily trials. In this task, animals develop ambivalence about goal box entry (reflected by the development of approach/avoidance “retreat” behaviors) that we have shown to reflect the dual positive (rewarding) and negative (anxiogenic) associations that subjects form with the cocaine-paired goal-box. To assess the involvement of 5-HT signaling within the BNST on this conflict behavior, prior to each trial rats received bilateral intracranial injections of CP94,253 (0.5µg and 1.0µg/side in 0.5µl or aCSF vehicle), a potent and selective 5-HT1B agonist that inhibits local 5-HT release via activation of terminal autoreceptors. Results indicated that CP94,253 did not alter the positive incentive properties of cocaine (start latencies were unaffected) nor did it alter gross motor behavior (as revealed in subsequent locomotor activity testing). Treatments did, however, selectively attenuate the negative effects of cocaine, as indicated by a dose-dependent decrease in the frequency of approach-avoidance “retreat” behaviors. This effect was independent of whether the manipulation occurred before (10 mins prior) or after (5 mins post-infusion) cocaine self-administration. We therefore conclude that 5-HT signaling within the BNST likely contributes to the negative/anxiogenic effects of cocaine. This work supported by NIDA grant DA-033370 awarded to AE.

      Cover page: Activation of 5-HT1b Receptors in the Bed Nucleus of the Stria Terminalis Attenuates the Negative/Anxiogenic Effects of Cocaine
      • Article
      • Peer Reviewed
      UC Santa Barbara Previously Published Works (2018)
      Cocaine administration has been shown to produce immediate positive (rewarding) and subsequent negative (anxiogenic) effects in humans and animals. These dual and opposing affective responses have been more difficult to demonstrate with administration of methamphetamine (meth). While animal studies have reliably demonstrated the positive reinforcing effects of the drug, reports of negative aftereffects following acute exposure have been few in number and contradictory in nature. The current research was devised to assess the effects of acute meth using a runway model of self-administration that is uniquely sensitive to both the positive and negative effects of a drug reinforcer in the same animal on the same trial. Male rats were allowed to traverse a straight alley once a day for 16 consecutive days/trials where entry into the goal box resulted in a single IV injection of meth (0.25, 0.5 or 1.0 mg/kg/inj.). The chosen doses were confirmed to be psychoactive as they produced dose-dependent increases in motoric/locomotor activation in these same subjects. The results demonstrated a U-shaped dose-response curve for the reinforcing effects of meth in that the intermediate dose group (0.5 mg/kg) produced the strongest approach behavior in the runway. Unlike other psychomotor stimulants, like cocaine, animals running for IV meth exhibited no evidence of any significant approach-avoidance behaviors reflective of the drug's negative anxiogenic effects. These results suggest that the abuse potential for meth is likely higher than for other shorter-acting psychomotor stimulants and reaffirms the utility of the runway procedure as a screen for a substance's abuse potential.
        Cover page: Methamphetamine self-administration in a runway model of drug-seeking behavior in male rats
        • Article
        • Peer Reviewed
        UC Santa Barbara Previously Published Works (2018)
        Recent research has identified the lateral habenula (LHb) as a brain region playing an important role in the production of stressful and anxiogenic states. Additionally, norepinephrine (NE) has long been known to be involved in arousal, stress and anxiety, and NE projections to the LHb have been identified emanating from the locus coeruleus (LC). The current research was devised to test the hypothesis that NE release within the LHb contributes to the occurrence of anxiogenic behaviors. Male rats were implanted with bilateral guide cannula aimed at the LHb and subsequently treated with intracranial (IC) infusions of the selective α2 adrenergic autoreceptor agonist, dexmedetomidine (DEX) (0, 0.5, 1.0 μg/side), prior to assessment of ambulatory and anxiogenic behavior in tests of spontaneous locomotion, open field behavior, and acoustic startle-response. Results demonstrated that DEX administration significantly reduced the overall locomotor behavior of subjects at both doses indicating that infusion of even small doses of this α2 agonist into the LHb can have profound effects on the subjects' general levels of alertness and activity. DEX was also found to attenuate anxiety as evidenced by a reduction in the magnitude of a startle-response to an acoustic 110 dB stimulus. Taken together, these results identify a role for NE release within the LHb in both arousal and anxiety.
          Cover page: Lateral habenular norepinephrine contributes to states of arousal and anxiety in male rats
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2020)
          Serotonergic hallucinogens such as lysergic acid diethylamide (LSD) induce head twitches in rodents via 5-HT2A receptor activation. The goal of the present investigation was to determine whether a correlation exists between the potency of hallucinogens in the mouse head-twitch response (HTR) paradigm and their reported potencies in other species, specifically rats and humans. Dose-response experiments were conducted with phenylalkylamine and tryptamine hallucinogens in C57BL/6J mice, enlarging the available pool of HTR potency data to 41 total compounds. For agents where human data are available (n = 36), a strong positive correlation (r = 0.9448) was found between HTR potencies in mice and reported hallucinogenic potencies in humans. HTR potencies were also found to be correlated with published drug discrimination ED50 values for substitution in rats trained with either LSD (r = 0.9484, n = 16) or 2,5-dimethoxy-4-methylamphetamine (r = 0.9564, n = 21). All three of these behavioral effects (HTR in mice, hallucinogen discriminative stimulus effects in rats, and psychedelic effects in humans) have been linked to 5-HT2A receptor activation. We present evidence that hallucinogens induce these three effects with remarkably consistent potencies. In addition to having high construct validity, the HTR assay also appears to show significant predictive validity, confirming its translational relevance for predicting subjective potency of hallucinogens in humans. These findings support the use of the HTR paradigm as a preclinical model of hallucinogen psychopharmacology and in structure-activity relationship studies of hallucinogens. Future investigations with a larger number of test agents will evaluate whether the HTR assay can be used to predict the hallucinogenic potency of 5-HT2A agonists in humans. "This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
