Tribute to: Self-administered nicotine activates the mesolimbic dopamine system through the ventral tegmental area [William Corrigall, Kathleen Coen and Laurel Adamson, Brain Res. 653 (1994) 278-284].

In this paper, Dr. Corrigall and collaborators described elegant experiments designed to elucidate the neurobiology of nicotine reinforcement. The nicotinic receptor antagonist dihydro-ß-erythroidine (DHßE) was infused in the ventral tegmental area (VTA) or nucleus accumbens (NAC) of rats trained to self-administer nicotine intravenously. Additionally, DHßE was infused in the VTA of rats trained to self-administer food or cocaine, and nicotine self-administration was assessed in rats with lesions to the peduculopontine tegmental nucleus (PPT). A number of key themes emerged from this fundamental study that remain relevant today. The primary finding was that infusions of DHßE in the VTA, but not in the NAC, lowered nicotine self-administration, suggesting that nicotinic receptors in VTA are involved in the reinforcing action of nicotine. This conclusion has been confirmed by subsequent findings, and the nature of the nicotinic receptors has also been elucidated. The authors also reported that DHßE in the VTA had no effect on food or cocaine self-administration, and that lesions to the PPT did not alter nicotine self-administration. Since this initial investigation, the question of whether nicotinic receptors in the VTA are necessary for the reinforcing action of other stimuli, and by which mechanisms, has been extensively explored. Similarly, many groups have further investigated the role of mesopontine cholinergic nuclei in reinforcement. This paper not only contributed in important ways to our understanding of the neurochemical basis of nicotine reinforcement, but was also a key catalyst that gave rise to several research themes central to the neuropharmacology of substance abuse. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Teneurin C-terminal associated peptide (TCAP)-1 modulates dendritic morphology in hippocampal neurons and decreases anxiety-like behaviors in rats.

Teneurin C-terminal associated peptide (TCAP)-1 is a member of a novel family of neuropeptides that has been highly conserved throughout evolution. TCAP-1 is expressed in the limbic system in areas such as the hippocampus and amygdala. In vitro, TCAP-1 increases cytoskeletal proteins in immortalized neurons and modulates neurite outgrowth in cultured primary hippocampal neurons. In vivo, TCAP-1 blocks stress-induced c-Fos in the hippocampus and amygdala, and modulates stress-induced anxiety-like behaviors. This suggests that TCAP-1 plays a role in the remodeling of limbic system networks to alter stress behaviors. Dendritic spines on the apical and basilar shafts of hippocampal neurons are sensitive to stress and many receive incoming excitatory synaptic connections. In this study, repeated daily injection of TCAP-1 for 10 days increased spine density in the CA1 and CA3 regions of the hippocampus without affecting spine density in the amygdala. Further investigation of the CA3 region indicated that TCAP-1 did not affect the morphology of apical dendrites, but decreased branching in the basilar dendrites 90-130 µm away from the soma. Moreover, TCAP-1 treatment increased open arm time and decreased closed arm entries on the elevated plus maze, a test of anxiety-like behavior. These results suggest that TCAP-1 may be associated with anxiety-like behavior via regulation of dendritic morphology in the hippocampus, independent of amygdalar modification.

Teneurin C-terminal associated peptide (TCAP)-1 attenuates corticotropin-releasing factor (CRF)-induced c-Fos expression in the limbic system and modulates anxiety behavior in male Wistar rats.

The teneurin C-terminal associated peptides (TCAPs) are a novel family of four endogenous peptides that have previously shown bioactive properties both in vitro and in vivo. Previously we have shown that repeated intracerebral injections of synthetic TCAP-1 modulate anxiety-like behaviors in three tests of anxiety, although the neural substrates responsible for these effects were previously unknown. In the current study, we examined both c-Fos induction and behavioral responses in the elevated plus maze and open field tests after a single intracerebroventricular dose of TCAP-1 followed by an intracerebroventricular injection of CRF in male Wistar rats. The results indicate that TCAP-1 injection attenuated the CRF-induced increase in c-Fos expression in the limbic system and many of the areas associated with the behavioral responses to stress, including the hippocampus, central and basolateral nuclei of the amygdala, medial prefrontal cortex, and dorsal raphe nucleus. Other areas, such as the paraventricular nucleus of the hypothalamus, bed nucleus of the stria terminalis, medial nucleus of the amygdala, and locus coeruleus, displayed CRF-induced c-Fos levels that were unaffected by TCAP-1. Furthermore, TCAP-1 administration increased stretched-attend postures, a type of risk-assessment behavior, on the elevated plus maze. These results indicate that TCAP-1 may play a potential role in the regulation of stress by blocking CRF-mediated activity in specific stress-sensitive areas of the brain.

