Perseverative behavior in rats with methamphetamine-induced neurotoxicity

Abstract

Methamphetamine induces monoamine depletions thought to contribute to cognitive and behavioral dysfunctions. Previously, we reported that methamphetamine-induced neurotoxicity is associated with impaired formation of stimulus-response associations. Additionally, subjective observations suggested that behavioral flexibility might be affected. Thus, the present study examined whether methamphetamine neurotoxicity induces perseverative behavior. Rats were pretreated with (±)-methamphetamine (4×10 mg/kg, 2-hr intervals) or saline. Three weeks later, rats were trained to press a lever on one side of an operant chamber and then retrieve the reinforcer from a magazine on the opposite side until they reached criterion (>50 reinforcers/30-min). After four consecutive sessions performing the task at criterion, rats were sacrificed and brains removed for monoamine determinations. Methamphetamine-pretreated rats had ~50% loss of striatal dopamine and prefrontal serotonin. Methamphetamine- and saline-pretreated rats were not different in the number of sessions required to reach criterion or in the total numbers of lever presses and or head entries made across the four consecutive sessions at criterion-level performance. However, methamphetamine-pretreated rats earned fewer reinforcers, because they made extra lever-presses and head entries when they should have been retrieving the reinforcer or returning to the lever. Latencies for methamphetamine-pretreated rats to switch between the two behaviors also were significantly slower than latencies for controls. Interestingly, the degree of additional lever-presses negatively correlated with serotonin-transporter binding in the prefrontal cortex, even in saline-pretreated controls. These data suggest that methamphetamine-induced partial monoamine toxicity is associated with perseveration and that the degree of perseveration may depend on serotonin innervation of the frontal cortex.

Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies

“…Blockade of D 1 R or D 2 R in mPFC in rat reduced behavioural flexibility; it acted primarily by increasing perseveration (Floresco et al, 2006), which is not tested in the LNR paradigm. It is therefore possible that in reversal learning tasks, mPFC mainly contributes to overcoming perseveration rather than to LNR (Allen and Leri, 2014;Son et al, 2013). Furthermore, neurotransmitters other than DA, in particular serotonin, may modulate mPFC-dependent cognitive flexibility (Clarke et al, 2004;van der Plasse and Feenstra, 2008).…”

Juveniles ofLymnaeasmart snails do not perseverate and have the capacity to form LTM

“…Later on, the term may have come to signify reverberating neuronal activity that occurred as part of a 'dual process' in memory consolidation (McGaugh, 2000). However, the term now is typically used in descriptions of more pathological behaviours occurring as a result of damage to specific circuits in the CNS Sotres-Bayon et al, 2004;Son et al, 2013 (Thomas et al, 2016), and it has also been shown that growing up in an enriched laboratory environment (i.e. a more natural environment) lessens perseveration (Campbell et al, 2013).…”

Changes in Neural Circuitry Regulating Response-Reversal Learning and Arc-Mediated Consolidation of Learning in Rats with Methamphetamine-Induced Partial Monoamine Loss

“…Rats were treated with a neurotoxic regimen of ( ± )-METHHCl (4 Â 10 mg/kg, free base, at 2-h intervals, s.c.; NIDA, Research Triangle Park, NC, USA) over the course of 1 day as previously described (Daberkow et al, 2008;Son et al, 2013). The day after treatment, rats were returned to their home cages and given free access to food and water until training began.…”

“…DAT and SERT autoradiography was performed as detailed previously (Barker-Haliski et al, 2012a;Boja et al, 1992;Pastuzyn et al, 2012;Son et al, 2013). For striatal sections, the buffer contained fluoxetine (Sigma-Aldrich, St Louis, MO, USA) to block binding to the SERT, whereas for prefrontal cortical (PFC) sections, fluoxetine was omitted from the buffer, as PFC sections incubated in buffer containing fluoxetine showed no staining (data not shown).…”

“…METH-induced neurotoxicity causes partial depletions of dopamine (DA) and serotonin (5-HT) (Wagner et al, 1980). As in human METH abusers (Dean et al, 2013), this partial monoamine loss is associated with cognitive deficits, including impairments in odor and object recognition, attentional setshifting (Marshall and O'Dell, 2012), sequential motor learning (Chapman et al, 2001;Daberkow et al, 2005), formation of stimulus-response associations (Son et al, 2011) and inhibitory control over behavior (Son et al, 2013). The deficits in basal ganglia-mediated behaviors may arise secondary to impaired phasic DA neurotransmission in the partially denervated striatum (Howard et al, 2011(Howard et al, , 2013a.…”