            Cover page: Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species
            • Article
            • Peer Reviewed
            UC Santa Barbara Previously Published Works (2015)
            In addition to its initial rewarding effects, cocaine has been shown to produce profound negative/anxiogenic actions. Recent work on the anxiogenic effects of cocaine has examined the role of corticotropin releasing factor (CRF), with particular attention paid to the CRF cell bodies resident to the extended amygdala (i.e., the central nucleus of the amygdala [CeA] and the bed nucleus of the stria terminalis [BNST]) and the interconnections within and projections outside the region (e.g., to the ventral tegmental area [VTA]). In the current study, localized CRF receptor antagonism was produced by intra-BNST, intra-CeA or intra-VTA application of the CRF antagonists, D-Phe CRF(12-41) or astressin-B. The effect of these treatments were examined in a runway model of i.v. cocaine self-administration that has been shown to be sensitive to both the initial rewarding and delayed anxiogenic effects of the drug in the same animal on the same trial. These dual actions of cocaine are reflected in the development of an approach-avoidance conflict ("retreat behaviors") about goal box entry that stems from the mixed associations that subjects form about the goal. CRF antagonism within the VTA, but not the CeA or BNST, significantly reduced the frequency of approach-avoidance retreat behaviors while leaving start latencies (an index of the positive incentive properties of cocaine) unaffected. These results suggest that the critical CRF receptors contributing to the anxiogenic state associated with acute cocaine administration may lie outside the extended amygdala, and likely involve CRF projections to the VTA.
              Cover page: CRF antagonism within the ventral tegmental area but not the extended amygdala attenuates the anxiogenic effects of cocaine in rats
              • Article
              • Peer Reviewed
              UC Santa Barbara Previously Published Works (2019)
              Recent work has implicated the Lateral Habenula (LHb) in the production of anxiogenic and aversive states. It is innervated by all the major monoamine neurotransmitter systems and has projections that have been shown to modulate the activity of both dopaminergic and serotonergic brain regions. Cocaine is a stimulant drug of abuse that potentiates neurotransmission in these monoamine systems and recent research suggests that the drug's behavioral effects may be related in part to its actions within the LHb. The present research was therefore devised to test the hypothesis that alterations in serotonin (5-HT) function within the LHb can affect the behavioral response to cocaine. Male rats were fitted with intracranial guide cannula and trained to traverse a straight alleyway once a day for a 1 mg/kg i.v. injection of cocaine. Intra-LHb pretreatment with the 5-HT1B agonist CP 94,253 (0, 0.1, or 0.25 μg/side) attenuated the development of approach/avoidance "retreat" behaviors known to be a consequence of cocaine's dual rewarding (approach) and anxiogenic (avoidance) properties. This effect was reversed by co-administration of a selective 5-HT1B antagonist, NAS-181 (0.1 μg/side), demonstrating drug specificity at the 5-HT1B receptor. These data suggest that 5-HT1B signaling within the LHb contributes to the anxiogenic effects of cocaine.
                Cover page: Activation of 5-HT1B receptors in the Lateral Habenula attenuates the anxiogenic effects of cocaine.
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2020)
                The ergoline d-lysergic acid diethylamide (LSD) is one of the most potent psychedelic drugs. 1-Acetyl-LSD (ALD-52), a derivative of LSD containing an acetyl group on the indole nitrogen, also produces psychedelic effects in humans and has about the same potency as LSD. Recently, several other 1-acyl-substitued LSD derivatives, including 1-propanoyl-LSD (1P-LSD) and 1-butanoyl-LSD (1B-LSD), have appeared as designer drugs. Although these compounds are assumed to act as prodrugs for LSD, studies have not specifically tested this prediction. The present investigation was conducted to address the gap of information about the pharmacological effects and mechanism-of-action of 1-acyl-substituted LSD derivatives. Competitive binding studies and calcium mobilization assays were performed to assess the interaction of ALD-52, 1P-LSD, and 1B-LSD with serotonin 5-HT2 receptor subtypes. A receptorome screening was performed with 1B-LSD to assess its binding to other potential targets. Head twitch response (HTR) studies were performed in C57BL/6J mice to assess in vivo activation of 5-HT2A (the receptor thought to be primarily responsible for hallucinogenesis). Finally, liquid chromatography/ion-trap mass spectrometry (LC/MS) was used to quantify plasma levels of LSD in Sprague-Dawley rats treated with ALD-52 and 1P-LSD. 1-Acyl-substitution reduced the affinity of LSD for most monoamine receptors, including 5-HT2A sites, by one to two orders of magnitude. Although LSD acts as an agonist at 5-HT2 subtypes, ALD-52, 1P-LSD and 1B-LSD have weak efficacy or act as antagonists in Ca2+-mobilization assays. Despite the detrimental effect of 1-acyl substitution on 5-HT2A affinity and efficacy, 1-acyl-substitued LSD derivatives induce head twitches in mice with relatively high potency. High levels of LSD were detected in the plasma of rats after subcutaneous administration of ALD-52 and 1P-LSD, demonstrating these compounds are rapidly and efficiently deacylated in vivo. These findings are consistent with the prediction that ALD-52, 1P-LSD and 1B-LSD serve as prodrugs for LSD. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.
                  Cover page: Pharmacological and biotransformation studies of 1-acyl-substituted derivatives of d -lysergic acid diethylamide (LSD)
                  • Article
                  • Peer Reviewed
                  UC Santa Barbara Previously Published Works (2017)