Repeated intracerebral teneurin C-terminal associated peptide (TCAP)-1 injections produce enduring changes in behavioral responses to corticotropin-releasing factor (CRF) in rat models of anxiety.

The teneurin C-terminal associated peptides (TCAP) are a recently discovered family of peptides encoded by a bioactive neuropeptide-like gene sequence found at the carboxy terminus of the teneurin transmembrane proteins. TCAP is structurally related to the corticotropin-releasing factor (CRF) family of peptides. Synthetic TCAP-3 and TCAP-1 are active in vitro in stimulating cAMP and proliferation in neuronal lines. TCAP-1 mRNA is expressed in limbic brain regions and modulates acoustic startle behavior in rats when injected into the basolateral amygdala. In the current study, TCAP-1 was administered into the cerebral ventricles once per day for 5 days to rats. At 1-3 weeks after the last TCAP-1 treatment, the rats were tested in the elevated plus maze, open field test, or the acoustic startle test, with or without an acute CRF injection 30 min prior to the test. The results show a difference in behavioral response between TCAP-treated and saline-treated rats, but only when an acute CRF challenge is delivered prior to testing. In the plus maze and open field tests, acute CRF effects were enhanced by prior TCAP-1 treatment, whereas in the acoustic startle test, the acute CRF effects were diminished by prior TCAP-1 administration.

Corticotropin-releasing factor (CRF)-induced behaviors are modulated by intravenous administration of teneurin C-terminal associated peptide-1 (TCAP-1).

The teneurin C-terminal associated peptides (TCAP) are a recently discovered family of bioactive peptides that can attenuate aspects of the behavioral stress responses of rats. Because TCAP has some structural similarity to the corticotropin-releasing factor (CRF) family of peptides, and modulates elements of the stress response, TCAP may act to modulate CRF actions in vivo. This hypothesis was tested by investigating anxiety-related behaviors in male rats following repeated intravenous (IV) TCAP-1 administration with either an acute intracerebroventricular (ICV) or IV CRF challenge. TCAP-1 alone did not affect behavioral responses significantly, however did significantly affect CRF-regulated behaviors depending on CRF's mode of injection. In both the elevated plus-maze and the open field tests, TCAP-1 had an anxiolytic effect on ICV CRF responses as indicated by decreased stretched-attend postures in the elevated plus maze (p<0.05), and increased center time and center entries in the open field (p<0.05). However, prior TCAP-1 treatment has an anxiogenic effect on the IV CRF-induced behaviors (decreased center entries and total distance in the open field (p<0.05)). TCAP-1's actions are not mediated through acute changes in glucocorticoid levels and may occur via a central action in the brain. A fluorescently (FITC)-labeled TCAP-1 analog was IV-administered to investigate whether IV TCAP-1 has the potential to regulate central mechanisms by crossing the blood-brain barrier. FITC-TCAP-1 was detected in blood vessels and fibers in the brain indicating that uptake into the brain is a possible route for its interaction with CRF and its receptors. Thus, TCAP may modulate CRF-associated behaviors by a direct action in the CNS.

Individual differences in elevated plus-maze exploration predicted progressive-ratio cocaine self-administration break points in Wistar rats.

RATIONALE: There are considerable individual differences in vulnerability to drug addiction, but the mechanisms underlying such differences are poorly understood. Cocaine has potent reinforcing effects that support operant responding. However, cocaine also elicits aversive reactions and produces an approach-avoidance conflict in rats. We hypothesized that preexisting individual differences in open arm exploration on the elevated plus-maze, a well-known model for the study of clinically effective anxiolytic drugs, would predict individual differences in cocaine-motivated behavior. OBJECTIVES: To assess whether individual differences in sensitivity to anxiety-like behavior on the plus-maze predict motivation to self-administer intravenous (i.v.) cocaine. MATERIALS AND METHODS: Rats were assessed drug-free for individual differences in open arm exploration on the elevated plus-maze, and later trained to perform an operant response for i.v. cocaine (0, 0.1, 0.3, 0.6, 0.9, 1.2, and 1.5 mg kg(-1) infusion(-1)) on a progressive-ratio reinforcement schedule. Rats were split at the median into low and high open arm explorers based on time spent in the open arms of the plus-maze. Self-administration levels were compared across groups. RESULTS: Rats identified as high open arm explorers on the elevated plus-maze attained higher levels of operant responding for cocaine. Open arm times and break points were significantly correlated at the highest cocaine doses (1.2 and 1.5 mg kg(-1) infusion(-1)). CONCLUSIONS: These results indicate that individual differences in anxiety-like behavior on the elevated plus-maze predict motivation to self-administer cocaine, and suggest the possibility that reduced sensitivity to aversive stimuli may be associated with increased vulnerability to the rewarding properties of cocaine.

Effects of central neurokinin-1 receptor antagonism on cocaine- and opiate-induced locomotor activity and self-administration behaviour in rats.

The neuropeptide substance P (SP) and its preferred receptor, the neurokinin-1 (NK-1) receptor, have been implicated in some of the reward-related behavioural effects of abused drugs, including psychostimulants and opiates. The first objective of the present series of experiments was to assess the role of the NK-1 receptor in two reward-related behavioural effects of cocaine: locomotor activity and self-administration. In tests for locomotor activity, rats were given intracerebroventricular (ICV) infusions of the selective NK-1 receptor antagonist, GR82334 (0, 10, 50 pmol), prior to systemic injections of cocaine. In self-administration experiments, rats were trained to self-administer cocaine on a fixed-ratio 5 (FR5) schedule of reinforcement. Following acquisition of stable responding, animals were pretreated with GR82334 (0, 2, 10, 50 pmol; ICV) prior to subsequent self-administration sessions. Based on evidence suggesting a potentially selective role for NK-1 receptors in opiate reward, we also examined the effects of GR82334 on morphine-induced locomotor activity and heroin self-administration. Results showed that GR82334 had no effect on cocaine-induced locomotor activity or cocaine self-administration, but attenuated morphine-induced locomotor activity and increased heroin self-administration. These findings suggest that endogenous activity at NK-1 receptors may play a specific role in opiate-induced, but not cocaine-induced, locomotor activation and reinforcement.

Activation of central neurokinin-1 receptors induces reinstatement of cocaine-seeking behavior.

A number of neurochemical systems have been implicated in mediating relapse to drug-seeking behavior. Substance P (SP) is a neuropeptide that interacts with some of these systems, suggesting a possible role for SP and its preferred receptor, the neurokinin-1 (NK-1) receptor, in the mediation of relapse. In this study, we examined whether selective activation of NK-1 receptors induces reinstatement of cocaine-seeking behavior, and whether endogenous activity at these receptors is involved in mediating cocaine-induced reinstatement. For each experiment, rats were trained to self-administer cocaine for 8--10 days, and following a period of extinction, tests for reinstatement were given. To examine the effects of NK-1 receptor activation on reinstatement of cocaine-seeking behavior, animals received an intracerebroventricular (ICV) infusion of the selective NK-1 receptor agonist, [Sar(9)Met(O(2))(11)]-SP (0, 1, 3 microg), immediately prior to the test session. To examine the role of endogenous NK-1 receptor activity on cocaine-induced reinstatement, rats were pretreated with ICV infusions of the selective NK-1 receptor antagonists, RP 67580 (0, 0.1, 0.5, 2.5 nmol) or GR 82334 (0, 2, 10, 50 pmol), prior to systemic priming injections of cocaine (10mg/kg or 20mg/kg; i.p.). The results showed that [Sar(9)Met(O(2))(11)]-SP induced reinstatement of cocaine-seeking behavior, but that RP 67580 and GR 82334 had no effect on cocaine-induced reinstatement. These findings suggest that while activation of NK-1 receptors is capable of inducing reinstatement of cocaine-seeking behavior, endogenous activity at these receptors is not involved in mediating the priming effects of cocaine on reinstatement of drug-seeking behavior.

Infusion of the substance P analogue, DiMe-C7, into the ventral tegmental area induces reinstatement of cocaine-seeking behaviour in rats.