                  Rationale

                  Cocaine produces significant aversive/anxiogenic actions whose underlying neurobiology remains unclear. A possible substrate contributing to these actions is the serotonergic (5-HT) pathway projecting from the dorsal raphé (DRN) to regions of the extended amygdala, including the bed nucleus of the stria terminalis (BNST) which have been implicated in the production of anxiogenic states.

                  Objectives

                  The present study examined the contribution of 5-HT signaling within the BNST to the anxiogenic effects of cocaine as measured in a runway model of drug self-administration.

                  Methods

                  Male Sprague-Dawley rats were fitted with bilateral infusion cannula aimed at the BNST and then trained to traverse a straight alley once a day for a single 1 mg/kg i.v. cocaine infusion delivered upon goal-box entry on each of 16 consecutive days/trials. Intracranial infusions of CP 94,253 (0, 0.25, 0.5, or 1.0 μg/side) were administered to inhibit local 5-HT release via activation of 5-HT1B autoreceptors. To confirm receptor specificity, the effects of this treatment were then challenged by co-administration of the selective 5-HT1B antagonist NAS-181.

                  Results

                  Intra-BNST infusions of the 5-HT1B autoreceptor agonist attenuated the anxiogenic effects of cocaine as reflected by a decrease in runway approach-avoidance conflict behavior. This effect was reversed by the 5-HT1B antagonist. Neither start latencies (a measure of the subject's motivation to seek cocaine) nor spontaneous locomotor activity (an index of motoric capacity) were altered by either treatment.

                  Conclusions

                  Inhibition of 5-HT1B signaling within the BNST selectively attenuated the anxiogenic effects of cocaine, while leaving unaffected the positive incentive properties of the drug.
                    Cover page: Attenuation of the anxiogenic effects of cocaine by 5-HT1B autoreceptor stimulation in the bed nucleus of the stria terminalis of rats
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