RATIONALE: The mesocorticolimbic dopamine (DA) system is critically involved in mediating reinstatement of drug-seeking behaviour. Substance P (SP) is a neuropeptide that significantly interacts with the mesocorticolimbic system, therefore suggesting a possible role for the SP system in the mediation of relapse. OBJECTIVES: This study examined the effects of injections of the SP analogue, DiMe-C7, into the ventral tegmental area (VTA) on reinstatement of cocaine-seeking behaviour, as well as on locomotor activity in rats. Additionally, this study examined whether these effects are DA-dependent. METHODS: Rats were trained to self-administer cocaine for 15 days followed by 15 days of extinction. Reinstatement of cocaine-seeking behaviour was then measured in response to bilateral intra-VTA microinjections of DiMe-C7 (0, 0.1, 0.5 and 2.5 microg). In a separate group of rats, locomotor activity was measured in response to intra-VTA injections of DiMe-C7 (0, 0.5, 1.5 and 3 microg). The effects of pre-treatment with DA receptor antagonists on DiMe-C7-induced reinstatement and locomotor activity were also examined. Animals were pre-treated with the D(1) and D(2) receptor antagonists, SCH23390 and haloperidol (0, 0.01 and 0.03 mg/kg, IP), respectively, prior to receiving intra-VTA injections of DiMe-C7 (0 and 2.5 microg). RESULTS: Infusion of DiMe-C7 into the VTA increased locomotor activity and induced reinstatement of cocaine-seeking behaviour. Both SCH23390 and haloperidol blocked intra-VTA DiMe-C7-induced locomotor activation. In addition, SCH23390 attenuated DiMe-C7-induced reinstatement of cocaine-seeking behaviour, while haloperidol had no effect. CONCLUSIONS: These results suggest that interactions between SP and the mesocorticolimbic DA system may play a role in mediating reinstatement of cocaine-seeking behaviour and that the involvement of these interactions in reinstatement are dependent upon D(1) receptor mechanisms.

Cholecystokinin modulation of locomotor behavior in rats is sensitized by chronic amphetamine and chronic restraint stress exposure.

DA release in the nucleus accumbens (NAcc) is a critical substrate mediating locomotor behavior. Cholecystokinin (CCK) is co-localized with dopamine (DA) in up to 90% of mesolimbic DA neurons. We have previously shown that while CCKA receptor antagonists generally do not affect locomotor behaviors, systemic administration of a CCKA receptor antagonist attenuates amphetamine (AMPH)-induced locomotion in animals previously treated chronically with AMPH, suggesting that chronic stimulant pretreatment may sensitize CCK systems. The present studies examined this issue by testing the effects of CCKA antagonists on AMPH- and novel environment-induced locomotor activity following two manipulations which are known to alter mesolimbic system function: Chronic AMPH administration and chronic restraint stress (RS). Additionally, CCK immunoreactivity in the mesolimbic system following these manipulations was examined using immunohistochemistry. Results indicated that intra-NAcc microinjections of the selective CCKA receptor antagonist PD-140548 attenuated AMPH-induced and novel environment-induced locomotion only in animals which had previously been exposed to chronic AMPH or chronic RS pretreatment. However, chronic AMPH and chronic RS did not produce detectable changes in the number of CCK-immunostained neurons in the ventral tegmental area (VTA) or substantia nigra (SN), or in CCK levels in any of the subregions of the NAcc. Together, these results suggest that the role of endogenous CCK in the modulation of locomotor behaviors is sensitized following chronic psychostimulant or chronic RS exposure. However, this sensitization does not appear to be accompanied by changes in the overall basal levels of CCK or in the number of CCK-positive cells within the mesoaccumbens system.

Cholecystokinin receptor subtypes: role in the modulation of anxiety-related and reward-related behaviours in animal models.

Cholecystokinin (CCK) is an abundant and widely distributed neuropeptide that plays a modulatory role in a variety of behaviours. This paper focuses on the role of CCK in modulating anxiety-related and reward-related behaviours in key brain regions of the amygdala and mesolimbic dopamine system, respectively. The role of CCK in mediating aspects of these behaviours has been studied in a variety of behavioural paradigms, but inconsistent results have led to confusion regarding the precise role of the receptor subtypes in mediating behaviour. The confusion in the literature may come in part from the diverse behavioural paradigms that are used, the differences in regional effects of CCK manipulations in different areas and at different receptor subtypes in these areas and the dependence of the behavioural outcome on the baseline state of arousal of the animal. Evidence on the role of CCK in anxiety-related and reward-related behaviours in various animal models indicates that CCK-B receptors in the basolateral amygdala are important mediators of anxiety-related behaviours and that CCK-A and CCK-B receptors in the nucleus accumbens are important in mediating different aspects of reward-related behaviour. Emphasis is placed upon the role of CCK as a neuromodulator that is recruited only under conditions of high frequency neuronal firing.

Decreased CCK(B) receptor binding in rat amygdala in animals demonstrating greater anxiety-like behavior.

RATIONALE: The potentiation of the acoustic startle response (ASR) by stimuli associated with aversive events is mediated via the amygdala and is used as an index of "anxiety" and "fear". In laboratory animals, cholecystokinin(B) (CCK(B)) agonists increase anxiety and fear and activation of amygdala CCK(B) receptors potentiates ASR. Additionally, antagonism of CCK(B) receptors attenuates fear-potentiated ASR. OBJECTIVES: To investigate the putative role of CCK(B) receptors in individual differences in fear and anxiety, we examined individual differences in amygdala CCK(B) receptor binding for animals demonstrating low versus high baseline and fear-potentiated ASR. Additionally, we examined individual differences in CCK(B) binding for animals demonstrating low versus high anxiety-like behavior on the elevated plus-maze (EPM). METHODS: Male Wistar rats were tested in the ASR, fear-potentiated ASR, and EPM paradigms. Following testing, brain slices were mounted and incubated with 50 pM (125)I-CCK8 (non-sulfated), a selective CCK(B) receptor ligand, in the presence or absence of 1 micro M non-radioactively labeled CCK and then exposed on tritium-sensitive film for 2-3 days. RESULTS: Animals with high fear-potentiated ASR showed decreased CCK(B) receptor binding in both the basolateral and central amygdaloid nuclei. Animals with high anxiety-like responses on the EPM showed decreased CCK(B) binding in the basolateral, but not central, amygdala. There were no differences in amygdala CCK(B) binding in animals demonstrating low versus high baseline ASR. None of the groups showed differences in CCK(B) receptor binding in the nucleus accumbens. CONCLUSIONS: These results show that there is a down-regulation of amygdala CCK(B) receptor binding in animals demonstrating greater anxiety-like responding in the fear-potentiated ASR and EPM models of anxiety, possibly as a compensation for increased CCK activity.

Low-dose dexamethasone challenge in women with atypical major depression: pilot study.

OBJECTIVE: To examine if atypical depression may be associated with hypersuppression of the hypothalamic-pituitary-adrenal (HPA) axis. METHOD: Eight women with atypical major depression and 11 controls with no history of psychiatric illness, matched on age and body mass index, were challenged with low-dose dexamethasone (0.25 mg and 0.50 mg in random order and 1 week apart). Dexamethasone was self administered at 11 pm, and plasma cortisol samples were drawn at 8 am and 3 pm on the following day. RESULTS: After the 0.50-mg dexamethasone challenge, mean suppression of morning cortisol was significantly greater in patients with atypical depression (91.9%, standard deviation [SD] 6.8%) than in the controls (78.3%, SD 10.7%; p < 0.01). CONCLUSION: These preliminary data add to the growing body of literature that suggests atypical depression, in contrast to classic melancholia, may be associated with exaggerated negative feedback regulation of the HPA axis.

Cholecystokinin modulation of mesolimbic dopamine function: regulation of motivated behaviour.

This article reviews evidence and presents a hypothesis regarding the effects of stress on motivated behaviour, and in particular the observation that stress can have both motivationally inhibitory and motivationally facilitatory effects. This issue will be addressed with regard to psychostimulant self-administration, and the role that the neurobiological mechanisms underlying motivated behaviour are thought to be involved in the evolution of addictions. Evidence from animal studies shows that stress and stress-related hormones such as corticosterone can facilitate mesolimbic dopamine function and the behavioural effects of psychostimulants, particularly at lower levels of stress. Conversely, higher levels of stress can inhibit motivated behaviour, and evidence is presented that this may occur in part through the effects of the neuropeptide cholecystokinin (CCK), acting through CCK-B receptors in the nucleus accumbens. Individual differences in endogenous CCK and dopamine systems are hypothesized to be important modulators of individual differences in motivated behaviour.